key: cord- -wrru zg authors: pfeil, alena; mütsch, margot; hatz, christoph; szucs, thomas d title: a cross-sectional survey to evaluate knowledge, attitudes and practices (kap) regarding seasonal influenza vaccination among european travellers to resource-limited destinations date: - - journal: bmc public health doi: . / - - - sha: doc_id: cord_uid: wrru zg background: influenza is one of the most common vaccine-preventable diseases in travellers. by performing two cross-sectional questionnaire surveys during winter and winter among european travellers to resource-limited destinations, we aimed to investigate knowledge, attitudes and practices (kap) regarding seasonal influenza vaccination. methods: questionnaires were distributed in the waiting room to the visitors of the university of zurich centre for travel' health (cth) in january and february and january prior to travel health counselling (cth and cth ). questions included demographic data, travel-related characteristics and kap regarding influenza vaccination. data were analysed by using spss(® )version . for windows. differences in proportions were compared using the chi-square test and the significance level was set at p ≤ . . predictors for seasonal and pandemic influenza vaccination were determined by multiple logistic regression analyses. results: with a response rate of . %, individuals were enrolled and ( . %) provided complete data. seasonal influenza vaccination coverage was . % (n = ). only ( . %) participants were vaccinated against pandemic influenza a/h n , mostly having received both vaccines simultaneously, the seasonal and pandemic one. job-related purposes ( , %), age > yrs ( , %) and recommendations of the family physician ( , . %) were the most often reported reasons for being vaccinated. in the multiple logistic regression analyses of the pooled data increasing age (or = . , % ci . - . ), a business trip (or = . , % ci . - . ) and seasonal influenza vaccination in the previous winter seasons (or = . , % ci . - . ) were independent predictors for seasonal influenza vaccination in or . influenza vaccination recommended by the family doctor ( , . %), travel to regions with known high risk of influenza ( , . %), and influenza vaccination required for job purposes ( , . %) were most frequently mentioned to consider influenza vaccination. conclusions: risk perception and vaccination coverage concerning seasonal and pandemic influenza was very poor among travellers to resource-limited destinations when compared to traditional at-risk groups. previous access to influenza vaccination substantially facilitated vaccinations in the subsequent year. information strategies about influenza should be intensified and include health professionals, e.g. family physicians, travel medicine practitioners and business enterprises. pandemic and seasonal influenza are still a challenging field of the public health system. influenza -a mild to severe respiratory infection caused by rna viruses of the family orthomyxoviridae -is one of the most common vaccine-preventable disease in travellers. worldwide, between ' and ' deaths are estimated to be due to seasonal influenza infection each year [ ] . influenza is also responsible for tremendous economic costs both from admissions to hospital and loss of productivity [ ] . influenza affects all age groups and is usually self-limited. common symptoms include acute fever, muscles pain, headache, cough and chills [ ] . special risk groups, such as very young children, the elderly and those suffering from chronic lung or heart diseases are at risk for serious influenza complications, e.g. bacterial pneumonia [ , ] . influenza reaches peak prevalence in winter in the northern hemisphere (nov-apr) -as well as in the southern hemisphere (apr-oct) and circulates yearround in the tropics [ , ] . seasonal influenza vaccination is an effective prevention strategy and is therefore routinely recommended for special risk groups [ , ] . of note, the seasonal influenza vaccine recommendations of the u.s. centres for disease control were recently expanded and include now about % of the population [ ] . influenza is known to be a quite frequent infection among travellers to tropical and subtropical destinations compared to other infections, e.g. vector-borne ones. about one of hundred travellers abroad gets infected [ ] . the risk of infection depends on the travel destination and the season. travellers crossing hemispheres may be confronted with different antigenic variants of the influenza virus. by returning home, the new variant may be transmitted to contact persons [ ] . the first pandemic of the st century has highlighted the need for international influenza prevention strategies [ ] . the objective of this study was to investigate the vaccination coverage as well as knowledge, attitudes and practices (kap) regarding influenza vaccination among travellers to resource-limited countries to improve or adapt current preventive strategies. two cross-sectional surveys were conducted at the university of zurich centre for travel' health during january and february and january , respectively. selfadministered, anonymous questionnaires including items were distributed to travellers waiting for pre-travel health advice. participation was voluntary. individuals above years, understanding german or english, residing in switzerland and planning to travel to a resourcelimited destination were included. questions included demographic data (gender, age, nationality, education, profession), travel-related characteristics (destination country, duration of stay, influenza risk perception, previous travel health advice, travel purpose, travel costs) and general attitudes and practices towards influenza vaccination (vaccination coverage, reasons to be vaccinated, reasons to refuse vaccination, motivations to consider vaccination with options for multiple answers except for the vaccination coverage). in , an additional question targeting the pandemic influenza a/h n vaccination coverage was included. the questionnaires were checked for completeness. a written letter of exempt was received by the ethical commission of the canton of zurich. statistical analyses were conducted by using spss ® version . for windows. differences in proportions of demographics, travel-related data and attitudes and practices were compared using the chi-square test. the significance level was set at p ≤ . . for the multiple logistic regression analysis the surveys were analysed as well as pooled dataset and each survey, cth- and cth- , separately. the seasonal influenza vaccination was used as outcome and all demographic, travel-related and attitude-and practices-related factors were evaluated as independent predictors. odds ratios (or) were determined by stepwise backward elimination of variables with p > . . for sensitivity analyses, each dataset of the cth studies, and , was analysed separately and additionally, predictors for pandemic influenza vaccination were determined by multiple logistic regression analyses. from a total of eligible individuals, ( . %) were included in the analysis ( figure ). overall, ( . %) were females and ( . %) males. the great majority of participants ( , . %) were between and years old with a median age of years (range - yrs). only ( . %) responders were above years of age. in general, participants were highly educated with ( . %) being university graduates. overall, the characteristics of participants planning to travel to resource-limited destinations are presented in table . of all vaccinated participants, ( %) declared to be vaccinated for business reasons and ( %) due to age ( travel as risk factor for an influenza infection is poorly established among international travellers when regarding the low vaccination coverage as well as the low selfperceived travel-associated risk estimates. of note, previous influenza vaccinations facilitated receiving an influenza vaccination in the following year by about times. therefore, easy access to the influenza vaccine is important. high media coverage was not considered sufficient to increase the vaccination rate substantially as is indicated by the low increase of the vaccination coverage between the two surveys in and and also by the low pandemic influenza vaccination coverage of only . %. therefore, multiple efforts need to complement one another including information strategies provided by family physicians and travel medicine practitioners, but also job-and age-related activities need to be considered. our sample of travellers is comparable to other studies performed at our centre for travel' health [ ] with respect to the age distribution, educational level and travel duration. inherent limitations include a selection bias: frequently visited destinations such as the middle east, north africa and the caribbean are underrepresented as travellers to those destinations generally do not consider a pre-travel health consultation as indicated [ ] but destinations with higher risk for faecal-orally transmitted infectious diseases, such as td or bacterial meningitis, are well represented, such as e.g. india and sub-saharan countries. therefore, our sample may represent a best practice sample. the fact, that the high proportion of university graduates indicates a health literate population may result in an even overestimated risk perception as well as influenza vaccination coverage. all data collections relied on self-reported information. hence, the results of the studies might be limited by a potential bias such as disclosure bias, although self-report of influenza vaccination status has been found to be reliable when checked against medical record documentation [ ] . most seasonal influenza activity occurs during november to april on the northern hemisphere and vaccination is usually administered between october and november. therefore, travellers visiting the opposite hemisphere have to be counselled accordingly and the seasonal influ-enza vaccine also for the southern hemisphere has to be available as there is year-round influenza activity in tropical and subtropical areas. risk perception and vaccination coverage regarding seasonal and pandemic influenza was very poor among european travellers to resource-limited destinations reducing the burden of influenza-associated complications with antiviral therapy the pathology of influenza virus infections influenza: changing approaches to prevention and treatment in travelers the scientific basis for offering seasonal influenza immunisation to risk groups in europe absolute humidity and the seasonal onset of influenza in the continental united states influenza virus infection in travelers to tropical and subtropical countries awareness of vaccination status and its predictors among working people in switzerland influenza vaccination coverage rates in five european countries during season / and trends over six consecutive seasons centers for disease control and prevention (cdc) -cdc's advisory committee on immunization practices (acip) recommends universal annual influenza vaccination knowledge, attitudes and practices in travel-related infectious diseases: the european airport survey h n influenza influenza vaccination uptake and socioeconomic determinants in european countries we thank all participating travellers and we acknowledge the technical assistance of patricia blank. the authors declare that they have no competing interests.authors' contributions tds, mm and ch conceived and supervised the study. ap performed all data collection and data analysis and drafted the manuscript. mm participated in designing the study and the questionnaire and organised access to the data of the airport-study. all authors have read and approved the final manuscript. key: cord- -lzhobnch authors: zhang, j.; while, a. e.; norman, i. j. title: seasonal influenza vaccination knowledge, risk perception, health beliefs and vaccination behaviours of nurses date: - - journal: epidemiol infect doi: . /s sha: doc_id: cord_uid: lzhobnch the relationship between knowledge, risk perceptions, health belief towards seasonal influenza and vaccination and the vaccination behaviours of nurses was explored. qualified nurses attending continuing professional education courses at a large london university between april and october were surveyed ( / ; response rate · %). of these, · % worked in hospitals; · % reported receiving seasonal influenza vaccination in the previous season and · % reported never being vaccinated during the last years. all respondents were categorized using two-step cluster analyses into never, occasionally, and continuously vaccinated groups. nurses vaccinated the season before had higher scores of knowledge and risk perception compared to the unvaccinated (p< · ). nurses never vaccinated had the lowest scores of knowledge and risk perception compared to other groups (p< · ). nurses' seasonal influenza vaccination behaviours are complex. knowledge and risk perception predict uptake of vaccination in nurses. annual epidemics of seasonal influenza result in about - million cases of severe illness and - deaths worldwide [ ] . healthcare workers (hcws) can be a key source for influenza transmission in communities and hospitals as they are exposed to both infected patients and high-risk groups [ , ] . vaccination is the most effective way to prevent infection and severe outcomes [ ] and the principal measure to reduce the impact of epidemics, such as hospitalization, mortality and morbidity [ , [ ] [ ] [ ] . moreover, studies suggest that the vaccination of hcws has substantial economic benefits as well as health-related benefits, including reduced absenteeism from work and the extra costs of sick leave and staff replacement [ , , ] . for the above reasons, the world health organization (who), united kingdom department of health (doh) [ ] , united states centers for disease control and prevention (cdc), other healthcare professional organizations and many countries' government agencies [ , , ] strongly recommend the annual seasonal influenza vaccination of hcws. however, studies suggest that influenza vaccine uptake in hcws is often low worldwide [ ] [ ] [ ] [ ] . for example, the overall seasonal vaccination rate in england for hcws was . % for the / season [ ] . nurses, as the group having the most patient contact, are more reluctant to be vaccinated than other hcws [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . although predictors influencing nurses' vaccination practices have been identified to some extent regarding knowledge and risk perception [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , further studies are needed to explore the influences on nurses' attitudes and practices regarding influenza vaccination and to identify the major influencing factors for their vaccination behaviours. this study aimed to examine the relationship between knowledge, risk perceptions, health beliefs towards seasonal influenza and vaccination and the vaccination behaviours of nurses. a cross-sectional survey was conducted of qualified nurses between april and october, . qualified nurses attending continuing professional education courses at a large university in central london were invited to participate in the study. potential respondents were given a study information sheet and a questionnaire by the investigator. completed questionnaires were collected immediately by the investigator or returned by mail to the research team using freepost addressed envelopes. questionnaire completion was anonymous so that it was not possible to follow up non-response. ethical approval was obtained from the university ethics committee. the questionnaire collected the following data : ( ) knowledge about seasonal influenza and vaccination ( items requiring true, false or unsure responses) included five dimensions to assess general information, severity of influenza, influenza vaccination, high-risk groups and vaccination-recommended groups; ( ) risk perception ( items with a -point likert scale) towards influenza and pandemic with three dimensions (i.e. personal vulnerability to illness, negative consequences of contracting influenza and severity of influenza) ; ( ) health locus of control including internal, chance and powerful others dimensions assessed by the multidimensional health locus of control (mhlc) scales [ ] ( items) ; ( ) vaccination behaviours (nine items) including vaccination status (whether respondents had been vaccinated in the previous season), vaccination intent (whether respondents intended to be vaccinated next season) and vaccination history (how many times respondents had been vaccinated in the last years) ; ( ) reasons for accepting or refusing vaccination using two open questions; and ( ) demographic characteristics ( items) including gender, age group, highest educational qualification, place of work, clinical speciality, year of qualification as a nurse and whether or not respondents had direct patient contact. the cronbach's a-coefficients for the three newly developed scales (sections , , ) ranged from . to . and principal components analysis produced a good fit and confirmed the internal design of the instrument. statistical analysis was performed using spss version . (spss inc., usa). the x test or fisher's exact test was used to explore the statistical differences between categorical variables. the independentsamples t test was used to compare statistical difference between continuous variables in two groups. the one-way between-groups analysis of variance (anova) was used to explore the differences between more than two groups. logistic regression was performed to explore the impact of the variables on vaccination status. the two-step cluster analysis procedure was performed to explore the natural groupings (i.e. clusters) within the respondents. the clustering criterion was that the solution had smaller values of schwarz's bayesian information criterion (bic), a reasonably large ratio of bic changes and a large ratio of distance measures. a p value < . was considered to denote statistical significance. in total, questionnaires were distributed and were returned representing a response rate of . %. the characteristics of the respondents are summarized in table . overall / respondents ( . %) reported receiving a vaccination in the previous season with . % never receiving a vaccination during the last years. there was no difference in the demographic characteristics of the vaccinated or unvaccinated respondents in the previous season. the number of years qualified as a nurse for the two groups were . ¡ . years and . ¡ . years (p= . ), respectively. comparison of knowledge and risk perception scores and sub-scores of mhlc are summarized in table . there were significant differences in knowledge scores and risk perception between the vaccinated and unvaccinated nurses and between those with vaccination intent, no intent or unsure. there was no significant difference in the sub-scores of mhlc between the vaccinated and unvaccinated (data not shown in table) but there was a significant difference for the sub-score of powerful others between those groups with different vaccination intent. direct logistic regression was performed to assess the impact of a number of factors on the likelihood that respondents had been vaccinated in the previous season. the model contained five independent table , only two of the independent variables made a unique statistically significant contribution to the model (knowledge score and risk perception score). the strongest predictor of vaccination status was the risk perception score, recording an odds ratio of . , indicating that respondents who had higher risk perception scores were > . times more likely to have been vaccinated in the last months than those with lower scores, controlling for all other factors in the model. knowledge score with an odds ratio of . indicated that knowledgeable respondents were more likely to be vaccinated than the unknowledgeable, controlling for other factors in the model. the two-step cluster analysis procedure was used to explore the natural groupings within the respondents. first, the auto-clustering exploratory analysis was performed using the categorical variables of vaccination status, vaccination intent, vaccination history and the continuous variables of knowledge score and risk perception score. of the respondents, were automatically excluded from the analysis due to missing values on one or more of the variables. of the respondents assigned to clusters, ( . %) were assigned to the first cluster, ( . subsequently the analysis was performed using the combined categorical variables of vaccination status in the previous season (=yes) and vaccination history and the continuous variables of knowledge and risk perception scores. the results were auto-clustered into four groups but not explainable. the procedure was repeated with the cluster number fixed to due to the values of bic, ratio of bic changes and ratio of distance measures. of the total vaccinated respondents, were excluded due to missing values. of the remaining respondents, ( . %) were assigned to cluster and ( . %) to cluster . vaccinated cluster comprised those vaccinated only in the previous season, i.e. the newly vaccinated group and vaccinated cluster contained those vaccinated in the previous season who had more than one previous vaccination, i.e. the continuously vaccinated group. then, the same analysis was repeated for the unvaccinated respondents and two clusters emerged, i.e. unvaccinated cluster (never vaccinated) and unvaccinated cluster (used to be vaccinated). the analysis had therefore separated the respondents into reasonable categories. a comparison of variables across all clusters revealed that the never vaccinated had the lowest knowledge score, risk perception score and powerful others sub-score of mhlc compared to the other clusters (p< . , p< . , p= . , respectively) and this difference was statistically significant. for the vaccinated, there were no significant differences across any variable for the newly vaccinated and continuously vaccinated clusters although there was a trend of higher average scores for knowledge and risk perception in the newly vaccinated cluster compared to those of the other clusters (p= . , p= . , respectively). for the unvaccinated, there were no statistically significant differences across the variables except for the mhlc 'powerful others ' sub-score (p= . ). further comparisons were performed to explore whether there were differences across the different items of knowledge and risk perception in the clusters. in the clusters of never vaccinated, other vaccination history and vaccinated with intent, there were significant differences in knowledge related to general information, high-risk groups and vaccination of recommended groups with p values of < . , < . and < . , respectively. on average those never vaccinated had the lowest score while those vaccinated with intent had the highest scores across all knowledge items. for only one item of risk perception, i.e. personal vulnerability to illness, was there a significant difference between the clusters of never vaccinated and other vaccination history and between never vaccinated and vaccinated with intent (p< . respectively). those never vaccinated had the lowest average score. there was no statistically significant difference in the knowledge and risk perception item scores between the two vaccinated clusters. however, the newly vaccinated usually had higher scores than those of the continuously vaccinated except for one item, i.e. the vaccination of recommended groups. similarly, for the two unvaccinated clusters there was no difference for knowledge scores, but there was a significant difference in one risk perception item, i.e. personal vulnerability to illness (p= . ). those never vaccinated had a lower score for this item than those who used to be vaccinated and they were also less knowledgeable compared to the other group. tables and . in this study, the seasonal influenza vaccination rate in nurses was . % which is higher than previous reports of vaccination coverage ranging from . - . % in hcws in uk [ , , ] and % in nurses reported by chalmers [ ] and similar to o'reilly et al.'s reported vaccination coverage of nurses in elderly care units [ ] . this higher vaccination rate might be explained to some extent by the uk media reports of the risk of seasonal influenza and h n pandemics in which may have increased the sample nurses' risk perception towards influenza and consequently changed their vaccination decisions as noted in a previous study [ ] . this study found that vaccination behaviours in nurses were more complex requiring an analysis of both vaccinated and unvaccinated nurses' behaviours. more levels of vaccination behaviours existed in the sample with the two-step cluster analysis revealing three whole population clusters, i.e. those never vaccinated, those vaccinated this season with intent next year, and those with other vaccination history. two clusters, the newly vaccinated and continuously vaccinated, were identified for the vaccinated group and another two clusters, never vaccinated and used to be vaccinated, were identified in the unvaccinated group. to improve the influenza vaccination rates in nurses, it may be helpful to develop different strategies which target the nurse groups of the never vaccinated and the occasionally vaccinated. we found that a lack of knowledge about influenza and vaccination was a strong predictor of nurses' vaccination behaviours, especially for those never vaccinated. this cluster had the lowest knowledge score, suggesting that increasing their knowledge might improve their vaccination behaviours. however, it seems there are 'persistent decliners ' who are in the 'habit ' of not having a vaccination. this suggests that future educational campaigns need to be persistent, durative, and intensive if their vaccination behaviours are to be modified. for those who had been vaccinated in the past but not in the current season, knowledge was also a predictor for their vaccination behaviours, which suggests that current vaccination campaigns have failed to address their misgivings about vaccination to maintain their compliance with the annual vaccination recommendation for hcws. between those occasionally vaccinated and continuously vaccinated, knowledge levels were not significantly different but the newly vaccinated in had on average higher knowledge scores than those continuously vaccinated. this may reflect an increase in their risk perceptions towards influenza due to widespread reporting of the risks in the media encouraging them to be vaccinated for the first time in their lives. this suggests that timing may be crucial to the success of vaccination campaigns making behaviour modification easier. future studies are required to explore the relationship between the content and timings of vaccination campaigns and nurses' first vaccination uptake. this study showed that the perception of personal vulnerability to illness was important in nurses making vaccination decisions. but perceptions of the negative consequences of contracting influenza and severity of influenza were not major factors, a finding which is consistent with findings of previous studies [ ] . this suggests that future educational campaigns might be more effective if they focus on the negative personal consequences of contracting influenza and its sequelae rather than nurses' professional duty to protect patients or other vulnerable groups. additionally, the reasons which nurses gave for having vaccination focused upon their personal health motivation rather than a professional responsibility regardless of whether they were vaccinated or unvaccinated. concerns about the vaccine's side-effects and effectiveness or safety were the two most frequent reasons for not having a vaccination indicating continuing misconceptions about influenza vaccine in nurses. future educational campaigns may wish to consider providing targeted information to change these widespread myths in nurses. however, these concerns did not seem to influence vaccination decisions because both vaccinated as well as unvaccinated nurses noted these reasons against vaccination. it may be the case that days of minor discomfort postvaccination is tolerable when set against a year's influenza protection. unvaccinated nurses reported 'no need ' as their reason not having a vaccination which is consistent with their low-risk perception of contracting influenza. the convenience of the vaccination programme was identified as an organizational reason highlighting the importance of easy access to vaccination to increase its coverage in nurses. our analysis of health locus of control data found that those never vaccinated had a lowest 'powerful others ' locus of control for their vaccination behaviours, indicating that they did not believe their health was something over which they had no control [ ] . this pattern of health beliefs towards influenza vaccination is consistent with their low-risk perception of personal vulnerability to illness and 'no need ' as their reason refusing vaccination and may be an important factor for never vaccinated nurses. further studies are needed to explore what may influence this pattern of health locus of control in order to modify nurses' vaccination behaviours. some organizations have recently required mandatory seasonal influenza vaccination for hcws as a professional and ethical obligation to protect their patients' health [ , ] . however, ethical issues have been raised with mandatory vaccination because, while promoting the interests of patients and employers, it challenges hcws' personal autonomy and freedom of choice [ , ] . moreover, it has been suggested that vaccination is not the only avenue of influenza prevention and there are several other important measures that healthcare organizations may take to protect both patients and hcws [ ] . further previous studies have also suggested that not all hcws support mandatory vaccination [ ] . until mandatory influenza vaccination for hcws is accepted worldwide, continued efforts to improve nurses' vaccination behaviours will be required. this study has some limitations. first, there is possible selection bias of a convenience sample ; however, the broad range of qualified nurses together with a high response rate strengthen the results. the extent of bias is unknown especially regarding nurses not working in london or in different care settings. second, the survey relied on self-report vaccination data ; however, zimmerman et al. [ ] found that selfreport data were reliable in comparison with medical records. third, the three factors explored relating to nurses' vaccination behaviours explained only . - . % of the variance according to the logistic regression analysis (although it was statistically significant) and therefore our results cannot fully explain nurses' vaccination behaviours. additional predictors will need to be introduced into the model in future studies to fully explain nurses' vaccination behaviours. in conclusion, this study revealed that nurses' influenza vaccination behaviours are complex. knowledge and risk perception were identified as two predictors influencing nurses' vaccination decisions with the health belief pattern of 'less powerful others ' being an important predictor in the never vaccinated ; however, there are other influential factors which need to be identified in future studies. world health organization. world health organization (who) influenza (seasonal) factsheet n preventing nosacomial influenza by improving the vaccine acceptance rate of clinicians assessing the role of basic control measures, antivirals and vaccine in curtailing pandemic influenza : scenarios for the us, uk and the netherlands effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care : a randomised controlled trial effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents : cluster randomised controlled trial organizational and environmental factors that affect worker health and safety and patient outcomes effectiveness of influenza vaccine in health care professionals : a randomized trial summary of flu immunisation policy centres for disease control and prevention. prevention and control of influenza. recommendations of the advisory committee on immunization practices (acip) prioritization strategies for pandemic influenza vaccine in countries of the european union and the global health security action group : a review national seasonal influenza vaccination survey in europe influenza vaccination coverage rates in five european countries during season / and trends over six consecutive seasons influenza vaccination among primary healthcare workers influenza vaccination acceptance among health-care workers : a nationwide survey influenza vaccination uptake monitoring on behalf of the department of health attitudes, knowledge and factors related to acceptance of influenza vaccine by pediatric healthcare workers correlation between healthcare workers' knowledge of influenza vaccine and vaccine receipt factors affecting nurses' decision to get the flu vaccine factors affecting influenza vaccine uptake among health care workers knowledge and attitudes about influenza vaccination amongst general practitioners, practice nurses, and people aged and over influenza vaccination coverage among hospital personnel over three consecutive vaccination campaigns influenza vaccination rates and motivators among healthcare worker groups influenza vaccination in paediatric nurses : cross-sectional study of coverage, refusal, and factors in acceptance predictors of influenza vaccination amongst australian nurses impact of severe acute respiratory syndrome and the perceived avian influenza epidemic on the increased rate of influenza vaccination among nurses in hong kong influenza vaccination among registered nurses : information receipt, knowledge, and decision-making at an institution with a multifaceted educational program understanding healthcare worker uptake of influenza vaccination : a survey accessed trends in influenza vaccination coverage rates in the united kingdom over six seasons from - to - pandemic h n (swine flu) and seasonal influenza vaccine uptake amongst frontline healthcare workers in england avian flu : the creation of expectations in the interplay between science and the media development of the multidimensional health locus of control (mhlc) scales policy statementrecommendation for mandatory influenza immunization of all health care personnel revised shea position paper : influenza vaccination of healthcare personnel mandatory vaccination of health care workers the ethics of mandatory vaccination against influenza for health care workers point counterpoint : mandatory flu vaccination for health care workers beliefs on mandatory influenza vaccination of health care workers in nursing homes : a questionnaire study from the netherlands sensitivity and specificity of patient self-report of influenza and pneumococcal polysaccharide vaccinations among elderly outpatients in diverse patient care strata we are grateful for the statistical advice of peter milligan. none. key: cord- -elhgew x authors: spier, r.e. title: ethical aspects of vaccines and vaccination date: - - journal: vaccine doi: . /s - x( ) - sha: doc_id: cord_uid: elhgew x nan published by elsevier science ltd. all rights reserved printed in great britain pii: so - x( ) - - x/ $ + . r. e. spier traditional certainties no longer serve our societies as well as they might. technical developments over a broad range of engineering disciplines have radically changed the nature of the physical world in which we live. our knowledge base has expanded concurrently, enabling us to provide materially based and more convincing answers to questions which baffled our antecedents of years ago. this requires that we review and reconsider the ethical guidelines for behaviour which have been largely founded on philosophies and concepts whose origins may be traced back to between and years ago. an example of the implications of these changes may be seen in the area of vaccines and vaccination which evinces the pressing need to review traditional ethical positions to take the maximum advantage of the potential for animal and human benefit inherent in this prophylactic approach to healthcare. in this paper i examine some of the general ethical issues thrown up by recent advances in the field of vaccines and vaccination. it will touch on issues of the putative autonomy of the individual and way we will have to reassess the cost ((risk * the magnitude of the damage) + cost of manufacture and distribution + surplus) to benefit relationship. issues subtended from the effect of vaccines on the magnitude of populations will be followed by transcultural issues implicit in vaccine testing and delivery. the use of vaccines to obviate behavioural changes (technical fixes), generate transcendental concerns and provide new threats via biological warfare agents will also be treated. it is part of current medical practice when dealing with patients to extol four basic ethical principles: autonomy, beneficence, non-maleficence and justice. however, when we consider issues related to vaccination the principle of autonomy (self-determination; freedom from interference unless the act harms others (j.s. mill); as in un or cfe declarations on human rights) is challenged. while the principle of autonomy may be asailed from a number of different facets such as the competence of an individual to provide informed consent, the rights of a fetus if the pregnant mother decides to be immunized or the implicit implications of the social contract entered into when an individual chases to dwell in a particular society, i will examine in university of surrey, school of biological sciences, guildford, surrey gu xh, uk more detail a further issue involving the expression of social responsibility. it is well known that when a high proportion of a population is vaccinated, those who have not been immunized become protected by the decrease in the level of the pathogenic organism (the herd effect). the question which this poses is, do those who have opted against vaccination have the right to benefit from the expense and the risks of vaccine-induced damage accepted by those who have been vaccinated? not only that, but such unvaccinated individuals pose a threat to the vaccinees as they serve as a reservoir in which the disease can be maintained and propagated. were the society to collectively determine that all its citizens should receive the vaccine then the principle of patient autonomy is infringed. an intermediate position might be to levy a special cash buy-out dispensation to those who refuse vaccination as a contribution to the costs incurred by those who have accepted the risks of vaccine-induced damage. whatever the outcome in any particular society it is clear that vaccination poses a challenge to accepted ethical positions, the resolution of which will be dependent of the degree of social coherence and farsightedness. for much of the last years commercial companies have been required to provide products to the marketplace and society's judgement on the company has been via the acceptability of the product at the price demanded. the function of the company was to accumulate profits for its shareholders and top managers (incentives) and society did not interfere with the way the product was made, nor with the product spectrum on offer. this ethic too, is in need of review. vaccines are a clear benefit to society as a whole. however, there is a risk of vaccine-induced long-term and severely debilitating damage [well recognized for polio vaccines and less well established for any other vaccine cf. swine fever (inactivated influenza) vaccines and guillain-barre syndrome] which is especially poignant when incurred after the vaccination of a -month-old healthy infant. under present conditions the manufacturing company may be sued for damages both actual and punitive (if wilful negligence is proven). but is this the appropriate ethic? may not the society, in accepting the benefit of widespread vaccination, compensate those who suffer damage at a level communsurate with the damage? of course, were the manufacturer culpably negligent in a procedural ethical aspects of vaccines and vaccination: r. e. spier matter, then compensation would also be due from that source. resulting from this liability situation, vaccine manufacturers are reluctant to venture into vaccine projects. also, as the cost of obtaining a product license is estimated to be some $ - million, the implications for the cost of a dose of vaccine is more driven by the cost of the regulatory procedure than the production cost (which rarely exceeds the cost of the bottle plus label). the ethical issue here is whether the regulatory hurdle which has to be overcome is really operating in society's best interests. nothing we eat or do is without the risk of incurring damage. vaccines are not different in that respect. yet the cost of obtaining a license to manufacture and distribute implies that the cost of the vaccine has to be many dollars merely to recoup the costs involved. does this mean that the rich should pay a high price for a vaccine and thus subsidize the provision of cheap vaccines to the poor? or is it the job of the elected representatives of the people to act as purchaser on behalf of the poor and provide the vaccine manufacturer compensation through the tax system or other fiscal dispensation? vaccines for diseases which afflict a few are not a commercial proposition unless communal support is provided. vaccines which lead to a decrease in the need for over-the-counter or prescribed medicaments are also unlikely to be made by commercial concerns. the reluctance of pharmaceutical companies to workup a vaccine for helicobactu pylori which would prevent the recurrence of stomach ulcers and hence stomach cancers is evident from the research programmes of those companies which make anti-ulcer drugs. research on vaccines which would prevent the common cold (caused by a combination of rhinoviruses, coronaviruses and admoviruses) is also conspicuous by its absense. but prophylaxis as an approach to healthcare is also underfunded by society at large. therapeutic research receives over times the funding of prophylaxis; and this is particularly difficult to understand when there are many inexpensive ways of achieving prophylaxis, of which vaccination, which affects the immune system, is but one. other methods of prevention focus on the protection of the immune system to decrease the probability that it will be overwhelmed by an endogenous or exogenous pathogen; such procedures may be termed 'fence vaccines". a new relationship between industry and the community is indicated. the former is now required to recognize that it will be judged as much by the ethicality of its actions as the efficacy of its products. for the pharmaceutical industry, ethics is not an optional extra: it is essential. an ethical argument which is proscriptive of the use of vaccines in the developing and less developed world (containing % of the world's . billion people) is that they will lead to an increase in an already unsustainable population. this will have sequellae via an increase in suffering from malnourishment, population migrations and war. however, recent figures published by unicef refute these projections' and show that the average number of children born to a woman of the developing world throughout the period of her fertility has dropped from . to . between and . this would indicate that more, rather than fewer, vaccines are required; and indeed vaccines protective to the diarrhoeal and respiratory diseases of childhood are on test in the field, while candidate vaccines aimed at controlling malaria languish in laboratory fridges. population may not only be affected by a decrease of infant mortality but also by an increase in the average age of the community. as the level of communicable disease wanes, people live longer and society then has to adjust its working conditions such that there are productive positions for the older people to occupy. it is clearly not practicable to socially provide for protracted retirements, so the emphasis on life-long learning, skill changing, job flexibility and part-time working will become the norms of future social development. is it appropriate to use a technical fix when an almost cost-free change of behaviour will achieve the same effect? such an ethical problem is thrown up by the willingness of our communities to spend billions of dollars to provide therapeutic and prophylactic agents to control the spread and effects of the human immunodeficiency virus (hiv), while the disease would be eliminated were people to engage in safe, condom-protected, intercourse in their pre-or extramarital sexual relationships where the prospective partners had not been thoroughly tested for the presence of serum antibodies to the virus. this provision also applies to the transmission of the viruses which cause hepatitis b, genital herpes, as well as the cancers wrought by the papilloma virus. as a corollary to the practise of safe sex, it might also be expected that gonorrhoeal infections would decline, as would those caused by treponema sllphilis and the yeast candida. many of the food-and water-borne diseases caused by bacteria of the salmonella. escherichia, shigella, listeria, campylobacter and vibrio groups would be eliminated were drinking and washing water to be prepared according to the highest standards prevalent in most developed countries. however, the engineering requirements to achieve this in the short term are daunting. whereas the prospect of the development of orally deliverable vaccines which would provide protection against the diseases caused by the above pathogenic bacteria is a task which may be brought to a successful conclusion within the next decade. a further case where vaccines are used to preclude the expenditure of monies is to protect people from the effects of the diseases of propinquity; typhus and tuberculosis. both of these diseases flourish when people are housed in crowded insanitary conditions. it may be that the vaccination route is cost-effective in monetary terms but this should not be used as a way of avoiding the social improvements which would enhance ethical aspects of vaccines and vaccination: r. e. the dignity of citizens, as well as improving health. spier their infectious disease-causing organisms do not recognize national boundaries. transworld travel for tourism and business is increasing exponentially and with it are opportunities for disease-causing organisms to travel. we are also presented with a situation in which tests of vaccines in developing countries can be effected at considerably less expense than in a developed country. this has led to a series of ethical issues which are exacerbated by the different cultures of the people who may be engaged in the vaccine trials. for example, is it possible to obtain the informed consent of a person who is illiterate and who does not understand the implications of something like a vaccine with which (s)he is totally unfamiliar ? a second issue might be that the removal of blood or tissue for sampling might be regarded as an attempt to capture the spirit of the so deprived individual. additionally, there may be taboos about removal of blood via venipuncture and in some cultures the insertion of needles into bodies may have overtones not foreseen in western cultures. on removal of a sample containing cellular material from the body of an individual (generally a tissue responsible for a pathogenic effect) one obtains the opportunity to work with a highly selected and unique genome. were the genes of that cell to be used to make a pharmaceutical to particularly benefit people in the developed world, what sort of compensation should acrue to the source of the cell line from which the gene was obtained? current thinking by the nuffield ethics committee" would have it that the cell provider has not contributed to the inventive step in the drug or prophylactic development and therefore is not to be compensated. however, if advantage is taken of the uniqueness of the material derived from a person of the developing world then it would be churlish not to recognize this through some financial contribution to the individual and his/her community. one might ask, to what extent is a prophylactic trial in the developing world relevant to the circumstances prevalent in the developed world? are the conditions leading to infection and the challenge organisms relevant? are the people in whom the vaccine is tested likely to respond in an immunologically equivalent manner when the history of the exposure of their immune systems to disease is dissimilar in many ways to a person of the developed world? in the event that there is damage to an individual as a result of exposure to vaccine in a trial, what are the levels of compensation and who pays? and indeed, is it ethical that a person in the vaccine-producing country should enjoy the benefits which have been won at the expense of the risk-taking of a person in less privileged circumstances? to some extent many of these questions may have answers were the developed country vaccine producer to agree up-front to provide cost-free vaccine to all the people of the country in which the vaccine trial had been effected. in that way something of a bargain may be established such that overt exploitation has been subverted into mutual gain. in all such situations it would not be an acceptable ethic to effect trials with placebo controls which did not provide the best possible protection. similarly it would be counterproductive to use vaccines whose safety was an issue and where a less damaging vaccine could be made available, albeit at greater expense. in addition, there is the overriding consideration that if nothing is attempted then there would be a known tally of deaths and disease and our efforts to combat that embody a justification for effecting vaccine experimentation. a definition of the transcendental might be 'that which is outside the cause-and-effect system', where the latter implies that all which exists and the way it interacts is delimited by the energy and matter of its constitution. for example, ghosts, fairies, trolls, spirits, jinn and souls are described in such a way that they perform their tasks with scant regard for the properties of matter and energy, as do the panoply of deities which have been posited as having creative and control capabilities with regard to the affairs of humans. nevertheless, such considerations cannot be obviated when we review the reactions of community members to the production and use of vaccines, particularly when some of the most emphatic proscriptive reactions emanate from the leadership of recognized deitic religions. in kirkpatrick's book on inoculation published in there is the astonishing report of the abreaction of the church to vaccination because, as a result of the possibility of dying from the vaccine of the day (smallpox, occasionally contaminated with syphilis), it may be construed that the vaccinee was indeed seeking to commit suicide, which was sinful. in modern times there were a series of reports in the uk media' wherein the catholic church was seeking to prevail on its susceptible female members to forego vaccination protective against rubella, as the vaccine was prepared from the cells of an aborted human fetus: for human abortion is contrary to the teachings of that church. on a more esoteric plane, it is possible to argue that, through the use of vaccines, mankind has developed a capability which may eventually rid the world of those infectious microoganisms which have been the bane of our struggle to survive. this depletion of the deitic armamentarium may be construed as seeking to deny the deity of one of its controlling effector systems; namely, the threat of divine retribution through the causation of plagues . alternatively, it may be held with equal rectitude, that the deity ordained us to discover and use vaccines as part of its (undisclosed) master plan. consonant with this latter controversy, there are those who assert that it is unnatural to disturb the ways of nature and as vaccines are a creation of mankind, they are not natural and are therefore to be condemned. as this contention rests on the definition of what is natural it is possible to reconstrue this issue totally were we to assert that whatever exists is natural: merely by virtue of its existence. it would follow that there does not exist anything which is artificial (in the sense of unnatural) which implies that all the products of the arts (techniques, crafts, skills) of humans (and animals) are natural and are incorrectly designated as artificial unless the meaning of that term were changed to its more appropriate designation, as works which are the product of humankind's arts (hence arti-ficial; made by art). now that it is practicable to identify a defective gene in an adult, child or even embryo, techniques are in development to repair, exchange or inactivate that gene specifically. these methods imply the existence of 'genetic vaccines'. however, these self-same methods may be used not just to correct defects but to enhance characteristics we may desire to accentuate'. as the word 'disease' is defined as a state of being in which one is not-at-ease, it is not difficult to use the word to describe a situation where a person is not at ease with their height, intelligence, running or ageing, speed etc. this raises the ethical question of the use of genetic vaccines to prevent the disease resulting from such deeply held feelings. there is little doubt that the remediation and/or prevention of situations which cause physical pain is encouraged and applauded by society. the same cannot be asserted where the pain ethical aspects of vaccines and vaccination: r. e. spier may be psychological. nevertheless, this latter pain is just as actionable as the physical pain (indeed it is physical, but of the activities of the brain as opposed to muscle). indeed, not only would we relieve suffering but we might also achieve a human being who is more functionally capable of making a more extensive contribution to society; a feature which is not given to all pain-killing remedies. that such measures might be construed as interfering with some transcendental plan cannot be denied, but the ethic of beneficence might be applied to progress the use of these genetic vaccines in all their manifestations. were we to have an effective orally deliverable contraceptive vaccine' (pregnancy results from the infection of the female by a male spermatozoan) then ethical considerations will be required to determine the way in which such a powerful tool for population control might be used. the contamination of drinking water supplies with a contraceptive vaccine would act counter to the autonomy principle of ethics and could be held to be an affront to the dignity of humanity in denying individuals control over their own fertility. notwithstanding this clear ruling, it is possible to conceive of conditions in which a decrease in population levels is an urgent necessity and the use of an orally delivered contraceptive vaccine might be the only way of achieving that end without recourse to widespread sterilization. as with any other tool, we have to adopt an ethic which permits its appropriate use; what we need to do ahead of time is to discuss and debate what those circumstances might be. anthrax bacteria, botulinum toxin, the plague bacillus (yersinia pestis), measles and influenza viruses have all been proposed as agents of human destruction in the context of international and intranational conflict. both smallpox and measles have been implicated in the decimation of the indigenous populations of the americas during the colonization processes beginning in the s. vaccines protective against these diseases, therefore, become defensive devices which would have to be surmounted by a would-be aggressor. genetic engineering may be used to attempt to enhance the lethality of existing agents or make otherwise benign adding an ethical dimension to industry's external relationships legislators agents lethal. it is unlikely that an increase in lethality can be achieved through the manipulation of the genes which code for toxin structure, for the sophistication of the binding site of these toxins, coupled with the evolution of the enzyme which causes the damage, has probably reached the maximum level of efficacy as a result of the evolutionary process by which it was formed. the addition of new strain of toxin genes to a particular bacterial cell may also be assayed. but the common pattern of bacterial toxins leads to vaccine solutions which are likely to be cross-protective, irrespective of how many toxin genes are compiled in any one bacterial cell. perhaps. of more serious consequence, would be the engineering-out of the epitopes which evoke the immune system to produce toxin-neutralizing antibodies. when this occurs epitopes which heretofore were immunosuppressed become immunodominant'. this would call for the development of a new vaccine which could be made by using the newly engineered binding portion of the toxin molecule to induce neutralizing antibodies to the fully constituted toxin (binding portion plus enzymatic component). this process could be repeated many times. in addition to the manipulation of the toxin system, developments occur in the methods for the dissemination of the agents. while it is possible to conjure scenarios of contaminated water supplies and recognize that the air handling systems of large buildings may constitute a means of agent distribution, the mechanisms for the protection of such seemingly open targets are well in place already; for we do treat water supplies with inactivants and it is recognized that the circulation of air within air-conditioned buildings is fraught with problems if people's natural illnesses are circulated by air-handling equipment devoid of high performance filtration systems. to meet the contingencies of noxious agent distribution the stratagem of 'fence vaccination" may be brought into play. the cycle of measure/countermeasure with which we are familiar in the area of conventional and nuclear weapons has its echoes in the area of biological warfare. that we have a duty to defend the life of our peoples is an ethical principle which few would dispute. in the context of this paper, the pursuit of vaccines to existing and potential biological warfare agents is not just a job done in response to real or perceived threats but should become a mission whose importance ranks so highly that it has to be included with the strategic planning we have to undertake to survive. as in other areas of defensive reaction, we might expect the vaccine production techniques to be enhanced with regard to both the ability to manufacture high quality immunogenic preparations rapidly and also with respect to the engineering of those immunogens. these abilities will have spin-off effects with regard to our ability to produce vaccines protective against the biological agents which pose threats from natural sources, such as influenza viruses whose type changes require us to make immunogenically unique vaccines on a year-by-year basis. we have also to take note of the emergent infectious agents (ebola, hantavirus, hiv) which have achieved a degree of notoriety in recent years"'. our ability to respond to such agents has been slow, cumbersome, disorganized and paltry in relation to the importance of the test situation which these agents proffer. our ethics require that we improve on this performance. vaccine manufacturers must obtain a licence to enable them to market their vaccine products to the wider society. this licence is obtained on the recommendation of a body called a regulatory agency (the fda division of biologics in the usa, the committee for medicines in the uk, etc.). obtaining regulatory agency acceptability" of a vaccine product is a process which may take - years and cost $ - million dollars. as can be seen from figure , the regulatory agency is subject to being influenced by the society which it is set up to serve. in addition to this necessary connection to the regulatory agency, industry may opt to receive from universities and publicly funded research institutes information and materials which enable it to embark on new vaccine projects. this interaction between the private and public sectors is fraught with ethical problems stemming from the difference in the culture of the two types of institution". this has been rendered particularly acute in recent years when attempts have been instigated to make the publicly funded institutions behave as if they were private, profit-making bodies. the insinuation of industrialists into the peer review process for grant applications generated by academics has been one area where the bicameral functionality of the seconded industrialist leads to the funding of conservative research projects which do not compete with the industrialist's undisclosed mission. in this, society is not well served by the monies it sets aside for both academic and publicly funded research. society is not amorphous. it has structure through its institutions. the institutions which affect the way the regulatory process works may be identified as being ( ) the ethical bodies; ( ) the media; ( ) legislatures; and ( ) the educational system (figure ). the ethical bodies include recognized religions whose leaders provide ethical guidance to the members which impinges on the production and use of vaccines, while bearing in mind current social exigencies. there are secular sources of ethical guidelines which are not as well organized and overt. such individuals might recognize that ethics are not guidelines which are provided by the pronouncemnts of a deity but are rather the set points in the control system which modulates human social behaviour with the objective of promoting both the survival of the individual, society and other biotic entities as wealth and the occasion permits'". the media are informed by the religous ethicists as well as picking up on the raw nerve endings of the fears and sensitivities of their fellow socialites. they do not hesitate to evoke the image of the entity created by victor frankenstein at the prospects of the slightest opportunity of affecting a deliberate change to the genetics of the human species. our tradition encourages us to regard monsters as the avenging agents of personal wrongdoing; so such buttons do not require much pressing to evoke negative reactions to vaccine volume number ethical aspects of vaccines and vaccination: r. e. spier the prospects of experiments gone awry. the third effector on the way the regulatory agencies behave is the legislature. it is by law that pharmaceutical products have to be safe, efficacious and be made by a demonstrably consistent process. but how safe is safe? and what is efficacious? and what are the limits by which we define consistency? the answers to each of these questions pose ethical problems. it is recognized that a balance has to be struck between the urgency of the need (if we don't have the agent, people will die) and the side-effects of the product. education is a key feature when we consider how humans behave socially. some attribute the education of children to parents only, and see the education institutions as providing knowledge and capability, but not ethics. others would have us believe that we receive effective training in ethics thoughout our lives from all kinds of sources of which educational institutions are prominent. it is a matter of choice as to whether an individual believes that 'you can't teach an old dog new tricks'. it is a matter of record that modern adults have to relearn their new car's control systems and idiosyncrasies each time they change their car. learning to programme a video, access and use the internet, come to terms with computers, air travel and internationally derived food menues has come to many people late in life, yet they have made changes to their behaviours in the light of these new developments. we are indeed open to lifelong education for which our modern universities are reorganizing. these considerations provide opportunities for industry to accept a new mission. while they have accepted for many years the need for sympathetic public relations (with the media) and for lobbying activities (to affect the laws which receive legislative approval), they have not until now perceived that they have also to meet the challenge of ethics providers. this can be effected at two levels; the one, via the bodies which focus on the generation of ethical guidelines; the other, the educational system from the earliest grades to those who return to education in their third age or later. industrialists will have to recognize that ethics matters. they will have to support institutions which engage in devising an ethics which is wholly compatible with living in a modern world with ever changing technologies and concepts about the nature of life and the way the world works. and they must engage in the promotion of ethics in a society which is hungry for a new ethical synthesis (figure ) . all this has to be done at arm's length. there is no substitute for the realization that we all are members of the community and responsible in some measure for our mutual well-being: sectors cannot profit at the expense of other segments. this concurrence of aims needs a reaffirmation; it is hoped that industry will see its future success through the inclusion of this mission in its project portfolio. introducing fence vaccines the state of the world's children. unicef the analysis of inoculation comprising the history, theory and practice of it: with an occasional consideration of the most remarkable appearances in the small pocks in sickness and in health the sunday times, / / , news section p. which describes a genetically engineered anti-pregnancy oral vaccine based on salmonella evidence of cryptic v epitope(s) on native hiv- virions: immunophysicochemical analysis the coming plague; newly emerging diseases in a world out of balance on the acceptibility of biopharmaceuticals ethical aspects of the university-industry interface ethics as a control system component key: cord- -mc t authors: steinegger, benjamin; cardillo, alessio; rios, paolo de los; gómez-gardeñes, jesús; arenas, alex title: interplay between cost and benefits triggers nontrivial vaccination uptake date: - - journal: nan doi: . /physreve. . sha: doc_id: cord_uid: mc t the containment of epidemic spreading is a major challenge in science. vaccination, whenever available, is the best way to prevent the spreading, because it eventually immunizes individuals. however, vaccines are not perfect, and total immunization is not guaranteed. imperfect immunization has driven the emergence of antivaccine movements that totally alter the predictions about the epidemic incidence. here, we propose a mathematically solvable mean-field vaccination model to mimic the spontaneous adoption of vaccines against influenzalike diseases and the expected epidemic incidence. the results are in agreement with extensive monte carlo simulations of the epidemics and vaccination coevolutionary processes. interestingly, the results reveal a nonmonotonic behavior on the vaccination coverage that increases with the imperfection of the vaccine and after decreases. this apparent counterintuitive behavior is analyzed and understood from stability principles of the proposed mathematical model. the quantitative study of disease propagation has captured the attention of statistical physicists for a long time [ ] [ ] [ ] . specifically, this approach has shed light on many conundrums by considering the networked structure of contacts, their timevarying and multilayer character, as well as the recurrent nature of mobility patterns [ ] [ ] [ ] [ ] [ ] . vaccination, whenever possible, is the most effective way to harness and prevent the spreading of a disease [ ] . under normal circumstances, the decision of getting vaccinated can be considered as an act of cooperation, since it bestows benefits on the whole population at the expenses of single individuals. notwithstanding, we are recently witnessing the emergence of widespread antivaccine movements, which are mainly fueled by misconceptions and mischievous news about vaccines [ ] [ ] [ ] [ ] [ ] [ ] [ ] . scientists (including physicists) are devoting tremendous efforts in designing efficient immunization strategies [ ] as well as shedding light on the mechanisms behind the deliberate decision of not getting vaccinated and their harmful consequences [ , ] . vaccination can be modeled as a strategy of a game. under such premises, the evolution of vaccines' voluntary adoption can be investigated using the machinery of game theory [ , ] and statistical physics [ , ] . the first studies carried out on vaccination games use classical game theory, with single round games in which agents have perfect knowledge of their odds to get infected [ , ] . in reality, however, individuals are not perfectly aware of the risk to get infected, and vaccination coverage may evolve in time as a byproduct of personal experiences or imitation. therefore, evolutionary game theory is the natural workbench to tackle the problem. the seminal works in this direction assumed the simultaneous evolution of vaccination and spreading dynamics [ ] [ ] [ ] . a different approach was used in the case of seasonal influenza, by considering that the spreading process reaches its stationary state before vaccination games take place [ ] [ ] [ ] [ ] . here, we introduce a mean-field framework to mimic the spontaneous adoption of vaccines against influenza-like diseases. our model captures the essence of previous approaches to gauge, analytically, the risk of epidemic outbreaks. in particular, we use a minimal evolutionary vaccination game to infer the strategies adopted before an epidemic season. this, in turns, allows us to estimate the risk of future outbreaks by encapsulating agents' strategies into an epidemic model. we get analytical results and insightful conclusions from the analysis of this framework in well-mixed populations. more specifically, we unveil how the interplay between the probability of infection, vaccine effectiveness, and cost, gives rise to nonlinear responses in vaccine uptake. our analysis reveals a nonmonotonic behavior on the vaccination coverage which, surprisingly, increases as the vaccine quality deteriorates. such counterintuitive behavior is analyzed and understood from stability principles of the proposed mathematical model. let us consider a well-mixed population of n agents or individuals. we assume that this population has initially undergone a susceptible-infected-recovered (sir) disease spreading [ , ] . to stay simple and keep the problem still analytically solvable, we set the disease incidence in such previous season equal to α. such quantity is an input parameter of the model and acts as a proxy for the perception of infection risk, e.g., advised through the mass-media. after the first outbreak, the vaccination dynamics takes place. as a result, agents converge to the decision of vaccinating (v) or not (nv). the resulting strategy is the outcome of the evolutionary dynamics (see below) given the previous incidence, α, infection probability, β, recovery cost, t , the cost of the vaccine, c, and its failure rate, γ , or equivalently, its effectiveness ( − γ ). the corresponding vaccine coverage-given by the fraction of vaccinated agents y eq -is used as the input of a new sir spreading process, having the same β and t . the results of the sir dynamics allow us to estimate the total infection incidence, r ∞ , as a function of the relevant parameters, especially α. the mathematical definition of α is the probability of infection, in the previous outbreak, of an agent without protection against the disease. vaccination dynamics consists of a repeatedly played two strategy game, in which agents either take the vaccine (s = v) or not (s = nv). agents will decide according to: (i) the cost associated to uptaking the vaccine (c) and (ii) the recovery cost (t ) weighted by the perceived risk of getting infected by a contact in a future outbreak. the latter risk depends on the previous incidence α, the infection rate β, and the vaccine effectivenesss ( − γ ). it is worth stressing that the vaccination cost should not be seen purely as a financial one. it also includes, for example, vaccine hesitancy [ , ] . the payoffs associated to each of the four possible encounters between pairs of agents are: where p s →s is the payoff accumulated by an agent with strategy s when it meets another having strategy s (s ,s ∈ {v ,nv }). as explained above, the prefactors of the recovery cost (t ) in eq. ( ) are modulated by the perceived risk of infection given the previous outbreak, encapsulated in α, and the probability that an individual playing with strategy s is infected by another with strategy s . the fitness of an agent i, π i , is defined as the sum of payoffs accumulated across its pairwise interactions. every agent i with strategy s i chooses randomly another one j , with strategy s j , compares their fitness (π i , π j ) and if π j > π i adopts j 's strategy with probability: . ( the strategies of the agents are updated synchronously after each round of the game. using the above update function, and assuming that agents are well-mixed, the mean outcome of the individual decisions follows the so-called replicator equation [ ] :ẏ where y is the fraction of vaccinated agents, π v the average payoff of a vaccinated agent, and π the average payoff of the population. according to the payoffs in eq. ( ), the replicator equation readṡ the above equation admits two trivial equilibrium points (y eq = and y eq = ), and a third, nontrivial, one: the criteria for the existence of the nontrivial equilibrium point have an intuitive interpretation. in fact, the condition y * > is equivalent to p nv→ nv < p v→ nv , which translates into a vaccination thresholdβ = c/αt ( − γ ). in other words, it is impossible to observe vaccination in a system where c > t , i.e., where vaccinating costs more than recovery. the criterion y * < translates into p v→ v < p nv→ v , corresponding to β <β/γ . if this condition is not fulfilled, a vaccinated agent has a higher payoff than a nonvaccinated one regardless of the opponents strategies, hence leading to full vaccination. in the next section, we analyze the stability of the equilibrium points. the evolution of y is ruled by eq. ( ). to analyze the stability of its fixed points, we need to evaluate the derivatives of the selection gradient, f (y), corresponding to the right-hand side of eq. ( ): evaluating the derivative at the internal fixed point, y * , we get if the internal fixed point lies in ( < y * < ), then it is stable, since df (y) dy | y=y * < . otherwise, if (y * < ) or (y * > ), then the fixed point y * is unstable. evaluating the derivative at the monomorphic states (y eq = and y eq = ), we get consequently, the derivative evaluated at the monomorphic states corresponds to the existence criteria y * > and y * < , respectively. therefore, the monomorphic states are unstable in the presence of the internal fixed point, y * , and reach stability depending on whether y * < or y * > . these findings are summarized in fig. , which presents the selection gradient as a function of the vaccination coverage, y, in the presence of the internal fixed point, y * . one can see that y * is stable and as the internal fixed point is shifted to y * = or y * = , the corresponding monomorphic state reaches stability. therefore, the vaccination coverage, y eq , being defined by the stable equilibrium point, is given by the internal fixed point y eq = y * forβ β β /γ , whereas for β <β andβ/γ < β it is given by y eq = and y eq = , respectively. according to eq. ( ), high values of c are detrimental for vaccination, while high values of t and β boosts it. additionally, the vaccination coverage depends exclusively on the ratio between vaccination and recovery costs, which we denote as f = c/t . therefore, considering eq. ( ), one can see that full vaccination cannot be stable for a perfect vaccine unless f = . more subtle is the dependence on the vaccination quality γ . in fact, lowering vaccine quality increases vaccine coverage (dy * /dγ > ) if the fraction of effectively vaccinated agents y eff > . , where y eff = ( − γ )y. noteworthy, albeit the quality of the vaccine worsens, agents will choose more often to vaccinate. at first glance, the increase in vaccine uptake as its effectiveness decrease may seem counterintuitive. the rationale behind this is as follows: as γ increases there is a competition between the increasing risk of getting infected and the reduced protection bestowed by the vaccine itself, as shown in fig. . to shed light on such competition, one may look at the decrease of the vaccine's effectiveness − γ as a dynamical process. as effectiveness decreases, the risk for a not vaccinated agent of getting infected by a previously vaccinated one becomes y eff × βαγ . conversely, the risk of a vaccinated agent to get infected by a nonvaccinated becomes ( − y eff ) × βαγ . comparing these two risks, the vaccinated agent has an advantage over the nonvaccinated if y eff > ( − y eff ), which translates into y eff > . . hence, the counterintuitive act of vaccinating when the efficiency of the vaccine is low turns out to be a rational decision to mitigate the infection pressure. moreover, the existence-for each infectivity β-of a maximum fraction of vaccinated agents, y * max , delimitates a region of "tolerable effectiveness" beyond which agents decide to non vaccinate. also, the position of y * max versus β splits the phase space into two distinct regions (fig. inset) . interestingly, this effect has been observed previously in other coevolutionary models [ ] [ ] [ ] , but never explained hitherto. at variance with y, the fraction of effectively vaccinated agents, y eff , is always lowered by a decrease of the vaccine quality, i.e., d[( −γ )y * ] dγ < . therefore, the higher vaccination coverage is not counterbalancing the lower vaccine quality. let us analyze this dependency more in detail. there are three different regimes regarding the dependency of the vaccination coverage, y eq , on γ . the first one is the absence of vaccination independently of γ , corresponding to β < c αt = f α . in the second regime y * (γ = ) < . the vaccination coverage is monotonously decreasing with γ . therefore, maximal vaccination coverage is reached for a perfect vaccine γ = . the condition y * (γ = ) < . is equivalent to β f α . in the third regime β > f α , the dependence of y * on γ is non monotonous, wherefore the vaccination coverage is maximal for a non perfect vaccine. the vaccine quality maximizing the vaccination coverage is then found from dy * /dγ = , giving the vaccine quality maximizing the vaccination coverage can also be seen as a tolerance threshold. if − γ becomes worse than − γ c , agents start refusing taking the vaccine and the vaccination coverage drops rapidly, as illustrated in fig. . from there, the maximal vaccination coverage in the three regimes is then given by the maximal vaccination coverage, y * max , as a function of β is presented, instead, in the inset of fig. . after discussing the outcome of the vaccination dynamics, we now turn our focus towards its impact on the subsequent - epidemic outbreak. assuming that the vaccination dynamics always ends up in the unique stable equilibrium point, y eq ; we can use such information to compute the extent of a future epidemic outbreak by using a sir compartmental model [ ] . the dynamics of the sir model is then given by where s, i , and r denote the fraction of susceptible, infected, and recovered agents, respectively. the aforementioned quantities fulfill the conservation law s + i + r + ( − γ )y eq = . note that μ = /t indicates the recovery probability in agreement with the vaccination game. the fraction of recovered agents after the epidemics dies out, r ∞ , is given by the following trascendental equation: where i is the initial fraction of infected agents. equation ( ) has no analytical solution, hence it must be solved numerically. nevertheless, in an infinite size system (n → ∞), the term i can be neglected since i . thus, a nonnegligible fraction of recovered agents, r ∞ , exists if where β c denotes the epidemic threshold. as expected, if the system displays no vaccination, y eq = , and the above criteria reduces to the purely epidemic sir threshold β c = μ. instead, for the full vaccination case, y eq = , the criteria becomes β c = μ/γ . finally, for the internal fixed point, y eq = y * , the existence of r ∞ > in eq. ( ) implies surprisingly, this condition is independent of β. therefore, the increased vaccination coverage balances the increased transmission probability in the subsequent epidemic outbreak. in fig. , we display the vaccination coverage, y eq (panel a), and the fraction of recovered agents, r ∞ (panel b), as a function of the previous season incidence α, and the probability of infection β in the case of a perfect vaccine (γ = ). as expected, a remarkably high fraction of recovered agents is observed for a highly infective epidemic (large β) paired with a small fraction of infected agents in the previous outbreak (small α). in fig. (b) , one can observe that, given a value of α, the fraction of recovered individuals is maximal at the vaccination thresholdβ. a way of finding the maxima and minima of the fraction of recovered agents, r ∞ , is considering its derivative with respect to the tranmission probability, β, d r ∞ dβ . note that in an infinite system, the transcendental equation eq. ( ) takes three different forms depending on the vaccination coverage: to find an explicit expression for d r ∞ dβ , we derive both sides of eq. ( ) and subsequently rearrange terms, which leads to to infer information about the sign of d r ∞ dβ we need to bound r ∞ . by using again eq. ( ) and the inequality −e −x > x +x , we find a lower bound for r ∞ as these lower bounds can then be combined with the inequality e λ μ r ∞ + λ μ r ∞ . the strict inequality holds for all r ∞ > . this enables us to develop the expressions for the derivative in eq. ( ) , leading to the cases β <β andβ γ < β are as expected. in these regimes the vaccination coverage does not vary with β (y eq = and y eq = , respectively), wherefore r ∞ increases monotonously with β. in the intermediate regimeβ < β < β/γ , though, where y eq = y * , r ∞ monotonously decreases with β ( dr ∞ dβ < ). consequently, vaccination emerges in a way such that it outweighs the increased transmission probability and hinders the epidemic spreading, as illustrated in fig. (c) . from these considerations, we can conclude that the fraction of recovered agents is locally maximal at β =β, and locally minimal at β =β/γ . the numerical exploration of the parameter space has confirmed hitherto that the former is also a global maximum. moreover, the highest fraction of recovered, r max ∞ , for a fully vaccinated population (y eq = ) would correspond to meaningless values of the parameters. depending on the parameters, the system will not be in all of the three regimes presented in eq. ( ) as the transmission probability, β, is varied. if the parameters are such thatβ/γ > , the system will never fall in the third regime. consequently, r ∞ monotonously decreases once vaccination emerges. similarly, one might haveβ > for which the system shows no vaccination and r ∞ monotonously increases with β. the different cases are illustrated in fig. (c) . to validate that the previous equations are actually describing the behavior of the considered system, we have compared the analytical results discussed above with those obtained via monte carlo simulations. the simulations have been made for a system of n = agents updating their strategy accordingly to eq. ( ), and averaged over n real = realizations. the difference between theory and the simulation for the vaccine coverage, y, and fraction of infected agents, r ∞ , is plotted in figs. (a) and (b) . the maximal differences for y and r ∞ are around . % and . %, respectively. the average relative errors, instead, are . % for y and . % for r ∞ . the agreement between analytical and numerical simulations, σ , is thus ∼ %. we want to remark also that preliminary analysis made in the case of discrete interactions encoded as networks showed similar results, although we lack an analytical solution. notwithstanding, the well-mixed population proves to be a good approximation for the vaccination dynamics on networks. this is very likely due to the vaccination cost term in the total payoff, which does not scale with the degree of nodes. additionally, the nontrivial increase in vaccine uptake-as effectiveness decreases-is also observed in simulations on networked populations [ ] . summing up, we have presented a mean-field model to predict vaccine uptake for influenzalike diseases using the disease incidence during previous outbreak season as a proxy for the "perception of infection risk." the model predicts the existence of a tolerance range of vaccine effectiveness, where a nontrivial increase in vaccination coverage takes place as the vaccine inefficiency increases. albeit appearing irrational and counterintuitive at first sight, such behavior is-instead-due to the interplay between the vaccination game and the disease spreading processes. the model predicts also that highly infective-but under control-epidemics might prove dangerous for future infections, since they alter the "risk perception" of the agents and induce them to nonvaccination. finally, as mentioned in the introduction, the timescale between the two dynamics (decision and spreading) has always been considered fixed. the sole exception, up to our knowledge, are childhood diseases with long term immunity [ , ] . the framework presented here could be used to fill the gap among different model formulations and unify them. epidemic processes in complex networks population biology of infectious diseases: part i infectious diseases of humans epidemic spreading in scale-free networks impact of non-poissonian activity patterns on spreading processes the physics of spreading processes in multilayer networks three faces of node importance in network epidemiology: exact results for small graphs critical regimes driven by recurrent mobility patterns of reaction-diffusion processes in networks the vaccine wars on the wrong side of history barriers of influenza vaccination intention and behavior-a systematic review of influenza vaccine hesitancy understanding vaccine hesitancy around vaccines and vaccination from a global perspective: a systematic review of published literature retracted: ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children factors associated with refusal of childhood vaccines among parents of school-aged children: a case-control study the impact of social networks on parents' vaccination decisions sources and perceived credibility of vaccine-safety information for parents statistical physics of vaccination advocating for vaccination in a climate of science denial on the benefits of explaining herd immunity in vaccine advocacy evolutionary dynamics-exploring the equations of life game theory evolving game theory and physics coevolutionary games-a mini review group interest versus self-interest in smallpox vaccination policy vaccination and the theory of games a game dynamic model for delayer strategies in vaccinating behavior for pediatric infectious diseases evolutionary game theory and social learning can determine how vaccine scares unfold the interplay of public intervention and private choices in determining the outcome of vaccination programmes imitation dynamics of vaccination behavior on social networks rational behavior is a "double-edged sword" when considering voluntary vaccination evolutionary vaccination dilemma in complex networks imperfect vaccine aggravates the long-standing dilemma of voluntary vaccination epidemic spreading in multiplex networks influenced by opinion exchanges on vaccination imitation dynamics predict vaccinating behavior key: cord- -j pyadqi authors: ishimori, shingo; kamei, koichi; ando, takashi; yoshikawa, takahisa; kano, yuji; nagata, hiroko; saida, ken; sato, mai; ogura, masao; ito, shuichi; ishikura, kenji title: influenza virus vaccination in children with nephrotic syndrome: insignificant risk of relapse date: - - journal: clin exp nephrol doi: . /s - - - sha: doc_id: cord_uid: j pyadqi background: immunization with various vaccines is considered desirable for children with idiopathic nephrotic syndrome (ns) because of their high risk of severe infections. vaccinations may precipitate relapses of ns, but there is no available data regarding inactivated influenza (flu) virus vaccines. methods: we retrospectively reviewed the medical records of children with ns who had received flu vaccines between and . the day of flu vaccination was defined as day , and the period between the pre-vaccination and the post-vaccination days was defined as − x to + y. the risk ratios and their % confidence intervals for ns relapse rate were estimated by generalized estimating equation (gee) poisson regression. results: a total of pediatric patients received flu vaccines. the mean age at onset of ns was at . ± . years old. there were ns relapses between days − and + . compared with the relapse rate in the − to interval ( . times/person-year), those in to + ( . ), + to + ( . ), + to + ( . ), + to + ( . ), and + to + ( . ) days groups were slightly increased, but without significance. multivariate analysis using gee poisson regression also showed no significant increase in relapse rate in each day group compared with days − to . risk ratios for ns relapse were significantly higher in children who were treated with steroids at the first vaccination. conclusions: our results suggest that flu vaccines should not be avoided in children with ns based on the potential for ns relapses. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. more than half of children with idiopathic nephrotic syndrome (ns) develop frequent relapses or steroid dependence. these children require various immunosuppressants to prevent relapses of ns. children with ns are therefore exposed to the risk of recurrent infections and are at high risk of severe infections because of their relatively immunocompromised state. these infections also have the potential to precipitate ns relapses. notably, upper respiratory viral infections are common and may precipitate or induce relapses of ns [ ] . several reports have described relapse of ns related to influenza (flu) virus in a season of pandemic influenza [ , ] . guidelines recommend that these children should have flu vaccinations to reduce the risk of having serious infections [ ] . however, relapse of ns can reportedly occur after various vaccinations [ ] [ ] [ ] [ ] [ ] [ ] . although inactivated flu vaccinations could also precipitate relapses of ns [ , ] , no data are available on the relative risk of ns relapse related to flu vaccines. we report a retrospective cohort study of children with ns who received inactivated subunit-antigen flu vaccination in our hospital, with a focus on relapses of ns related to flu vaccinations. we examined data from children who were enrolled in the ns database of the national center for child health and development in tokyo, japan. children were eligible for this study if they were newly diagnosed with idiopathic ns between the ages of months and years and if their last relapse was steroid-sensitive ns (ssns), regardless of history of steroid-resistant ns (srns). excluded were children with ns secondary to nephritis and those with congenital ns. this study was conducted in accordance with the declaration of helsinki and with the ethical guidelines for medical and health research involving human subjects created by the ministry of health, labor and welfare in japan. in accordance with these guidelines, informed consent was not obtained from patients or their parents for this study. the national center for child health and development ethics review board approved this study (approval number: ). in the present study, the definitions of general conditions in pediatric ns were made according to clinical guidelines issued by the japanese society for pediatric nephrology [ , ] . idiopathic ns in children was defined as hypoalbuminemia (serum albumin levels ≤ . g/dl) and severe proteinuria (≥ mg/h/m in pooled nighttime urine or an early morning urine protein creatinine (cr) ratio > . g/g cr). complete remission was defined as a urine protein creatinine ratio < . g/g cr or ≤ − protein on dipstick testing of early morning urine for three consecutive days. ssns was defined as complete remission in < weeks after starting daily prednisolone (psl) therapy. the relapse of ns was defined as ≥ + protein on dipstick testing of early morning urine for three consecutive days. frequently relapsing ns (frns) was defined as two or more relapses within months of the initial response, or more than four relapses within any -month period. steroid-dependent ns (sdns) was defined as two consecutive relapses during psl tapering or < days after discontinuation of psl therapy. srns was defined as the absence of complete remission after ≥ weeks of daily psl therapy. the day of inactivated subunit-antigen flu vaccination was defined as day , and the period from the pre-vaccination to the post-vaccination days as − x to + y, respectively. 'day ′ is not necessarily the timing when patients had an influenza vaccine for the first time since they developed ns. in our study, we included children who received several times of vaccinations. the ns relapse rate was defined as the number of relapses one person had within one year. the duration of rituximab (rtx) therapy was defined as the period from the day of rituximab administration to the day of b cell recovery (cd + b cell count of ≥ % of total lymphocytes). we reviewed the following data: sex, age at onset of ns, age at first inactivated subunit-antigen flu vaccination, observation period, the total number of ns relapses, the total number of flu vaccinations, the total number of flu infections, use of rtx at first vaccination, and use of psl at flu vaccinations. we also reviewed types of ns (srns, frns, sdns); we reviewed renal histopathology (minimal change, focal segmental glomerulosclerosis, diffuse mesangial hypercellularity, or no history of renal biopsy) and also use of immunosuppressants at first vaccination (cyclosporine, mycophenolate mofetil, mizoribine, cyclophosphamide, tacrolimus). we compared ns relapse rates between days − and (the day of flu vaccination) with relapse rates from days to + , + to + , + to + , + to + , and + to + . based on the background that the side effects of an inactivated vaccine generally occur within a month of its administration, we subdivided into the relapse rate in the post-vaccination period from days to + . in addition, to compare with ns relapse rates between days − and as the controlled pre-vaccination period, it was decided to examine ns relapse rates between days and + during the post-vaccination period. our policy was to administer inactivated subunit-antigen flu vaccine to consenting children with ns, except during any period of psl therapy of ≥ mg/kg/day. the other exception was if the patient was in a relapse of ns. in japan, children younger than years generally have a flu vaccination twice per year and those older than the relapse rate of ns was calculated by the person-year method. the risk ratio between pre-and post-vaccination was calculated with % confidence intervals (cis) on the basis of the person-year method. risk ratios and their % cis for the ns relapse rate were also estimated by generalized estimating equation (gee) poisson regression. this regression was adjusted for parameters, including treatment with various immunosuppressants or no treatment, treatment with rtx or no treatment, treatment with psl or no treatment, and flu infection in the same flu epidemic season or no flu infection. all statistical analyses were performed using the sas software package for windows, release . (sas institute inc. cary, nc). a p value < . was considered statistically significant. available for assessment were children with ns who were newly diagnosed between and . of these, children ( boys) received flu vaccines. the clinical characteristics of these children are shown in table . the total number of flu vaccinations was . vaccination details are as follows: children received one vaccination, received two vaccinations, received three vaccinations, seven received four vaccinations, four received five vaccinations, and one received seven vaccinations. no patients experienced fever or symptoms of an allergic reaction that required any treatment after flu vaccination, even though the quantity of the flu vaccine in japan since was changed. one boy received an inactivated subunit-antigen flu vaccine; he was taking oral anti-allergic medicines because he had suffered from local swelling of the arm following a flu vaccination before the onset of ns. a greater proportion of patients were taking immunosuppressants at the time of flu vaccination ( . %) of the children with a history of srns than of the other children who did not have a history of srns. only those with complete remission at the time of flu vaccination were included. the use of immunosuppressants, however, was similar among the children with and without a history of srns (data not shown). we could not evaluate the infection rate of children with ns because there were no data from children who received no flu vaccines but did not contract the flu. comparison of the relapse rate between the preand post-vaccination periods, and the risk ratio for nephrotic syndrome relapse in the post-vaccination vs. pre-vaccination periods compared (fig. ) . multivariate analysis showed that being administered psl (at first vaccination) was a significant independent risk factor associated with ns relapses in all periods ( table ). in children with psl, the difference in the relapse rate in each post-vaccination period was not significantly different compared with the relapse rate in the pre-vaccination period from days - to (data not shown). moreover, these results did not change when we repeated the analysis with exclusion of data from children with a history of srns (data not shown). we examined data regarding times of flu vaccination. the mean age at vaccination in the group that was limited to a vaccine twice ( times) was significantly younger compared with the group that was limited to a vaccine once ( times) ( . ± . vs . ± . years, p < . ). in the once vaccination group, the relapse rate in the post-vaccination period from days to + was significantly higher than that in the pre-vaccination period. compared with the relapse rate in the pre-vaccination period from days − to , the difference in relapse rate in each post-vaccination period, except for from days to + , was not significant (fig. ) . however, in the twice vaccination group, the relapse rate in the post-vaccination period from days to + was significantly lower than that in the pre-vaccination period. compared with the relapse rate in the pre-vaccination period from days − to , the difference in relapse rate in each postvaccination period, except for from days to + , was not significant (fig. ) . however, the event of ns relapse from days to + in the twice vaccination group only occurred three times in three children. in our retrospective cohort study, we showed that inactivated subunit-antigen flu vaccination caused a slight, but nonsignificant increase in the risk of ns relapse ( . to . - . times in one person within a year) in children. because the relapse rate in the post-vaccination period from days to + in the once vaccination group was significantly higher than that in the pre-vaccination period, we consider that flu vaccination might be prone to precipitating relapse of ns in older children who have flu vaccine once a year. furthermore, inactivated subunit-antigen flu vaccination in children with ns did not precipitate srns or other severe adverse events. our results suggest that these children can be immunized without a significantly increased risk of ns relapse. to the best of our knowledge, this is the first published study of ns relapses and other adverse effects related to flu vaccination. in the present study, the relative risk of ns relapses was not significantly increased in the post-flu vaccination period compared with the pre-vaccination period. a small study of ns relapses in children [ ] , which used inactivated split-virion influenza vaccine same as japan, reported one relapse episode three months after flu vaccination and three episodes of relapse six months after regarding the rate of ns relapse due to flu vaccination. fernandes et al. [ ] reported a woman with ns had relapsed after monovalent whole-virion inactivated influenza vaccination [ ] . if we investigate the ns relapse associated with those different types of flu vaccines, we may get different results from the present study. ns relapses following the administration of other vaccines have also been reported. abeyagunawardena et al. [ ] showed an increased risk of ns relapse following meningococcal c conjugate vaccine administration [ ] . it was suggested that the decision to administer the meningococcal c conjugate vaccine should be carefully considered in children with ssns. yildiz et al. [ ] suggested that patients with ssns in hepatitis b virus (hbv) endemic regions should receive hbv vaccines because of the risk of hbv infections. they also suggested that hbv vaccines might trigger ns relapses in some pediatric patients with ns [ ] . to date, however, no reports have evaluated the details of relapses, such as the risk ratio of ns relapses, related to flu vaccination. in the current study, inactivated subunit-antigen flu vaccination in children with ns was not associated with severe adverse events. while an allergic reaction is a serious concern for immunized patients, none of the children in our study had these symptoms. although approximately onequarter of the children in this study had a history of srns, ns relapses were all steroid-sensitive between approximately days − and + . this suggests that no children who experienced relapses of ns became steroid-resistant after receiving an inactivated subunit-antigen flu vaccine. in another study, ns relapses after receiving varicella-zoster vaccines were all steroid-sensitive [ ] . an immunogenic stimulus may trigger ns relapse in children. the major pathogenesis of ns relapses related to various infections or vaccinations may involve activation of t cells in an acute process [ , ] . however, the precise mechanism of this pathogenesis has not been biologically demonstrated. in the present study, we found a significantly high risk of ns relapse in children who were treated with steroids at the first vaccination. flu vaccination in children taking steroids may occur soon after the last relapse of ns. if they are taking steroids when they have their flu vaccination, they may be susceptible to further ns relapse during this period. therefore, this result may be not because of the steroids, but due to it been soon after the relapse. flu infections have the potential to become severe [ ] , but the administration of flu vaccines is effective in reducing the prevalence of flu infections and the risk of severe flu infections. notably, inactive immunizations are effective against pediatric patients with ns, even when they are being treated with glucocorticoids or other immunosuppressive drugs [ ] . poyrazoglu et al. [ ] showed that pediatric patients with ns had adequate antibody responses to flu vaccination at months post-vaccination compared with healthy controls [ ] . although the present study was not intended to evaluate the efficacy of flu vaccination in preventing severe flu infections, none of the children in our study suffered from any severe infections. there are several limitations to the present study. it was a retrospective chart review in a single center and comprised of a limited number of patients. a randomized, controlled trial is ideal for evaluating risk ratios for ns relapses regarding flu virus vaccines. a study is required, with the primary outcome of the relative rate of ns relapse in children with flu vaccination compared with those without flu vaccination. however, the feasibility of this type of randomized, controlled trial is low owing to the difficulty in establishing the side effects of vaccinations as a primary endpoint. a second limitation of this study is that selection bias may have resulted from the fact that our hospital is a tertiary institution, and a high proportion of severe patients were referred to this hospital. therefore, we need to be careful if applying our results to all children who do not have frns or sdns at a general hospital. a further limitation is that the days of pre-and post-flu vaccination occurred from approximately fall to winter, when several infectious diseases become prevalent, and these infections could have resulted in ns relapses. in our study, we did not have data concerning other infections. a final limitation is that we did not examine the efficacy of the flu vaccinations because there was no data of children who received no flu vaccines but did not contract the flu. in conclusion, inactivated subunit-antigen flu virus vaccination in children with ns produces a slightly increased, but nonsignificant, risk of relapse. our results suggest that flu vaccines should not be avoided in children with ns for fear of potential ns relapses and other adverse events. flu vaccination in children taking steroids may occur soon after the last relapse of ns. therefore, providing flu vaccination soon after the last relapse of ns might risk further relapse. at the same time, pediatric nephrologists should consider a minimal increase in relapse due to vaccination against the substantial risk of flu infection and its consequences. role of respiratory viruses in exacerbations of primary nephrotic syndrome relapse of minimal change disease following infection with the pandemic influenza (h n ) virus nephrotic syndrome following h n influenza in a -year -old boy kdigo clinical practice guideline for glomerulonephritis efficacy of vaccination against viral hepatitis type b in children with the nephrotic syndrome varicella vaccination in children with nephrotic syndrome: a report of the southwest pediatric nephrology study group varicella vaccination in children with steroid-sensitive nephrotic syndrome risk of relapse after meningococcal c conjugate vaccine in nephrotic syndrome hepatitis b virus vaccination in children with steroid sensitive nephrotic syndrome: immunogenicity and safety? vaccine safety and immunogenicity of booster immunization with -valent pneumococcal conjugate vaccine in children with idiopathic nephrotic syndrome relapse of nephrotic syndrome following the use of pandemic influenza a (h n ) vaccine antibody response to influenza. a vaccination in children with nephrotic syndrome clinical practice guideline for pediatric idiopathic nephrotic syndrome : medical therapy clinical practice guideline for pediatric idiopathic nephrotic syndrome : general therapy prevention and control of influenza with vaccines: recommendation of the advisory committee on immunization practices, united states, - influenza season current status of vaccines and immune globulins for children with renal disease the authors thank benjamin phillis at the clinical study support center, wakayama medical university, for proofreading and editing the manuscript.funding none. conflict of interest shuichi lto has received honoraria from alexion pharma and sano-fi gebzyme. kenji lshikura has received research grant from novartis pharma k.k. shuichi lto has received research grant from astellas pharma.human rights all procedures performed in this study involving human participants were in accordance with the ethical standards set by the ethics board at national center for child health and development in which the study was conducted (approval number ) and with the helsinki declaration and its later amendments or comparable ethical standards. for this type of retrospective study, registration of clinical trials and informed consent were not needed. key: cord- -mkr n i authors: mah, catherine l. title: what’s public? what’s private?: policy trade-offs and the debate over mandatory annual influenza vaccination for health care workers date: - - journal: can j public health doi: . /bf sha: doc_id: cord_uid: mkr n i policy decisions about public health services differ from those for personal health services. both require trade-offs between such policy goals as liberty, security, efficiency, and equity. in public health, however, decisions about who will approve, pay for, and deliver services are often accompanied by decisions on when and how to compel individual behaviour. policy becomes complex because different stakeholders interpret evidence differently: stakeholders may assign different weights to policy goals and may even define the same goals differently. in the debate over mandatory annual influenza vaccination for health care workers, for example, proponents as well as opponents of mandatory vaccination may convey arguments in security terms. those in favour of mandatory vaccination emphasize subclinical infections and duty of care (public security) while those opposed emphasize risk of adverse events (personal security). proponents assert less worker absenteeism (efficiency) while opponents stress coercion and alternate personal infection control measures (liberty and individual rights/responsibilities). consequently, stakeholders talk past each other. determining the place of mandatory influenza vaccination for health care workers thus demands reconciling policy trade-offs and clarifying the underlying disputes hidden in the language of the policy debate. les décisions concernant l'orientation des services de santé publique diffèrent de celles qui portent sur les services de santé individuelle. les deux nécessitent des compromis entre les objectifs visés, que ce soit la liberté, la sécurité, l'efficacité ou l'équité. en santé publique toutefois, quand on a décidé qui doit approuver, payer et fournir les services, il faut souvent décider en plus quand et comment imposer des comportements individuels. les politiques de santé publique sont donc plus complexes, car les différents intervenants interprètent les données différemment : ils n'accordent pas nécessairement la même importance à chaque objectif stratégique et peuvent même définir autrement des objectifs identiques. dans le débat sur l'imposition ou non du vaccin antigrippal annuel aux travailleurs de la santé, par exemple, les partisans et les adversaires de la vaccination obligatoire peuvent invoquer la sécurité dans leurs arguments. ceux qui sont pour la vaccination obligatoire insistent sur les infections subcliniques et le devoir de diligence (la sécurité publique), tandis que ceux qui sont contre insistent plutôt sur le risque d'effets secondaires (la sécurité personnelle). les partisans préconisent une diminution de l'absentéisme chez les travailleurs (l'efficacité), tandis que les adversaires mettent en garde contre la coercition et préfèrent d'autres mesures personnelles de contrôle des infections (liberté et droits/responsabilités individuels). on assiste par conséquent à un dialogue de sourds. si l'on veut déterminer l'importance à accorder à la vaccination antigrippale obligatoire des travailleurs de la santé, il faut donc concilier les compromis stratégiques et clarifier les différends qui se cachent sous les mots utilisés dans le débat d'orientation des politiques. mots clés : politiques publiques; personnel médical et paramédical; lois; immunisation; pratiques de santé publique t he question of mandatory annual influenza vaccination for health care workers arises regularly in the process of influenza policy planning. terms such as "duty of care," "autonomy," and "rights" are wielded with considerable force by a variety of well-intentioned stakeholders. the following commentary addresses the policy challenges represented in the language used by proponents and opponents of mandatory annual influenza vaccination for health care workers, in an attempt to shed light on this heated debate. the question of mandatory annual influenza vaccination fits within the rubric of public health. definitions of what constitutes public health differ in terms of scope (scale of the community or population), intent (freedom from disease versus complete well-being), and function ("core" functions versus broad social determinants of health). in comparison with personal health services, however, it is generally accepted that public health incorporates the following dimensions: . public health is principally concerned with the health of populations rather than individuals. . public health assumes that certain goods cannot be provided adequately through market mechanisms; they cannot be restricted to those who wish to pay for them. this is also true for personal health services. in public health, however, the actions of individuals frequently have consequences for others that may not be predictable or apparent (externalities). these externalities may be negative (increased risk of infectious disease transmission) or positive ("herd" immunity). when positive and known, externalities can induce the "free-rider" problem: for example, individuals might be less likely to assume personal risks related to vaccination if they know that they are protected by herd immunity. the free-rider problem is sometimes used as a justification for coercion of individuals: for example, compulsory vaccinations. . public policy for health services recognizes that individuals acting solely in their own interests cannot adequately provide for the health of the popula-tion at large. the corollary is that collective action by the government on the part of its populace is required to achieve a state of public health, including protecting the public against identifiable health risks. , to the extent that governments act to constrain the actions of individuals in the public interest, public health policies represent the exercise of legitimate authority by a government; coercive or not. , , decisions on the financing, delivery and allocation of health services are accompanied by decisions on when and how to compel individual behaviour in the public interest. the issue of mandatoriness, or compulsion (through regulation), is therefore central to the mandatory influenza vaccination debate and should be separated from the issue of the perceived risks and benefits of vaccination itself. mandatory vaccination regulations have long been employed by governments as a public health policy instrument and have been supported by constitutional and common law jurisprudence in the us context. , in canada, a number of statutes and regulations at the federal and provincial/territorial levels govern immunization. from a policy perspective, mandatory vaccination regulations illustrate the tradeoffs that are central to public policy. as deborah stone has observed, four goals or values dominate the policy discourse: equity, efficiency, liberty, and security. policy decisions for the provision of goods such as health care rest largely on the trade-offs between these goals. the trade-off between security and liberty, or in other terms, a government's responsibility to reduce risk in the community and the rights of individuals as protected by law, is highlighted in public health. canadian federal and provincial requirements for compulsory vaccination, for example, are tempered by the presence of individual legal exemptions on religious, medical, or philosophical grounds. should health care workers undergo voluntary annual influenza vaccination? was the ontario government just in its efforts to impose compulsory influenza vaccination for paramedics in ? are there conditions under which mandatory vaccination of health care workers is fair? do the conditions differ for physicians in private offices versus hospital workers? how about volunteers? should mandatory influenza vaccination for health care workers be seen as protecting the public (public health context) or health care workers themselves (occupational health context)? should health care workers be required to take antiviral drugs in addition to/in lieu of vaccination? such questions illustrate the nuances in the tensions between security and liberty at the heart of the debate. as gostin has asked: "how do we know when the public good to be achieved is worth the infringement of individual rights?" complexity in the security/liberty problem also arises through issues unique to vaccination, in general, and annual influenza vaccination, in particular. first, vaccination clearly constitutes a medical intervention. compared to public health regulations such as smoking bans in public spaces, vaccination poses a palpable risk to the individual undergoing the intervention. second, vaccination is unique in that it serves a preventive rather than treatment function in the protection of the public's health. compared with other medical interventions such as compulsory antimicrobial treatment for communicable diseases, mandatory vaccination requires a clear assessment of immediate as well as long-term costs and benefits. finally, annual influenza is exceptional in that vaccines must be modified and readministered annually, according to the shifts in the immune make-up of the predominant viruses circulating worldwide each year. compared to one-time, "emergency" situations where liberty may be more easilyand arguably justifiably -overridden, compulsory annual influenza vaccination requires repeated impositions on the individual. one of the central difficulties in the current state of the mandatory vaccination debate is apparent in contradictions in the language used. different stakeholders interpret evidence differently; stakeholders may assign different weights to policy goals and may even define the same goals differently. consequently, stakeholders talk past each other. consider, for example, arguments emphasizing the "duty of care." [ ] [ ] [ ] [ ] [ ] [ ] [ ] such arguments frame the debate in terms of communal good over individual rights: an explicit valuing of security over liberty. "duty of care" suggests professional responsibility, which in public health has wider connotations than for personal care. public health professionals need to confront the question of to whom they owe a duty of loyalty. , to what extent are health care workers responsible for potentially vulnerable populations, or the community at large? to what extent are health care workers justified in valuing personal interests over those of their patients -and potential patients? in contrast, the language of "coercion" and "voluntary measures" highlights liberty issues, in both the negative (freedom from interference -the right to be free) and positive (freedom to act -opportunity) connotations. "duty of care" arguments thus talk past the opponents of mandatory vaccination, who stress coercion and the effectiveness of alternate personal infection control measures. even if policy-makers were to agree on a single goal, it would still be subject to ideological and normative assumptions. proponents of mandatory influenza vaccination, for example, may assert decreased worker absenteeism as a result of vaccination. though in part a security argument -for decrease in infectious risk to and stability of the health care workforce -this justification also suggests efficiency gains. efficiency also has normative -and negative -connotations: inefficiency means waste. similarly, the idea of security is complex because defining what individuals or societies "need" to be secure includes diverse dimensions. the definition of security in the public health context is particularly problematic because security arguments might be more compelling for specific conditions or in certain populations where ease or risk of disease transmission is high. in terms of language, proponents as well as opponents of mandatory vaccination may convey their arguments in security terms; proponents emphasize subclinical infections among workers and duty of care (public security) while opponents emphasize risk of adverse events (personal security/negative liberty). analysis of voluntary vaccination reveals similar disputes about the meaning of security: simeonsson et al.'s review suggests that "self-protection and personal health" are the top reasons for health worker acceptance of voluntary annual influenza vaccine, while the top reason for non-acceptance was "side effects." in both cases, workers have implied a valuing of personal security over public security. whether mandatory vaccination is "right" or "wrong," "fair," or "just" thus depends on a clear examination of which policy goals we want to achieve as a society. decision models in health care policymaking for personal health services have long taught us that different stakeholders assign different utilities or values to different health outcomes. a "rational" weighing of the evidence may not be sufficient to allow us to make good policy decisions, particularly when the public interest is at stake. in public health policy, recognition of shared goals is paramount. "good" intent, or even "good evidence," cannot be taken for granted as the sole prerequisite for public health policy decisions. determining the place of mandatory vaccination for health care workers demands reconciling policy trade-offs; the first step should be to clarify the underlying disputes hidden in the language of the policy debate. public health, ethics, and human rights: a tribute to the late jonathan mann public health law: power, duty, restraint learning from sars: renewal of public health in canada principles for the justification of public health intervention the end of liberalism: the second republic of the united states health care reform: lessons from canada school vaccination requirements: historical, social, and legal perspectives legislative and regulatory framework for reportable infectious diseases in canada: overview of compendium, draft available online at policy paradox: the art of political decision making, revised edition cats and categories: public and private in canadian healthcare public health law: power, duty, restraint individual rights, collective good and the duty of care national advisory committee on immunization. statement on influenza vaccination for the - season mandatory immunization of health care providers: the time has come influenza vaccination of health care workers: a duty of care semmelweis revisited: the ethics of infection prevention among health care workers requiring influenza vaccination for health care workers: seven truths we must accept counterpoint: in favour of mandatory influenza vaccine for all health care workers virulent epidemics and scope of healthcare workers' duty of care two concepts of liberty point: mandatory influenza vaccination for all health care workers? seven reasons to say randomized, placebocontrolled double blind study on the efficacy of influenza immunization on absenteeism of health care workers influenza vaccination of health care workers: institutional strategies for improving rates key: cord- -bhfghcby authors: zrzavy, tobias; kollaritsch, herwig; rommer, paulus s.; boxberger, nina; loebermann, micha; wimmer, isabella; winkelmann, alexander; zettl, uwe k. title: vaccination in multiple sclerosis: friend or foe? date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: bhfghcby multiple sclerosis (ms) is a debilitating disease of the central nervous systems (cns). disease-modifying treatments (including immunosuppressive treatments) have shown positive effects on the disease course, but are associated with systemic consequences on the immune system and may increase the risk of infections and alter vaccine efficiency. therefore, vaccination of ms patients is of major interest. over the last years, vaccine hesitancy has steadily grown especially in western countries, partly due to fear of sequelae arising from vaccination, especially neurological disorders. the interaction of vaccination and ms has been discussed for decades. in this review, we highlight the immunology of vaccination, provide a review of literature and discuss the clinical consideration of ms, vaccination and immunosuppression. in conclusion, there is consensus that ms cannot be caused by vaccines, neither by inactivated nor by live vaccines. however, particular attention should be paid to two aspects: first, in immunocompromised patients, live vaccines may lead to a stronger immune reaction with signs of the disease against which the patients have been vaccinated, albeit in weakened form. second, protection provided by vaccination should be controlled in patients who have been vaccinated while receiving immunomodulatory or immunosuppressive treatment. in conclusion, there is evidence that systemic infections can worsen ms, thus vaccination will lower the risk of relapses by reducing the risk of infections. therefore, vaccination should be in general recommended to ms patients. over the last years, especially in western countries, vaccine hesitancy has steadily grown and poses an increasing health concern ( ). the recent upsurge of measles in europe is an impressive example. anti-vaccinationists argue that possible side effects weigh out the benefits ( ) . especially sequelaes such as autism, multiple sclerosis (ms) and various neurological syndromes have been emphasized by the anti-vaccination lobby ( , ) . this alarming development is even partly supported by healthcare providers including some ms neurologists, who are afraid of iatrogenic deterioration of preexisting ms. indeed, studies linking vaccination and disease onset have been published. although these studies were often underpowered and lacked an adequate design in order to provide evidence of the suspected link, they caught public awareness leading to a drop of public vaccination coverage rates ( , ) . epidemiological studies and pharmacovigilance data have repeatedly demonstrated safety for the vast majority of vaccines. lately, a review concluded that there is no significant evidence for a causal relationship between the onset or deterioration of ms and vaccination against measles, mumps and rubella (mmr), influenza, hepatitis a, hepatitis b, human papilloma virus (hpv), diphtheria, tetanus, acellular pertussis, or meningococcal disease ( ) . some studies have even indicated a decreased risk for ms and reduced disease activity in preexisting ms ( ) . the aim of this review is to summarize data on vaccination and disease activity of both ms and acute disseminated encephalomyelitis (adem). moreover, vaccination-induced effects on the immune system are presented and potential interactions between ms and immunizations are discussed. vaccine-induced protection is a complex issue and depends on a cascade of mechanisms and mediators (figure ) . eventually, protection is accomplished either by antibodies or t celldependent factors or by a combination of both including neutralizing or antitoxic antibodies, cd + t cells, cd + t cells and corresponding cytokines (e.g., interleukin (il)- , , , , , , , , , and ) ( ) . generally, vaccines have to be capable of activating antigen-presenting cells (apcs) of the innate immune system, which subsequently present the vaccine epitope(s) to t cells-the so-called 'immunogenic potential' ( ) . in this context, dendritic cells play a pivotal role due to their enhanced capability to stimulate naïve t cells ( ) . the nature of vaccine-induced immunity depends on several parameters, of which the biological properties of the vaccine's epitope are of high importance ( ) . live vaccines are attenuated variants of pathogens that still can activate apcs, especially immature dendritic cells, patrolling through the body. this immunogenic potential is often lost by subcellular-or subunitbased vaccines ( ) , which is why these inactivated vaccine antigens are usually combined with so-called adjuvants to increase and modulate the vaccine's immunogenicity via a longer lasting and more effective activation of immune cells. one of the most widely used adjuvants are aluminum salts, which were originally thought to create a long-lasting depot of the antigen in order to provide its slow release, but have instead been shown to act on dendritic cells via prrs (pattern recognition receptors) leading to the secretion of pro-inflammatory cytokines ( ) . similarly, novel adjuvants like squalens or monophosphoryl lipid a (mpla-a detoxified lipopolysaccharide) aim to enhance the innate immune response, but never reach the immunogenic potential of live attenuated vaccines ( ) . adjuvants have been added to vaccines for more than years and over the last decades, considerable progress has been made in understanding their mode of action and to improve safety ( ) . besides the above mentioned aluminum salts, squalene and mpla, oil emulsions, saponin, toll-like receptor (tlr) agonists, enterotoxins, polysaccharides, and glycolipid adjuvants ( ) are used, all of which stimulate the immune system as well. aluminum adjuvants have now been used for decades and lots of experience has been gained on its use, effectiveness, and safety and they still remain the most frequently used adjuvants. their effects on the immune system comprise stimulation of macrophages and dendritic cells via prrs, inflammasome activation, il- β release and activation of th lymphocytes ( , ) . however, besides increased immunogenicity, aluminum adjuvants also increase reactogenicity and based on data from animal models and reports on narcolepsy, silicosis, guillain-barré-syndrome (gbs) and macrophagic myofasciitis, they are also discussed to induce autoimmunity ( ) . the second most commonly and long used adjuvants are oil emulsions. they have a strong reactogenic potential and can cause severe inflammatory local reactions such as ulceration and granulomas. the most well-known oil emulsion is complete freund's adjuvant. however, due to its potent reactogenicity, it is not suitable for human use. a possible association between oil emulsions and autoimmunity disorders has been hypothesized from animal models. oil emulsions are potent inducers of il- β and il- ( , ) . il- plays a major role in autoimmunity and ms and may trigger the migration of peripheral lymphocytes into the cns across the bbb ( , ) . frequently, a combination of adjuvants is used to increase immunogenicity of vaccines. as is an adjuvant emulsion containing squalene, dl-αtocopherol, and polysorbate . it is e.g., used for the pandemic swine flu vaccine pandemrix r ( ) or the fda-licensed h n monovalent influenza vaccine. in animal studies, autoimmunity was observed in connection with as ( ) and in humans, cases of narcolepsy have been reported ( ) . oil emulsions are often combined with tlr agonists such as mpla. generally, tlr agonist adjuvants activate the inflammatory transcription factor nfκb as is a combination of mpla and aluminum salts and is used as adjuvant in vaccines against hepatitis b (fendrix r ) and hpv, as well as in the new recombinant vaccine against herpes zoster. most polysaccharide adjuvants activate nfκb to induce immune processes (e.g., dextran, zymosan) ( ) . however, deltainulin for instance, a polysaccharide adjuvant used for advax r , acts via nfκb-independent mechanisms to enhance humoral and cellular immune responses. although the mechanisms are not yet fully understood, advax r has so far not shown inflammatory side effects and has proven safety in hepatitis b vaccination and influenza ( ) . after activation of the immune cascade and stimulation of dendritic cells, the latter increase their expression of mhc molecules and chemokine receptors such as ccr leading to their migration toward the draining lymph nodes in order to provide co-stimulatory signals for the differentiation of naïve t cells into immune effector cells ( ) . the activation of the immune cascade has various effects on t and b cells. in short, antigen-recognition by b cells leads to their activation and migration toward the t-b cell border of the lymph node, where they can subsequently receive additional stimuli by activated t helper (th) cells. these signals include cd interaction, secretion of cytokines by th or th cells, and finally the transformation of b cells into plasma cells predominantly secreting low affinity antibodies ( ) . later, the germinal center response contributes via affinity maturation (somatic hypermutation and affinity-based selection) and isotype switch to a sustained production of high affinity antibodies by predominantly plasma cells but also memory b cells. basically, in the lymph nodes, numerous b cells with various affinity compete for the antigens presented by follicular dendritic cells. these antigens are processed and further presented via mhc ii to follicular th cells, which provide costimulatory signals (e.g., cd , icos, and il- ) leading to survival and further proliferation of b cells with highest affinity for the antigen ( ) . in conclusion, vaccination-induced immune responses, including employed cell types and mediators, vary depending on the type of vaccine administration, kind of vaccine and choice of adjuvant. while antibodies will directly prevent and reduce infections, cd + and cd + t cells rather support the organism eventually reducing, controlling and clearing the pathogens. antibodies bind to their antigen, neutralize pathogens, activate macrophages and neutrophils as well as the complement system, while cd + and cd + t cells secrete cytokines, perforins, and granzymes ( ) . the choice of adjuvant seems to be critical, since some may cause problems in autoimmune diseases. thus, monitoring side effects regarding autoimmunity is essential. in the early days of vaccine development, louis pasteur used nerve tissue of infected animals to obtain a rabies virus vaccine ( ) . although saving countless lives it was recognized that active sensitization with neuronal tissue could occasionally lead to neuroparalytic autoimmune complications ( ) with self-limiting autoimmune encephalomyelitis that fulfilled the pathological criteria of ms ( , ) . advances in processing techniques and increasing insights in immunology led to modern vaccines devoid of neuronal tissue. ms is a chronic disease thought to be caused by immune-mediated mechanisms. thus, immune responses caused by vaccinations will affect the immune system. however, their effects on immunology per se, but especially those in ms patients, are scarcely understood. the same means by which infections can induce autoimmunity also apply for vaccination-induced immune activation. possible structural similarities between microbial epitopes and epitopes of the cns could lead to cross-reaction of antibodies via molecular mimicry as shown for streptococcal antibodies in heart tissue ( ) . additionally, epitope spreading is a mechanism leading to a broadening of the immune response from the dominant epitope to cryptic (intramolecular) or neighboring molecules (intermolecular) resulting in an increased antibody repertoire and cellular response ( ) . moreover, bystander activation, a process in which activated apcs stimulate autoreactive t cells, can occur ( ) . bacterial and viral infections can trigger relapses and mri activity in ms; vaccination has been proven to protect from or weaken infections, thus providing an "indirect" protection against ms disease activity ( ) . several reports on neurological disorders developing after immunization have been published including several cases on encephalomyelitic disorders (impaired consciousness, ataxia and optic neuritis) as well as demyelinating lesions in a patient with transverse myelitis after active immunization against influenza ( ) ( ) ( ) ( ) . immunization against rubella was associated with diffuse myelitis and recurrent relapses with optic neuritis, paraparesis and impaired motor function ( , ) . transverse myelitis ( ) as well as optic neuritis ( , ) were reported in patients vaccinated against measles, mumps and rubella. further cases with symptoms suggestive for disseminated encephalitis were reported after vaccination against diphtheriatetanus-poliomyelitis (dtp) ( ) and after immunization against smallpox, rabies or typhus ( ) . exacerbations of ms and demyelinating lesions were reported in ms patients and patients without a history of neurological conditions after immunization against hepatitis b ( ) . similarly, tourbah reported on patients with demyelinating lesions and clinical symptoms after vaccination against hepatitis b ( ) . in contrast to these case series, a case-control study (evidence class ii) ( ) including more than patients with ms or optic neuritis and controls without any underlying neuroimmunological disorder did not reveal an elevated risk for the development of ms or optic neuritis after immunization against hepatitis b, tetanus, influenza, measles/mumps/rubella, measles, or rubella ( ) . while hernan came to same results for immunization against influenza or tetanus in a case-control study (evidence class ii), active immunization against hepatitis b was reported to pose a higher risk for ms ( ) . the latter finding could, however, not be confirmed by confavreux in a large case-crossover study. additionally, no increased risk was seen for vaccination against tetanus and influenza as well ( ) . similarly, other class ii case-control studies did not report on an increased risk for ms after hepatitis b vaccination ( ) ( ) ( ) . an even decreased risk for ms was reported after tetanus immunization ( ) . in a large class i study, a patient register including , females vaccinated with the quadrivalent hpv vaccine was analyzed. thereof, , patients with ms and , patients with other demyelinating disorders were studied and no increased risk for cns manifestations was seen in this large cohort ( ). miller et al. performed a prospective class ii, randomized, double-blind, placebo-controlled study, which included ms patients, who received either standard influenza vaccination or placebo. for a months follow-up period, the occurrence of neurological symptoms or influenza was monitored and no differences were seen for relapse rates ( ) . a study by langer-gould reported on an increased risk for cns demyelinating diseases within the first days after vaccination. it was concluded that there is no increased risk for ms, but it seems that the transition from subclinical to overt autoimmunity in patients with existing disease is shortened ( ) . two major questions arise on the topic of "ms and vaccination": (i) can vaccines cause ms and (ii) can vaccines provoke or trigger relapses in patients with ms? (i) overall, the anecdotal reports associating ms onset and vaccination had limited reliability, lacked validity and could not be replicated in larger studies. therefore, there is consensus that there is yet no evidence that ms can be caused by vaccines neither by inactivated nor by live vaccines ( ). (ii) it is more difficult to assess the potency of vaccines to trigger relapses in ms patients. with respect to live vaccines it seems to be plausible that they may be able to provoke a deterioration of the disease, since they fulfill the criteria of an active infection with a replicative (although attenuated) organism. there is class iv evidence that at least the yellow fever (yf) d vaccine strain, which is derived from a natural occurring yf-virus and hasn't completely lost its neurotoxicity even after numerous passages, is able to provoke relapses in ms patients. however, it has to be kept in mind that the patient cohort had received immunomodulatory treatment and the sample size of this self-controlled case series study was rather small ( ) . the underlying potential immunologic mechanisms, which are responsible for this elevated relapse rate, are not understood yet and larger studies are necessary to confirm this association. hypotheses may be generated based on observations after infections with helminths, mycobacteria and epstein-barr virus, or by the immunologic properties of this particular vaccine strain ( ) . immunological analyzes showed that after immunization against yf, ms patients had a significantly increased mbp-and mog-specific response shown by increased numbers of cells secreting interferon, il- α, il- β and tumor necrosis factor compared to unvaccinated ms patients or ms patients vaccinated against influenza ( ) . still, there is no evidence for other live vaccines such as mmr to deteriorate ms ( , ) . for inactivated vaccines, there is already more evidence available that an association between ms relapses and different kinds of vaccines does not exist ( ) . even for vaccines, which were publicly accused to be associated with ms disease or relapse rate, like hpv or hepatitis b vaccines, there is no evidence to support any association between vaccination and clinical course of ms, as well as for vaccines containing inactivated neurotropic viruses like tbe ( , ) . it still remains unclear if inactivated vaccines may accelerate an upcoming relapse in patients with active ms by non-specific stimulation besides effects of vaccines on induction and the disease course of ms, potential immunological effects of adjuvants have to be considered as well. most experience on the possible induction of autoimmunity following administration of adjuvant-containing vaccines has been gained from animal models. however, results from experimental studies cannot be transferred to humans without reservation. first, the dose ratios tested in animal models are not the same as in humans and second, human immunology differs from animals. indeed, oil emulsions, aluminum salts and squalene have shown severe side effects in animal models, while they are considered to be safe in humans ( ) . an analysis performed by the european medicines agency (ema) ( ) investigated autoimmune disorders following vaccination against pandemic influenza a/h n between october and december ( ) . thirty percent of the million doses of the distributed vaccines contained aluminum salts and squalene-based adjuvants. overall, the study did not suggest a significant difference in the risk for autoimmune disorders for adjuvant and non-adjuvant vaccinations. adem was reported for people (adjuvant vaccines: , non-adjuvant vaccines: ), ms for people (adjuvant vaccines: , nonadjuvant vaccines: ), ms relapses for patients (adjuvant vaccines: , non-adjuvant vaccines: ), and one case of relapsing remitting ms was reported for adjuvant-containing vaccination ( ) . statistical analysis revealed only a nonsignificantly increased risk for gbs ( ) . also, a favorable benefitrisk profile of the vaccines was demonstrated ( , ) . in conclusion, following the reports from literature, all of the ema/fda-approved vaccines (with exception for yellow fever) and adjuvants do not show a significantly increased risk for ms and adem. constant improvement of basic immunological knowledge and technology will further improve the safety of adjuvants. table gives an overview of the recommendations of standard vaccinations in the general population and in ms patients. while there is a lot of literature on vaccination and risk for ms or ms relapses available, reports on vaccination and adem are scarce. yet, adem has been discussed to be a sequelae of vaccinations ( ) as well as to be preceded by infections. several cases of adem have been reported to be timely related to vaccinations against rabies ( ), hpv ( , ) , hepatitis a and b, diphtheria, tetanus and poliovirus ( ) , measles, rubella and booster immunization for japanese encephalitis ( ) . adem has been reported following vaccination against influenza, including eight cases after vaccination against h n . also, four adem cases after vaccination against yf can be found in literature ( , ) . besides case reports, there have been some observational studies, albeit all having their limitations. in out of reported cases of adem, patients had infections or vaccinations prior to disease onset ( ) . also, pellegrino et al. concluded a possible relation between post-vaccination adem in children and adults. four hundred four cases of adem were analyzed based on the data of the vaccine adverse event reporting system (vaers) database and the eudravigilance post-authorization module (evpm) ( ) . about % of the cases occurred between and days after vaccination, most commonly against influenza and hpv. a case-control study on vaccination against hepatitis b, influenza, polio, diphtheria, pertussis, tetanus, measles, mumps, rubella, japanese encephalitis, meningitis, hepatitis a, varicella and rabies did not reveal an increased risk for the onset of adem in the time spans of - days and - days after vaccination, but between and days ( ) . based on these reports, the risk for adem after vaccination cannot be completely ruled out. considerations on ms exacerbation and vaccination apply only for ms patients receiving no immunomodulatory/ immunosuppressive treatment. if any kind of immunosuppression is used for ms therapy, this choice of treatment will dominate the decision whether to vaccinate or not ( ) . in recent years, consensus statements on vaccinations during immunosuppressive treatments were published by various national and international societies and expert panels ( ) ( ) ( ) ( ) ( ) . there is consensus that inactivated vaccines will do no harm ( ) even in immunosuppressed patients. however, data on the efficacy of vaccinations in combination with the various available ms medications are missing. thus, for patients either receiving more than one immunomodulatory treatment or having underlying immunomodulating condition, the outcome is difficult to predict ( ). therefore, the success of vaccination should be verified by antibody testing if a valid test is available. except for a few treatments, which only lead to mild immunosuppression, live vaccines are contraindicated under immunosuppressive treatment. in some situations, risks and benefits of a live vaccine have to be weighed against each other, e.g., in varicella zoster virus (vzv)-negative ms patients under fingolimod treatment, varicella vaccination may be considered, since severe complications from natural varicella infection may outweigh the risk from this live vaccine. however, recommendations vary between different institutions even within the same country ( , , ) . a recent case report on a lethal vzv infection in an immunocompromised patient after vzv live vaccination drives the discussion on this issue ( ) . there is consensus about the timing of vaccination in patients, who will undergo immunosuppressive treatment: vaccinations should be given well in advance to the start of treatment (at least weeks for inactivated and ≥ weeks for live vaccines) and should be distinguished between primo-vaccinations and boosters. importantly, the refractory period after immunosuppression has to be considered as well, which may be up to year depending on the type of medication (e.g., rituximab or alemtuzumab) ( ) . vaccines will have various effects on the immune system, which greatly depend on the cell types typically engaged by the respective vaccines. the impact of immunosuppression on the various cell types (and possible mitigation of effects) should be taken into consideration. protective efficacy is mostly mediated by antibodies for the following vaccines: cholera, diphtheria toxoid, hepatitis a and b, haemophilus influenzae type b, influenza, japanese encephalitis, meningococcal ps and conjugates, papillomavirus, pneumococcal ps and conjugates, polio (sabin and salk), rabies, rotavirus, rubella, tetanus toxoid, typhoid ps, and yf. effects are solely born by t cells for tuberculosis (bcg), or by a combination of antibodies and t cells for measles and intranasal influenza vaccination. besides antibody-mediated protection, effects of t cells are discussed for pertussis ( ) . for patients receiving immunosuppressive treatment, vaccination control should be performed. for diphtheria, tbe (with caution), hepatitis a, b, haemophilus influenzae type b, measles, mumps, pneumococcus, polio, rubella, tetanus, rabies and varicella, standards are available and recommended to be tested. in general, to increase the validity of vaccination control, titers should be assessed in paired samples (before and after immunization) via the same method and at highquality standards ( ) . in general, patients should have received their recommended standard vaccines according to their region-specific vaccine guidelines. before certain immunosuppressive treatments are initiated, it is mandatory to exclude former infections and if necessary, vaccination should be considered according to the regulatory agencies. table provides an overview on necessary vaccinations according to fda/ema guidelines (extended vaccination reflects the authors' suggestion). for many immunotherapies, a prior exclusion of an ongoing vzv infection is required and vaccination should be offered to those, who haven't gained any immunity yet. additionally, vzv-seropositive patients undergoing immunotherapy should be offered vaccination as well to prevent zoster reactivation and late effects. recently, a non-live subunit vaccine has been authorized for vzv-seropositive patients. it possesses a better risk-benefit profile compared to the live vaccine and has already been approved by many countries ( ) . additionally, it should be considered to offer patients with upcoming fingolimod or alemtuzumab treatment the option of vaccination against hpv, as post-market surveillance showed increased reports of warts and cervical dysplasia due to these two ms therapies [ema; ( ) ]. furthermore, pneumococcal vaccine might be considered in patients receiving b cell-depleting therapies, as severe respiratory infections during phase iii studies were seen ( , ) . vaccine hesitancy is a major problem nowadays. the usefulness of active immunization is undisputed and has saved numerous lives. however, fear of possible, but also often unconfirmed, side effects has fostered this anti-vaccine sentiment. this has led to a recent outbreak of measles ( ) and curiously some viruses and disorders, which have been assumed to be eradicated, seem to become a hot topic for western health systems again. indeed, side effects upon vaccination may occur in rare cases, however, the benefits for individual people as well as the whole population will generally outweigh adverse effects. vaccine hesitancy results in a twofold problem: ( ) the missing protection for the unvaccinated people themselves but also ( ) a risk for people, who are not able to get vaccinated. the missing herd immunity poses a major problem for a group of patients with fragile health. for ms patients receiving immunosuppressive treatment, an acute infection can have dangerous sequelae. thus, if possible, ms patients should be vaccinated beforehand. the possible benefits outweighdependent on the individual case-the possible risks. an additional perspective raises the possibility of vaccination against ms. indeed, early approaches exploring vaccination with synthetic peptides in experimental animal models were successful, but translation into clinical treatment was so far unsatisfying ( ) ( ) ( ) . interestingly, it was recently shown that an anti-typhus vaccination (typhim vaccine) might have the potential to ameliorate the disease course of ms by targeting prohibitins on th cells. tested in an experimental ms model it led to decreased levels of il and increased numbers of foxp + regulatory t cells ( ) . further investigations are needed before studies should investigate treatment options for ms patients. still, it is a good example, how immunology of vaccination might overlap with and modulate the immunology of ms. theoretically, an increased immune response against different types of vaccines, such as live attenuated viruses, inactive attenuated viruses, or portions of bacteria and viruses, could trigger increased immune response to self-antigens ( , , ) , but an increased risk for ms itself or increased relapse rates after vaccination have not been show (with exception for yf) in case-control studies ( ) . there is, however, evidence that infections can trigger relapses in ms ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , which is why vaccination of ms patients should be pursued in order to reduce the risk of infections. to assure the best vaccination success, immunization and immunosuppressive treatments have to be well timed. vaccine hesitancy: definition, scope and determinants available online at a postmodern pandora's box: anti-vaccination misinformation on the internet the "urban myth" of the association between neurological disorders and vaccinations mass vaccination against hepatitis b: the french example central nervous system demyelinating diseases and recombinant hepatitis b vaccination: a critical systematic review of scientific production vaccines and multiple sclerosis: a systematic review tetanus vaccination and risk of multiple sclerosis: a systematic review vaccine immunology in: spwopokm, editor. plotkin's vaccines vaccine adjuvants: putting innate immunity to work in vivo activation of antigen-specific cd t cells superior immunogenicity of inactivated whole virus h n influenza vaccine is primarily controlled by toll-like receptor signalling aluminum hydroxide adjuvants activate caspase- and induce il- beta and il- release immunological mechanisms of vaccination vaccine adjuvants: from to and beyond comparative safety of vaccine adjuvants: a summary of current evidence and future needs adjuvants safety project c. safety of vaccine adjuvants: focus on autoimmunity adjuvant system as containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity cell recruitment and cytokines in skin mice sensitized with the vaccine adjuvants: saponin, incomplete freund's adjuvant, and monophosphoryl lipid a human t h lymphocytes promote blood-brain barrier disruption and central nervous system inflammation cellular mechanisms of il- -induced blood-brain barrier disruption induction of lupus autoantibodies by adjuvants increased incidence and clinical picture of childhood narcolepsy following the h n pandemic vaccination campaign in finland carbohydrate-based immune adjuvants extrafollicular antibody responses control systems and decision making for antibody production rabies vaccine prepared in human cell cultures: progress and perspectives the neuro-paralytic accidents of antirabies treatment autoimmune encephalitis in humans: how closely does it reflect multiple sclerosis? an immunological relationship between the group a streptococcus and mammalian muscle spreading of t-cell autoimmunity to cryptic determinants of an autoantigen antiviral immune responses: triggers of or triggered by autoimmunity? the risk of relapses in multiple sclerosis during systemic infections relapsing encephalomyelitis following the use of influenza vaccine ocular abnormalities after influenza immunization acute transverse myelitis after influenza vaccination: magnetic resonance imaging findings optic neuritis after influenza vaccination diffuse myelitis associated with rubella vaccination diffuse myelitis associated with rubella vaccination transverse myelitis after measles, mumps, and rubella vaccine optic neuritis complicating measles, mumps, and rubella vaccination optic neuritis following measles/rubella vaccination in two -year-old children relapsing acute encephalopathy: a complication of diphtheria-tetanus-poliomyelitis immunization in a young boy multiple sclerosis and vaccination central-nervous-system demyelination after immunisation with recombinant hepatitis b vaccine encephalitis after hepatitis b vaccination: recurrent disseminated encephalitis or ms? level of evidence reviews: three years of progress vaccinations and risk of central nervous system demyelinating diseases in adults recombinant hepatitis b vaccine and the risk of multiple sclerosis: a prospective study vaccines in multiple sclerosis study g. vaccinations and the risk of relapse in multiple sclerosis. vacc multiple scler study group hepatitis b vaccination and the risk of multiple sclerosis vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases multiple sclerosis and immunological-related risk factors: results from a case-control study quadrivalent hpv vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system a multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis adverse effects of vaccines: evidence and causality yellow fever vaccination and increased relapse rate in travelers with multiple sclerosis serious adverse events associated with yellow fever vaccine epstein-barr virus, cytomegalovirus, and multiple sclerosis susceptibility: a multiethnic study a controlled trial of tick-borne encephalitis vaccination in patients with multiple sclerosis vaccines and multiple sclerosis summary of product characteristics autoimmune disorders after immunisation with influenza a/h n vaccines with and without adjuvant: eudravigilance data and literature review available online at recommended adult immunization schedule, united states ständige impfkommission: empfehlungen der ständigen impfkommission (stiko) am robert koch-institut acute disseminated encephalomyelitis: an update biphasic demyelination of the nervous system following anti-rabies vaccination acute disseminated encephalomyelitis following vaccination against human papilloma virus two cases of acute disseminated encephalomyelitis following vaccination against human papilloma virus improvement of advanced postvaccinal demyelinating encephalitis due to plasmapheresis post-vaccination mdem associated with mog antibody in a subclinical chlamydia infected boy neurologic disease associated with d- yellow fever vaccination: a report of cases longitudinal myelitis associated with yellow fever vaccination acute fulminant demyelinating disease: a descriptive study of patients acute disseminated encephalomyelitis onset: evaluation based on vaccine adverse events reporting systems vaccines and the risk of acute disseminated encephalomyelitis disease-modifying therapies and infectious risks in multiple sclerosis idsa clinical practice guideline for vaccination of the immunocompromised host general best practice guidelines for immunization vaccination in immunocompromised host: recommendations of italian primary immunodeficiency network centers (ipinet) vaccination against infection in patients with multiple sclerosis tickborne encephalitis (tbe) vaccine to medically immunosuppressed patients with rheumatoid arthritis: a prospective, open-label, multi-centre study live zoster vaccination in an immunocompromised patient leading to death secondary to disseminated varicella zoster virus infection understanding the immunology of shingrix, a recombinant glycoprotein e adjuvanted herpes zoster vaccine warts and all: fingolimod and unusual hpv-associated lesions alemtuzumab versus interferon beta a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase trial ocrelizumab versus interferon beta- a in relapsing multiple sclerosis vaccination against experimental allergic encephalomyelitis with t cell receptor peptides the ups and downs of multiple sclerosis therapeutics antigen-specific tolerization approaches in multiple sclerosis targeting prohibitins at the cell surface prevents th -mediated autoimmunity immunization in patients with multiple sclerosis chlamydia pneumoniae infection of the central nervous system in multiple sclerosis epstein-barr virus and multiple sclerosis coronaviruses in brain tissue from patients with multiple sclerosis active human herpesvirus infection in patients with multiple sclerosis cerebrospinal fluid molecular demonstration of chlamydia pneumoniae dna is associated to clinical and brain magnetic resonance imaging activity in a subset of patients with relapsing-remitting multiple sclerosis multiple sclerosis, sporadic creutzfeldt-jakob disease and bovine spongiform encephalopathy: are they autoimmune diseases evoked by acinetobacter microbes showing molecular mimicry to brain antigens? the case for rhinoviruses in the pathogenesis of multiple sclerosis epstein-barr virus infection and multiple sclerosis: a review all authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © zrzavy, kollaritsch, rommer, boxberger, loebermann, wimmer, winkelmann and zettl. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -oy hsrpt authors: beutels, philippe p.a. title: economic aspects of vaccines and vaccination: a global perspective date: journal: the grand challenge for the future doi: . / - - - _ sha: doc_id: cord_uid: oy hsrpt nan a basic principle of economic decision-making is that in an environment of scarce resources choices have to be made in the allocation of these resources. this principle also applies to the provision of health care. the share of health-care expenditures in the gross domestic product (gdp) of most industrialised countries has increased from %- % in the early sixties to %- % in (from % to % in the usa) [ ] this rise has been attributed to medical advances (increasing the number and technological complexity of medical interventions), population aging, sociological changes (more, but smaller families and less familial support for the elderly) and insufficient productivity increases in the services sector. in less wealthy economies, medical decision-makers are faced with a smaller margin, and such a rise in health-care spending has not been observed yet. basically, the richer a country, the more it can afford (in nominal and in relative terms) to spend on health care. the two-way interaction between health and economic development is generally explained as follows. the healthier the population, the more adults can contribute to society by productive activity (i.e., work creating a surplus value in terms of capital gains and human resources), as well as by raising children in a stable environment, thus ensuring continued economic development. the process of economic development itself creates conditions (education, employment, infrastructure (including safe water and sanitation)), which provide a basis for continued improvement in longevity and health-related quality of life [ ] . individual good health can be seen as the product of some unknown complex function to which health care is only one of the inputs. other important inputs are: life-style variables (eating habits, smoking, etc.), environmental factors (urbanisation, climatic conditions, etc.), income, education and genetic predestination. furthermore, expenditures on health are not necessarily put to use in the most efficient economic aspects of vaccines and vaccination: a global perspective way. in this respect a distinction can be made between technical efficiency (providing maximal health care for a given cost, or delivering a certain service at minimal cost) and allocative efficiency (the distribution of resources across alternative services so as to maximise health gains, in accordance with preferences). finally, though much may be spent on health care, not all people may have equal access to health care of the same quality. indeed inequities in the consumption of health care may also interfere with the overall allocative efficiency of the system, and create inequities in health per se. therefore greater expenditures on health care are no guarantee for more global health. it should be noted that these observations do not plead for a reduction or containment of health-care budgets, but rather for a way of spending that ensures that societal goals are met. in order to achieve this, welfare economists focus research on two broad topics: efficiency and equity. efficiency relates to choosing options that maximise utility from marginal expenditures (i.e., by optimising the production process of health, for which health care is one of the inputs). equity relates to the fair distribution of all aspects related to health across members in society (e.g., equal access to care). clearly, there may exist a trade-off between efficiency and equity and giving priority to either of them is a normative issue that should be decided by social and political debate. vaccination is undoubtedly one of the major contributors to health improvements in the last three centuries. during this period, the impact of vaccination on longevity is undeniable, despite the fact that its partial contribution is difficult to distinguish from that of improved hygienic conditions and nutrition, and the discovery of penicillin [ , ] . all of these combined provided the basis for the so-called "epidemiological transition" in industrialised countries. at the same time, infectious diseases remain the main cause of death in many developing countries. despite the continuing expansion of the vaccine portfolio, implementing financially sustainable basic vaccination programs in poor countries remains problematic. though this is not so much an economic as a financial aspect, we will return to this issue in the section "financing vaccines". a number of peculiar characteristics set vaccination apart from other interventions in health care [ ] : ( ) since vaccination is (usually) a form of primary prevention, it intervenes in people (often children) who are generally in good health. but unlike most other prevention programs, the interven-tion itself can cause harm to the vaccine recipient, because in rare cases vaccine-associated adverse events (vaae) occur. this means that people make trade-offs between risks of vaccine-preventable disease and risks of vaae. the perception of these risks is quintessential to the individual demand for vaccines (if left to free-market mechanisms), and dominates the influence of other factors such as price [ ] . ( ) vaccination not only protects vaccine recipients, but it also reduces exposure of unvaccinated people, due to the reduced circulation of the infectious agent (if the transmission of infection occurs from human to human). this is not always beneficial for public health as the reduced risk of transmission leads to an increased average age at infection (with many "childhood" infections being more severe if contracted in adulthood) [ , ] . together with the first characteristic, this means that people generally have an interest in having everyone else vaccinated, but not themselves (or their children). ( ) a number of infections can be eradicated in the long run if vaccination efforts are sustained at sufficiently high coverage levels around the world. in other words, sometimes vaccination has the potential of making itself redundant. choices about eradication are closely linked to the welfare of future generations and societal time preference (see also below) [ , ] . since the perceptions outlined above are usually distorted by insufficient or biased information, government intervention (in the form of subsidies, or coercion) is desirable to ensure that vaccine uptake remains optimal. indeed, as uptake increases the risk of vaae remains constant, but individuals may perceive it to increase. at the same time the absence of vaccine-preventable disease may create a false sense of security, and lure people into believing that their risk of disease has reduced to zero as well, while this is highly dependent on historical and future rates of exposure and vaccination in the rest of the population. the vaccine market represents only . % of the global pharmaceutical market, but has high growth potential (estimated at - % per year by various sources, mainly due to new combination, new prophylactic and new therapeutic vaccines) [ ] . for a manufacturer, the contribution margins of vaccines are low compared to those of other products in both the developing and industrialised world (due to price and licensing regulations). the few suppliers of vaccines now aim to limit production to the projected global needs in any given year (unicef bought about % of "traditional" vaccine supply in , compared to about % in ). thus the market is very vulnerable to capacity problems: a problem with a single batch of vaccines by a single producer can have severe knock-on effects across the globe. this may also explain why, for some of the old vaccines, the price fluctuates, and has had the tendency to rise over the last years. close co-operation between demanders (governments or agencies) and suppliers is essential to ensure continued availability at the right time. vaccines are supplied under a tiered price system, with % of sales volume in developing countries and countries in transition, but % of sales revenue in industrialised countries [ ] . it is therefore not surprising that global vaccine manufacturers (with three big producers (glaxosmithkline, aventis and merck) occupying % of the global market) tend to focus on products for the industrialised world. it is to be expected that more combination vaccines will become available and existing combinations extended. examples of this include the hexavalent diphteria-tetanus-pertussis-inactivated polio virus -haemophilus influenza type b -hepatitis b (dtp-ipv-hib-hepb) vaccine, and the quadrivalent measles-mumps-rubella-varicella-zoster (mmrvz) vaccine. the research and development costs for these vaccines are high due to technical and regulatory complexity. the technicality, the multiple patents and requirements in terms of clinical trials (all demanding great time and money investments) increase barriers to enter the vaccine market. this may lead to more monopolistic behaviour, with risks to supply, choice and price. clearly, the benefits of combination vaccines are many. for instance, reductions in the number of injections and associated administration costs (including reduced money, time and pain costs for children and their parents), and reduced transmission by contaminated needles benefit recipients and the public health bodies. free-rider effects (important and not-soimportant vaccines can hook up with established vaccines, irrespective of how recipients perceive their importance) and economies of scope benefit manufacturers and perhaps public health bodies. these benefits will have to be traded off versus the higher price of combination vaccines. because governments, health insurers or agencies (unicef, paho) typically buy vaccines directly from producers, there is also little diversity on the demand side of the market. all of this implies that there is little competition on both sides of the market and that global societal goals (development and supply of affordable vaccines for poor countries as well as rich countries) are unlikely to be met by relying entirely on free-market mechanisms (particularly since these are hampered by (necessary) regulation with regards to quality control and licensing). by using economic evaluation we are essentially trying to answer the following questions [ ] : ) is the vaccination program under study worth doing compared to alternative ways of using the same resources? in other words: should the (health care) resources be spent on such a vaccination program, and not on something else? ) more specifically, if we are deciding to vaccinate against a particular disease, whom should we vaccinate, at which age, with which vaccine and how should the vaccine be delivered and administered in order to deploy our scarce resources in the most efficient way? most economic evaluations of vaccination are model-based, because the alternative, empirical analysis, is usually impractical, very time-consuming (for most vaccines it takes decades for the full effects to unfold), very expensive and potentially unethical. a complete economic evaluation should compare different options for an intervention, in terms of economic costs as well as health consequences. there may be several options to prevent an infectious disease, some of which are mutually exclusive, while others are complementary. the relevant costs and benefits need to be collected for each option, and calculated relative (incremental) to another option. the choice of the reference strategy against which the other options are evaluated can be highly influential for the results of the evaluation. unless it is a cost-ineffective strategy, current practice is the preferred strategy of reference. when a new vaccine is introduced, the reference strategy is often referred to as "doing nothing" (no vaccination), although in this case "doing nothing" usually means the treatment of cases as they arise, with the corresponding public health measures. a generalised distinction between the costs and benefits of vaccination is presented in table . the intervention costs dominate the cost side. these are the costs necessary to implement the vaccination program. additionally there are costs incurred to receive the vaccine. the benefits of vaccination are the gains in health and the avoided costs. direct costs can be avoided because less treatment is needed for curing or nursing the disease against which the vaccination program is aimed. additionally indirect costs can be avoided because vaccination may partly prevent people having to interrupt their normal activities in society because of their illness or the illness of their relatives. from the health-care payer's point of view, only direct medical costs need to be taken into account. however, from society's viewpoint, indirect non-medical costs are also relevant. other viewpoints can be those of patients, hospitals, travel clinics, insurance companies, employers, etc. (see fig. ). for each of these perspectives different costs and benefits may be relevant. this implies that it is possible for an intervention to be relatively cost-effective for one party involved, while it is not for another. different cost categories are listed in table . the listings in italics are often not taken into account, because they can be relatively small in comparison to the other costs and/or because they are difficult to estimate. sometimes their inclusion is not relevant to express the viewpoint of the analysis. however, if they are relevant for the viewpoint of the analysis, their impact on the results could be tested in a sensitivity analysis and their existence should be mentioned when the results are presented. some diseases affect expectations and behaviour beyond one degree of separation from the pathogen. for instance the global impact of the sars outbreak in was modest in disease burden ( probable cases, deaths) and associated health-care costs, but it had an impressive impact on the global economy (us$ - bn, or $ - m per case) in macro-economic terms (when the impact on consumption and investments are considered) [ , ] . a similar situation could arise for pandemic influenza, or any other disease that affects risk perceptions of consumers and investors (e.g., variant creutzfeld jacobs disease). however, for most currently vaccine-preventable diseases, micro-economic evaluation would provide an appropriate analytical framework, preferably adopting a societal perspective. in reality, decisions about universal vaccination are often taken from the perspective of the national health service (nhs) or the ministry of health and at best from the health-care payer's perspective (which in addition to the nhs costs also includes direct co-insurance and co-payments by the patient). indeed, decision-makers in health care tend to focus primarily on direct costs since these are most indicative of their immediate budgets, even if their decision has bearings on society at large. when it comes to estimating unit costs or prices, it should be noted that costs in an economic sense are opportunity costs: they represent a sacrifice of the next best alternative application [ ] . this entails that costs in an eco- philippe p.a. beutels health gains (physical and psychological) source: [ ] nomic sense are not necessarily the same as financial expenditures, and that they can also represent goods and services that are not expressed in monetary terms. however, market prices are often used as a proxy. if particular goods and services are not traded on a market, ("shadow -") prices of a similar activity can be used instead. for example, work of volunteers can be approximated by wages of unskilled labour. similarly, patients' leisure time could be based on average earnings or average overtime earnings. average costs per unit of output are the total costs of producing a quantity divided by that quantity. marginal costs constitute the additional costs of producing one additional unit of output. since decisions are made at the margin, marginal costs should be used where they are substantially different from average costs [ ] . for vaccination, this distinction is most relevant for estimating the costs of the program [ ] . the costs of adding a particular vaccine to the existing program depends on how well the schedule of the new vaccine fits in with the other schedules, whether specific precautions need to be taken, whether potential vaccinees need to be screened prior to vaccination or whether a specific target group is envisaged. the costs that are most heavily affected by adding a new vaccine to the existing program are the variable costs of the program (time spent per vaccinee, number of vaccines bought, etc.), whereas the influence on the fixed intervention costs (buildings, general equipment, etc.) is usually small (unless a new vaccine requires a substantially different infrastructure in terms of storage and transport). a good example of this is provided by hall et al. who examined the immunisation program in the gambia (more recently these results were confirmed by a similar analysis in addis ababa, ethiopia) [ , ] . they found that the additional costs of adding hepatitis b vaccine to the existing expanded program on immunisation (epi) vaccines (measles, polio, dtp and bacille calmette-guérin (bcg)), would be for % recurrent costs (of which % for purchasing hepatitis b vaccine (hepb)). still, the introduction of a new expensive vaccine could more than double the costs of the program in some countries because of its sheer price compared to other vaccines in the program. the main objective of vaccination is to prevent disease. the most important benefits from a public health point of view are therefore the health gains (see tab. ). these are both physical (avoiding illness, suffering, mortality, etc.), and psychological (avoiding distress, anxiety, etc.). specific vaccinerelated psychological health gains include the general feeling of well-being and security of vaccine recipients from knowing that they are protected against disease. this could evidently lead to behavioural changes (e.g., a vaccine against hiv/aids could have a large influence upon the sexual behaviour of vaccine recipients). the valuation of health outcomes has far-reaching consequences for the methodology and study design of applied analyses. generally, a distinction is made between four different methods, depending on the way in which health gains are measured [ ] . a cost-minimisation analysis compares the costs of equally effective alternatives, without quantifying the health gains. it differs from a pure cost philippe p.a. beutels source: [ ] analysis in that there is always more than one option analysed and that the effectiveness of the different alternatives is known to be equal. in a cost-effectiveness analysis, health gains are measured in one-dimensional natural units (e.g., infections prevented, hospitalisations prevented, deaths averted, life-years gained…), implying that only one aspect of effectiveness is considered (e.g., postponing the time of death) and other related aspects are not (e.g., the quality of life). the results of cost-effectiveness analyses (cea) are usually presented as a ratio. a cost-effectiveness ratio (cer) is a measure of the incremental costs, which are necessary to obtain one unit of a health gain by implementing a strategy j instead of a strategy i (expressed in incremental costs per life-year gained, incremental costs per infection prevented, etc.). the lower the ratio, the more efficiently strategy j gains health compared to strategy i. the units in which health gains are expressed should represent the final results or clinical endpoints of an intervention as adequately as possible, in order to enable comparison between different interventions [ ] . if, hypothetically, the cost-effectiveness of hepatitis b vaccination were $ per infection prevented, whereas hib vaccination is estimated at $ , per infection prevented, it is wrong to conclude that hepatitis b vaccination is more cost-effective (because it is less costly to prevent one infection). to make that judgement, the avoided effects would need to be expressed in a more comparable endpoint, like life-years saved. to make the comparison even more relevant, different health states should be weighed by their quality (scaled from (meaning death) to (meaning perfect health)). this approach is used in cost-utility analysis (cua), where health gains are measured in quality-adjusted life-years (qalys) saved or another combined measure of morbidity and mortality (e.g., disability-adjusted life-years (daly)). a cost-utility ratio (cur) is similar to a cer, except that the denominator contains the difference in qalys (or dalys), instead of the difference in natural units, such as cases avoided or life-years gained. the main advantage of cua over cea is that it allows comparison of very different health-care interventions, for instance, those that predominantly extend lives (e.g., flu vaccination of the elderly) with those that improve the quality of life (e.g., drugs against erectile dysfunction). in cost-benefit analysis (cba), the health gains are converted into monetary units, which, in theory, allows the many dimensions that are associated with an improvement in health status (over and above the length and health-related quality of life) to be included. there are benefits beyond the health outcomes such as information, caring, regret, anxiety reduction, communication and process utility (benefits from health-care use). further-more, option value (i.e., benefits derived from needing care in the future) and non-use value (i.e., externalities related to caring for the health of others) can also be (potentially) elicited [ ] . the results of a cba can be presented as the difference between costs and benefits (the net costs (or net savings)) or as a ratio. the benefit-cost ratio (bcr) expresses to which extent an investment in an intervention can be recovered by the consequences of that intervention (expressed as a unitless number or a %). cost-benefit analysis allows for comparisons between totally different projects in society (e.g., comparing a vaccination campaign with the construction of a new bridge). when budgets are very limited and many urgent interventions compete, as in developing countries, such cross-sector comparisons may actually be used in practice. clearly, the potential of cba to make such comparisons possible is a major advantage to aid decision-making. the strength of cba in theory, i.e., the explicit monetary valuation of health gains, has up till now been also its weakness in practical decisionmaking. in theory it seems preferable that the valuation of health gains (and of life) is done in an explicit, transparent and representative way as in cba, instead of the implicit, inconsistent and arbitrary way it is often done in today's decision-making. however, in a health-care environment the monetary valuation of health (and particularly of life) is often rejected on an emotional basis [ ] . additionally, economists have few credible arguments to counter these objections, as the current methods which place a monetary value on health (human-capital and willingness-to-pay methods) can hardly be called consistent and reliable in practice [ ] [ ] [ ] . in view of this, most economic evaluations in health care are based on cea or cua. the literature on these has increased exponentially since the s, for vaccines at least as much as for other interventions in health care, underlining the importance of a sound theoretical framework for these analyses [ ] . individuals (and societies), in general, prefer to receive benefits as early as possible and incur costs as late as possible. this so-called time preference means that the same amount of wealth or health would have a different value to a decision-maker in the present, if this amount is gained at different points in time. note that time preference has nothing to do with inflation. a vaccination program is an investment made in the present (i.e., the costs of buying and administering vaccines) to gain benefits spread out over the future (i.e., avoided costs of treatment, avoided morbidity and mortali-ty). discounting is a technique by which future events (e.g., costs and health outcomes) are valued less the further in the future they arise. the degree to which they are valued less is determined by the discount rate (frequently assumed to be constant through time): the higher the rate the less future benefits and costs are valued. although there is general agreement on the discounting of costs, the arguments for discounting non-monetised health outcomes are contradictory [ ] . discounting costs without discounting benefits leads, amongst others, to the paradoxical situation that any eradication program will yield infinite benefits [ ] . this would imply that all current resources should be spent on research of eradicable diseases, and the implementation of eradication programs, and not a single penny on cure. such paradoxes, and the observation that individuals generally have a positive discount rate for health, clearly indicates that health too should be discounted at a positive rate. but there is no general agreement on how the discount rate for health should compare to that of wealth. there are arguments to apply an equal discount rate to both costs and health effects [ , ] . the underpinnings and relevance of these are questionable, so that a lower discount rate for health effects than for costs has also been proposed [ , ] . because of the very long time spans over which benefits accrue, the analysis of most vaccination programs is very sensitive to discounting (of costs as well as health effects). nonetheless, this is no cause for a different approach to discounting for vaccination. still, further empirical research is needed to strengthen or to change the basis for conventional discount rates (mostly %, or %) and discount models (mostly stationary) [ ] . a slight decrease in discount rate (from, say, % to %) could change the cost-effectiveness of some vaccination programs from unattractive to attractive. also, it is likely that time preference in developing countries is substantially different (i.e., higher) from that in industrialised countries, particularly for those countries that have decreasing health (e.g., life-expectancy due to hiv/aids) or wealth (e.g., real gdp) expectations [ ] . in theory, decisions are made by interpreting the results of economic evaluation as follows. in figure a new program is plotted in terms of costs and effectiveness versus the reference strategy in the origin. if the new program is less costly and more effective than the reference, then the new program (a "dominant" strategy) should be implemented. likewise, if the new program is more costly and less effective than the reference, it should be rejected. in the other quadrants the decision is more complex, because it depends on a value judgement. if the incremental cer (or cur) is smaller than a given willingness to pay (or threshold cost-effectiveness criterion), "k", it would be acceptable. the question then is, how to determine k? this could be determined by social debate or by comparing it to what is widely accept-ed in practice. the most widely cited k in industrialised countries is $ , per qaly gained. there may also be a grey zone for k in which some interventions are implemented and others are not (e.g., between $ , per qaly gained and $ , per qaly gained), whereas under and above that grey zone all and none of the interventions are implemented, respectively. however, the greater the analytical uncertainty and the burden of disease, the more decisions are likely to deviate from such clear cut-off practices [ ] . different societies should have a different willingness to pay, though there are few instances in which societies (or their decision-makers) have tried to determine what the appropriate value of k is. the world bank has suggested using gnp per capita as a benchmark for k. note that in cba, k has already been given an explicit value. in league tables, many vaccination programs rank with the most costeffective interventions in health care in industrialised countries [ , [ ] [ ] [ ] . it is tempting to try and estimate the global historical value of vaccination. however, due to scarcity of data in most parts of the world such an exercise philippe p.a. beutels figure . the cost-effectiveness plane. cer: cost-effectiveness ratio, i.e., incremental costs divided by incremental effects; k = willingness to pay, or a cost-effectiveness ratio of acceptable magnitude. all points on a line in this plane have identical cost-effectiveness ratios. would be, by necessity, extremely crude. it seems clear, though, that the smallpox eradication program and the establishment of the epi have generated enormous benefits, not only by directly protecting against important vaccine-preventable diseases, but also by providing opportunities for health education and infrastructure in developing countries [ ] . yet the associated disease reduction in smallpox, measles and tetanus alone is bound to have been a cost-saving enterprise around the world (i.e., in the lower right quadrant of fig. ) , currently averting over million deaths per annum, compared to a "never having vaccinations" situation. however, when we are making choices today, we have to consider what additional benefits we will achieve by making additional investments, and this is bound to vary between countries at different stages of economic development, different epidemiologies of disease, and different historical vaccine-uptake levels. hence data from one country cannot always be simply extrapolated to another. in practice, there are many factors that come into play when decisions are made about new health-care interventions (see fig. ). in a democracy, a decision-maker receives a temporary, renewable mandate from the public to allocate a given budget. that person is well aware of the public perceptions of public health problems, and the impact of decisions thereon. at the same time, pressure groups may try to influence decision-makers or the public's perception. these pressure groups have vested interests in the decisions (be it as sellers of vaccines, or sellers of services for the cure of vaccine-preventable diseases). societal goals with regards to the decision can only be met by considering its medical, social, ethical and cost implications. the theoretical foundation of economic evaluation (so-called "pareto opti- figure . factors influencing decision-making in practice mality") addresses efficiency, without concern for distributional aspects (equity). therefore, economic evaluation combines the medical/epidemiological and cost implications, but does not consider the social and ethical implications depicted in figure (though in cba these aspects could theoretically be included, if a willingness-to-pay approach is used, and it is possible to weight quality-of-life gains to help achieve equity goals, as is commonly performed in dalys). therefore economic evaluation should be seen as an additional type of analysis that cannot stand on its own in its current form (it is an aid to decision-making, not a decision-maker in itself). at the same time, ideally, the influence of pressure groups, and the public's perceptions (rather than the public's true preferences) should be minimised in this process. it is noteworthy that most vaccination programs are likely to be equitable according to prevailing theories of justice [ ] . indeed, an analysis for bangladesh indicated that socio-economic inequalities in mortality of under- -year-olds were eliminated by measles vaccination [ ] . in the past, vaccination interests of poor and wealthy nations seemed more in tune than today. moreover, the research and development costs of the new generation of vaccines, based on biotechnology, are greater and the regulatory hurdles higher, meaning that new vaccines are much more expensive than the basic package of "traditional" vaccines. the first new expensive vaccine for global use was the hepatitis b vaccine, which became available in . the main reason why it was not immediately included in universal vaccination programs was its price, because initially the hepatitis b vaccine cost more than the other six epi vaccines put together. with the advent of more expensive vaccines, the introduction of a new vaccine is not as straightforward as it used to be in the industrialised world. in contrast to some of the "older" vaccines (e.g., measles, pertussis), newer vaccines may not result in net savings to the health-care system. nonetheless, if considered desirable, industrialised countries have no difficulty in financing the introduction of new vaccines, and ensuring the continuing uptake of old ones. for developing countries, the main difficulty is not so much to determine whether it would be cost-effective to introduce a vaccine, but to ensure that the introduction is financially sustainable. when external donors sponsor vaccination programs the sustainability takes the form of a partnership with shared responsibility and the promise by the receiver of the financing to create the conditions to become self-sufficient in the long run, either alone or by attracting further external funding. global immunisation efforts came under pressure as the epi, which was launched in the s as a way of building on the success of the smallpox eradication program, lost its momentum in the s, and failed to attain the year goal of % global vaccination coverage. indeed, global child-hood immunisation coverage against the six main target diseases (polio, dtp, measles and tuberculosis), which was less than % in , decreased from about % in to % in [ ] . coverage for the complete schedule of dtp remains well below % in tens of developing countries, mostly in sub-saharan africa. these countries are traditionally bottlenecks in the epi because of great financial constraints, the evolution of the hiv epidemic, logistical difficulties, poor governance and general socio-economic conditions (sometimes aggravated by war). as these factors evolved unfavourably in the s, international alliances shifted their efforts from reducing general global inequalities in health ("health for all") to more selective strategies, like the polio eradication program and the introduction of new and improved vaccines. the discrepancy between the developing and the industrialised world is likely to become greater, as private vaccine development focuses primarily on diseases that affect the wealthy. indeed, only about % of world drug sales is for african countries. it has been estimated that of all expenditures on health research (over $ billion per year), % is for diseases that affect % of the world's population [ ] . using recent examples, kaddar et al. assert that financing vaccination should be affordable by all countries, at least for the basic vaccines [ ] . the cost of fully immunizing a child with the basic vaccines is $ to $ , which typically represents % to % of public health expenditures, <$ . per capita or about . % of gdp. most vaccination costs are fixed costs of personnel and infrastructure, and the marginal costs of an additional vaccine may often be bearable for the domestic budget (though still highly dependent on vaccine price). as the th century drew to a close, the landscape of external vaccine financing underwent dramatic changes with the inception of the global alliance for vaccines and immunization (gavi) and the vaccine fund, with the aims to stimulate research and development for developing world problems, strengthen immunization systems, and promote and support the introduction of new and underused vaccines. gavi is an alliance of financiers (development banks, aid agencies, foundations), agencies (unicef, who), vaccine developers and manufacturers, as well as developing country governments, whereas the vaccine fund manages private financial resources, such as those from the bill &melinda gates foundation, and public contributions from a small number of wealthy countries. the first generation of vaccines, such as measles and oral polio vaccines, was used against common and serious childhood diseases afflicting all countries in the world. few of these vaccination programs were subject to economic analysis before introduction, and for good reason: the benefits were obvious and the costs low. indeed, they were probably amongst the most effective and cost-effective public health programs of the th century. this is no longer necessarily the case with new vaccine introductions. new vaccines are generally higher priced and unlikely to fall in price to the level of the first generation of vaccines. furthermore, they are often aimed at less common or less serious diseases (particularly in the industrialised world). thus, whether these vaccines are worth introducing is less clear. vaccine financing has recently changed with important initiatives stimulating development and use of vaccines for the developing world. these are to be welcomed as they may further alleviate the disease burden in developing countries at affordable cost, correct market imperfections with regard to research and development, and reduce inequalities in health. nonetheless, the introduction of new vaccines demands cautious planning. if it comes at the expense of the uptake of the first generation of vaccines, it may have a detrimental influence on the effectiveness and cost-effectiveness of the whole program. in view of all these developments, the role of economic evaluation in vaccine program design is only likely to increase in the future. world development indicators, online publication available on cd rom commission on macroeconomics and health: investing in health for economic development the conquest of smallpox an interpretation of the modern rise of population in europe economic evaluation of vaccination programmes in humans: a methodological exploration with applications to hepatitis b, varicella-zoster, measles, pertussis, hepatitis a and pneumococcal vaccination economic epidemiology and infectious disease infectious diseases of humans -dynamics and control increase in congenital rubella occurrence after immunisation in greece: retrospective survey and systematic review economics of eradication vs control of infectious diseases lecture at the advanced course in vaccinology, international vaccine institute assessing the economic impact of communicable disease outbreaks: the case of sars globalization and disease: the case of sars methods for the economic evaluation of health care programmes the cost of integrating hepatitis b virus vaccine into national immunization programmes: a case study from addis ababa cost-effectiveness of hepatitis b vaccine in the gambia providing health care. the economics of alternative systems of finance and delivery methodological issues and new developments in the economic evaluation of vaccines the economics of health and medicine estimating costs in costeffectiveness analysis evaluation of life and limb: a theoretical approach theory versus practice: a review of "willingness to pay" in health and health care discounting of life saving and other non-monetary effects foundations of cost-effectiveness analysis for health and medical practices discounting costs and effects: a reconsideration discounting for health effects in cost-benefit and cost-effectiveness analysis does nice have a cost-effectiveness threshold and what other factors influence its decisions? a binary choice analysis cost-effectiveness analysis and the consistency of decision making: evidence from pharmaceutical reimbursement in australia a comprehensive league table of cost-utility ratios and a sub-table of "panel-worthy" studies fivehundred life-saving interventions and their cost-effectiveness the societal value of vaccination in developing countries measles vaccination improves the equity of health outcomes: evidence from bangladesh the state of the world's children. early childhood the / gap report financial challenges of immunization: a look at gavi the author is grateful to dr john edmunds (health protection agency, uk) for constructive comments on an earlier version, and to the flemish fund for scientific research (fwo g. . ) and the european union funded project polymod (eu fp ) for financial support. key: cord- - zz x li authors: day, m. j.; horzinek, m. c.; schultz, r. d. title: compiled by the vaccination guidelines group (vgg) of the world small animal veterinary association (wsava) date: - - journal: j small anim pract doi: . /j. - . . .x sha: doc_id: cord_uid: zz x li nan one of the greatest successes of modern veterinary science has been the control of infectious disease through the development and implementation of vaccination programmes. this success is typified by the rapid decline in the prevalence of key canine infectious diseases (caused by canine distemper virus [cdv] , canine adenovirus [cav] and canine parvovirus [cpv] ) following the introduction of efficacious modified live virus vaccines. similar effects relate to the introduction of feline vaccines, with clear reduction in mortality caused by feline parvovirus (fpv; feline panleukopenia) and morbidity caused by feline calicivirus (fcv) and herpesvirus (fhv) infections. however, the success of these vaccines cannot be a cause for complacency, and indeed vaccine-related issues have featured high on the agenda of the veterinary profession over the past decade. there are many challenges remaining in small animal vaccinology, and in the wsava vaccination guidelines group (vgg) was convened with the specific remit of taking a global perspective on issues surrounding the practice of vaccination of dogs and cats. the vgg has met formally on three occasions and corresponded electronically between these meetings, and this document is the result of these deliberations. the vgg guidelines are built on those developed by the american animal hospital association (aaha) canine vaccine task force and the american association of feline practitioners (aafp) feline vaccine advisory panel. based upon a consensus among experts, these recommendations reflect a combination of opinion, experience, and scientific data, published and unpublished. the present vaccination guidelines are intended for the general veterinary practice and the shelter environment; they do not represent a standard of care or set of legal parameters. they have been drafted with the objective of educating and informing the profession and to recommend rational vaccine use for individual pets and dog/cat populations. if vaccination has been so successful, then why is it necessary to continually re-evaluate vaccination practice? there is little doubt that in most developed countries the major infectious diseases of dogs and cats are considered at best uncommon in the pet population, but there do remain geographical pockets of infection and sporadic outbreaks of disease occur, and the situation regarding feral or shelter populations is distinctly different to that in owned pet animals. however, in many developing countries these key infectious diseases remain as common as they once were in developed nations and a major cause of mortality in small animals. although it is difficult to obtain accurate figures, even in developed countries it is estimated that only - % of the pet animal population is vaccinated, and this is significantly less in developing nations. in small animal medicine, we have been slow to grasp the concept of 'herd immunity'that vaccination of individual pet animals is important, not only to protect the individual, but to reduce the number of susceptible animals in the regional population, and thus the prevalence of disease. a second major concept regarding vaccination of dogs and cats has been the recognition that we should aim to reduce the 'vaccine load' on individual animals in order to minimise the potential for adverse reactions to vaccine products. for that reason we have seen the development of vaccination guidelines based on a rational analysis of the vaccine requirements for each pet, and the proposal that vaccines be considered 'core' and 'non-core' in nature. to an extent this categorisation of products has been based on available scientific evidence and personal experience -but concerted effort to introduce effective companion animal disease surveillance on a global scale would provide a more definitive basis on which to recommend vaccine usage. in parallel with the categorisation of vaccines has been the push towards marketing products with extended duration of immunity (doi), to reduce the unnecessary administration of vaccines and thereby further improve vaccine safety. both of these changes have necessitated a frame-shift in the mindset of veterinary practitioners in a culture in which both veterinarian and client have become subservient to the mantra of annual vaccination. the following vgg guidelines are prepared when considering the optimum model of a committed pet owner, willing and able to bring their animal to the veterinarian, for the full recommended course of vaccination. the vgg is aware that there are less committed pet owners and countries where severe financial constraints will determine the nature of the vaccine course that will be administered. in situations where, for example, a decision must be made that an individual pet may have to receive only a single core vaccination during its lifetime, the vgg would emphasise that this should optimally be given at a time when that animal is most capable of responding immunologically, i.e. at the age of weeks or greater. the vgg has additionally considered vaccination in the shelter situation. the guidelines that we have proposed are those that we consider provides the optimum level of protection for these highly susceptible animals. the vgg also recognises that many shelters run with limited financial support which may constrain the extent of vaccination used. the minimum vaccination protocol in this situation would be a single administration of core vaccines at or before the time of admission to the shelter. this document seeks to address these current issues in canine and feline vaccinology, and to suggest practical measures by which the veterinary profession may move towards more rational use of vaccination in these species. the most important message of the vgg is therefore encapsulated in the single strap-line: we should aim to vaccinate every animal, and to vaccinate each individual less frequently the basic immunisation schedule guidelines and recommendations for core (recommended), non-core (optional), and not recommended vaccines for the general veterinary practice are given in table . the vgg considers that a core vaccine is one that all puppies throughout the world must receive in order to provide protection against infectious diseases of global significance. the vgg recognises that particular countries will identify additional vaccines that they consider core. a particular example of a vaccine that may be considered core in only some countries is that against rabies virus. in a geographical area in which this infection is endemic all dogs should be routinely vaccinated for the protection of both the pet and human populations. in some countries, mandatory rabies vaccination is a legal requirement, and is generally also required for international pet travel. non-core vaccines are those that are licensed for the dog and whose use is determined on the basis of the animal's geographical and lifestyle exposure and an assessment of risk-benefit ratios. not recommended vaccines are those for which there is little scientific justification for their use. pup vaccination and the month booster most pups are protected by maternally derived antibodies (mda) in the first weeks of life. in general, passive immunity will have waned by to weeks of age to a level that allows active immunisation. pups with poor mda may be vulnerable (and capable of responding to vaccination) at an earlier age, while others may possess mda at such high titres that they are incapable of responding to vaccination until $ weeks of age. no single primary vaccination policy will therefore cover all possible situations. the recommendation of the vgg is for initial vaccination at to weeks of age followed by a second vaccination to weeks later, and a third vaccination given between to weeks of age. by contrast, at present many vaccine data sheets recommend an initial course of two injections. some products are also licensed with a ' week finish' designed such that the second of two vaccinations is given at weeks of age. the rationale behind this protocol is to permit 'early socialisation' of pups. the vgg recognises that this is of great benefit to the behavioural development of dogs. where such protocols are adopted, great caution should still be maintained by the owner -allowing restricted exposure of the pup to controlled areas and only to other pups that are healthy and fully vaccinated. in immunological terms, the repeated injections given to pups in their first year of life do not constitute boosters. they are rather attempts to induce a primary immune response by injecting the attenuated virus (of modified live virus [mlv] vaccines) into an animal devoid of neutralising antibody, where it must multiply to be processed by an antigen presenting cell and stimulate antigenspecific t and b lymphocytes. in the case of killed (inactivated) vaccines, mda may also interfere with this immunological process by binding to and 'masking' the relevant antigens. all dogs should receive a first booster months after completion of the primary vaccination course. the vgg redefines the basic immunisation protocol as the ensemble of the pup regime plus this first booster. the month booster will also ensure immunity for dogs that may not have adequately responded to the pup vaccination course. dogs that have responded to vaccination with mlv core vaccines maintain a solid immunity (immunological memory) for many years in the absence of any repeat vaccination. following the month booster, subsequent revaccinations are given at intervals of three years or longer, unless special conditions apply. it should be emphasised that the considerations given above do not generally apply to killed core vaccines nor to the optional vaccines, and particularly not to vaccines containing bacterial antigens. thus leptospira, bordetella and borrelia (lyme disease) products require more frequent boosters for reliable protection. serological testing to monitor immunity to canine vaccines antibody tests are useful for monitoring immunity to cdv, canine parvovirus- (cpv- ), canine adenovirus- (cav- ), and rabies virus. antibody assays for cdv and cpv- are the tests of greatest benefit in monitoring immunity, especially after the puppy vaccination series. during recent years, many laboratories have standardised their methodologies for such testing. there are legal requirements for rabies antibody testing for pet travel between some countries. in-practice testing will probably become more popular as soon as rapid, simple, reliable and cost-effective assays are more widely available. a negative test result indicates that the animal has little or no antibody, and that revaccination is recommended. some of these dogs are in fact immune (false-negative), and their revaccination would be unnecessary. a positive test result on the other hand would lead to the conclusion that revaccination is not required. this is why robust yes/no answers must be provided by any assay. with cdv and/or cpv- tests, an animal with a negative result, regardless of the test used, should be considered as having no antibody and susceptible to infection. on completion of the puppy series at to weeks of age, an animal should have a positive test result, provided the serum sample is collected or more weeks after vaccination. seronegative animals should be revaccinated and retested. if it again tests negative, it should be considered a non-responder that is possibly incapable of developing protective immunity. testing for antibody is presently the only practical way to ensure that a puppy's immune system has recognised the vaccinal antigen. vaccines may fail for various reasons: ( ) mda neutralises the vaccine virus this is the most common reason for vaccination failure. when the last vaccine dose is given at $ weeks of age however, mda should have decreased to a low level, and active immunisation will succeed in most puppies (. %). ( ) the vaccine is poorly immunogenic poor immunogenicity may reflect a range of factors from the stage of vaccine manufacture to administration to the animal. for example, the virus strain, its passage history or production errors in the manufacture of a particular batch of product may be a cause of vaccine failure. post-manufacture factors such as incorrect storage or transportation (interrupted cold chain) and handling (disinfectant use) of the vaccine in the veterinary practice, may result in inactivation of an mlv product. ( ) the animal is a poor responder (its immune system intrinsically fails to recognise the vaccinal antigens) if an animal fails to develop an antibody response after repeated revaccination, it should be considered a non-responder. because immunological non-responsiveness is genetically controlled in other species, certain breeds of dogs have been suspected to be poor-responders. it is believed (but unproven) that the high susceptibility to cpv- recognised in certain rottweilers and dobermans during the s (regardless of their vaccination history) was due to a high prevalence of non-responders. in the usa today, these two breeds seem to have no greater numbers of non-responders than other breeds, possibly because carriers of the genetic trait may have died from cpv- . this may not be true for other countries. for example, in the uk and germany, the non-responder phenotype remains prevalent amongst rottweilers. most vaccinated dogs will have a persistence of serum antibody (against core vaccine antigens) for many years. immunologically, this antibody reflects the function of a distinct population of long-lived plasma cells (memory effector b cells). induction of immunological memory is the primary objective of vaccination. for core vaccines there is excellent correlation between the presence of antibody and protective immunity and there is long doi for these products. this correlation does not exist for many of the non-core vaccines and the doi related to these products necessitates more frequent revaccination intervals. antibody tests can be used to demonstrate the doi after vaccination with core vaccines. it is known that dogs often maintain protective antibody to cdv, cpv- , cav- , and cav- for three or more years and numerous experimental studies support this observation. therefore, when antibody is absent (irrespective of the serological test used) the dog should be revaccinated unless there is a medical basis for not so doing. antibody determinations to other vaccine components are of limited value because of the short time period these antibodies persist (e.g., leptospira products) or the lack of correlation between serum antibody and protection (e.g. canine parainfluenza). important considerations in performing antibody tests are the cost and the time to obtain results. the vgg recognises that at present such serological testing has limited availability and might be relatively expensive. however, the principles of 'evidence-based veterinary medicine' would dictate that testing for antibody status (for either pups or adult dogs) is better practice than simply administering a vaccine booster on the basis that this should be 'safe and cost less'. in response to these needs, more rapid, cost-effective tests are being developed. the basic immunisation schedule guidelines and recommendations for core (recommended), non-core (optional) and not generally recommended vaccines for the general veterinary practice are given in table . a particular example of a vaccine that may be considered core in only some countries is that against rabies virus. in a geographical area in which this infection is endemic all cats should be routinely vaccinated for the protection of both the pet and human populations. in some countries, mandatory rabies vaccination is a legal requirement, and is generally also required for international pet travel. in terms of feline core vaccines it is important to realise that the protection afforded by the feline calicivirus (fcv) and feline herpesvirus (fhv) vaccines will not provide the same efficacy of immunity as seen with the feline panleukopenia (feline parvovirus; fpv) vaccines. thus the feline core vaccines should not be expected to give the same robust protection, nor the duration of immunity, as seen with canine core vaccines. although the fcv vaccines have been designed to produce cross-protective immunity against severe clinical disease, there are multiple strains of fcv and it is possible for infection and mild disease to occur in the vaccinated animal. with respect to fhv, it should be remembered that there is no herpesvirus vaccine than can protect against infection with virulent virus, and that virulent virus will become latent and may be reactivated during periods of severe stress. the reactivated virus may cause clinical signs in the vaccinated animal or the virus can be shed to susceptible animals and cause disease in them. as discussed for pups, most kittens are protected by mda in the first weeks of life. however, without serological testing, the level of protection and the point at which the kitten will become susceptible to infection and/or can respond immunologically to vaccination is unknown. this is related to the level of maternal antibody and variation in uptake of mda between litters. in general, mda will have waned by to weeks of age to a level that allows an active immunological response, and an initial vaccination at to weeks of age followed by a second vaccination to weeks later is commonly recommended. many vaccines carry data sheet recommendations to this effect. however, kittens with poor mda may be vulnerable (and capable of responding to vaccination) at an earlier age, while others may possess mda at such high titres that they are incapable of responding to vaccination until sometime after weeks of age. therefore the vgg endorses the recent recommendation made in the aafp guidelines of administering the final kitten dose at weeks or older. all kittens should receive the core vaccines. a minimum of three doses -one at to weeks of age, a second to weeks later and a final dose at weeks of age or older should be administered. cats that respond to mlv core vaccines maintain immunity for many years, in the absence of any repeat vaccination. all cats should receive a first booster months after completion of the kitten vaccination course (this will ensure adequate vaccineinduced immunity for cats that may not have adequately responded to the primary course). following this first booster, subsequent revaccinations are given at intervals of three years or longer, unless special conditions apply. adult cats of unknown vaccination status should receive a single initial mlv core vaccine injection followed by a booster vaccination one year later. cats that have responded to vaccination with mlv core vaccines maintain a solid immunity (immunological memory) for many years in the absence of any repeat vaccination. it should be emphasised that the considerations given above do not generally apply to killed core vaccines nor to the optional vaccines, and particularly not to vaccines containing bacterial antigens. thus chlamydophila and bordetella products require more frequent boosters for reliable protection. any given time. just as the vaccination strategy varies with each individual pet, there is no one-size-fits-all strategy for vaccinating shelter animals. the likelihood of exposure and the potentially devastating consequences of infection necessitate a clearly defined shelter vaccination program. shelter medicine differs from individual care in that it has to practice in an environment where eradication of infectious disease cannot be attained. it is possible, however, to minimise the spread of infections within a high-density, high-risk population and maintain the health of not yet infected individuals. when the overall purpose is to place healthy pets into welcoming homes, the time and effort dedicated to controlling infectious disease is only one of many variables in the complex shelter medicine and husbandry equation. the recommendations provided here attempt to address some shelter-unique issues as they pertain to vaccination and disease control. guidelines and recommendations for vaccines to be used in shelters are given in tables and . if unambiguous documentation of vaccination is provided for an animal at the time of admission to a shelter, there is no reason to revaccinate. the vgg discriminates between a shelter and a boarding kennel/cattery. the latter are facilities where fully vaccinated animals may be temporarily boarded for relatively short periods of time (e.g. when owners are on vacation). it should be a requirement of entry to any such facility that the individual dog or cat is fully vaccinated with core products given according to the guidelines presented herein. the use of non-core vaccines against respiratory infections is also appropriate under these circumstances. in the past, veterinary practice has benefited from the annual administration of vaccines. by encouraging owners to bring their pets yearly for vaccination, veterinarians were able to recognise and treat disease earlier than might otherwise have been the case. in addition, the annual visit provided an opportunity to inform clients of important aspects of canine and feline health care. unfortunately, many clients have come to believe that vaccination is the most important reason for annual veterinary visits. veterinarians are now concerned that a reduction in vaccination frequency will cause clients to forgo the annual visits and that the quality of care will diminish. it is therefore essential that veterinarians stress the importance of all aspects of a comprehensive individualised health care program. emphasis should be placed on a detailed vaccination interview, a comprehensive physical examination by the veterinarian, and individualised patient care. the importance of dental care, proper nutrition, appropriate diagnostic testing and the control of parasites and of zoonotic diseases should also be addressed during evaluation of each pet. behaviour concerns should be discussed, as well as the necessity for more frequent examination of young and geriatric animals. the yearly health care/vaccination interview should assess the need for non-core vaccines for the pet. the practitioner should explain to the client the types of vaccines available, their potential benefits and risks, and their applicability to the particular animal, given its lifestyle and risk of exposure. whilst an animal might not receive core vaccination every year, most non-core vaccines do require annual administration -so owners will continue to see their animal vaccinated annually. the regional incidence and risk factors for various infectious diseases should also be discussed. ways to reduce the impact of acquired disease (e.g., avoiding overcrowding, improving nutrition, and restricting access to infected animals) should also be reviewed. vaccinations should be considered as only one component of a comprehensive preventative health care plan individualised based on the age, breed, health status, environment (potential exposure to harmful agents), lifestyle (contact with other animals), and travel habits of the pet. age has a significant effect on the preventative health care needs of any given individual. puppy/kitten programs have traditionally focused on vaccinations, parasite control, and neutering. today, opportunity exists to incorporate behaviour counselling and zoonotic disease management. for the aging pet, senior care programs are becoming increasingly popular. nutritional, dental disease, and parasite control assessment and counselling should take place on an individualised basis throughout the life of the pet. certain breeds are predisposed to various diseases. early detection (particularly of neoplasia) and management of breed-associated disease can significantly improve the quality of the animal's entire life. pets with chronic medical conditions warrant periodic scheduled medical progress examinations and testing. animals receiving certain medications also warrant therapeutic monitoring of blood levels and/or organ systems. the development of recheck protocols for chronic diseases and medications, which can be included in reminder systems, can greatly improve client compliance and, accordingly, pet care. the environment in which a pet resides can profoundly affect its health status and should be assessed during annual health care visits in order to define risk factors and develop appropriate preventative measures. by determining the extent to which dogs and cats come into contact with other animals in unobserved circumstances, veterinarians can assess the need for non-core vaccinations. dogs that visit kennels, grooming salons, common areas, and wooded, tick-infested areas are potentially at greater risk from certain infectious diseases than dogs that do not frequent these areas. just as the human population has become more mobile, so has the pet population, resulting in potential exposure to infectious agents, parasites, and environmental hazards not found in the home environment. determining past and anticipated future travel during each visit allows for greater individualisation of preventative care and diagnostic testing plans. at the time of vaccine administration, the following information should be recorded in the patient's permanent medical record: d date of vaccine administration, d identity (name, initials, or code) of the person administering the vaccine, d vaccine name, lot or serial number, expiry date, and manufacturer d site and route of vaccine administration. the use of peel-off vaccine labels and stamps that imprint the medical record with the outline of a pet facilitates this type of record keeping which is mandatory in some countries. adverse events should be recorded in a manner that will alert all staff members during future visits. informed consent should be documented in the medical record in order to demonstrate that relevant information was provided to the client and that the client authorised the procedure. at the very least, this notation should indicate that a discussion of risks and benefits took place prior to vaccination. adverse events are defined as any side effects or unintended consequences (including lack of protection) associated with the administration of a vaccine product. they include any injury, toxicity, or hypersensitivity reaction associated with vaccination, whether or not the event can be directly attributed to the vaccine. adverse events should be reported, whether their association with vaccination is recognised or only suspected. a vaccine adverse event report should identify the product(s) and animal(s) involved in the event(s) and the individual submitting the report. reporting field observations of unexpected vaccine performance is the most important means by which the manufacturer and the regulatory agency are alerted to potential vaccine safety or efficacy problems that may warrant further investigation. the purpose of pre-licensure safety studies is to detect relatively common adverse events. rare adverse events will be detected only by post-marketing surveillance through analysis of reported adverse events. adverse events should be reported to the manufacturer and/or the local regulatory authority. the vgg recognises that there is gross under-reporting of vaccine-associated adverse events which impedes knowledge of the ongoing safety of these products. the vgg would actively encourage all veterinarians to participate in such surveillance schemes. if a particular adverse event is well documented, reporting serves to provide a baseline against which future reports can be compared. in addition, reported adverse events can lead to detection of previously unrecognised reactions, detection of increases in known reactions, recognition of risk factors associated with reactions, identification of vaccine lots with unusual events or higher numbers of adverse events, and can further stimulate clinical, epidemiological, or laboratory studies. therefore, veterinarians are encouraged to report any clinically significant adverse event occurring during or after administration of any licensed vaccine. reporting a vaccine adverse event is not an indictment against a particular vaccine; it facilitates review of temporally associated conditions and adds to the safety database of the product. non-core. vaccination should be restricted to use in geographical areas where a significant risk of exposure has been established or for dogs whose lifestyle places them at risk. these dogs should be vaccinated at to weeks of age, with a second dose - weeks later, and then at intervals of - months until the risk has been reduced. this vaccine is the one least likely to provide adequate and prolonged protection, and therefore must be administered annually or more often. protection against infection with different serovars is variable. this product is associated with the greatest number of adverse reactions to any vaccine. in particular, veterinarians are advised of reports of acute anaphylaxis in toy breeds following administration of leptospirosis vaccines. the administration of rabies vaccine will be determined by whether the shelter is in a country in which the disease is endemic, and by local statute the version of these guidelines printed in this issue of the journal of small animal practice includes only the main text and tables of the guidelines document. the original document also includes (as appendices) individual fact sheets for the core canine and feline vaccines, and a series of frequently asked questions on canine and feline vaccination. it is hoped to print these in a subsequent edition of the journal but, from september , the entire vgg document will be available on the wsava web-site -http://www.wsava.org these wsava vaccination guidelines are reproduced here with permission from dr brian romberg, president of the wsava. the administration of rabies vaccine will be determined by whether the shelter is in a country in which the disease is endemic, and by local statute the vgg does not recommend the use of other feline vaccines in the shelter situation aaha canine vaccine guidelines the american association of feline practitioners feline vaccine advisory panel report the work of the vaccination guidelines group has been generously sponsored by intervet. the vgg is an independent group of academic experts who have formulated these guidelines without consultation with industry. key: cord- -fu b y authors: couto, carla r.; pannuti, cláudio s.; paz, josé p.; fink, maria c. d.; machado, alessandra a.; de marchi, michela; machado, clarisse m. title: fighting misconceptions to improve compliance with influenza vaccination among health care workers: an educational project date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: fu b y the compliance with influenza vaccination is poor among health care workers (hcws) due to misconceptions about safety and effectiveness of influenza vaccine. we proposed an educational prospective study to demonstrate to hcws that influenza vaccine is safe and that other respiratory viruses (rv) are the cause of respiratory symptoms in the months following influenza vaccination. hcws were surveyed for adverse events (ae) occurring within h of vaccination. ae were reported by % of the hcws. no severe ae was observed. a subset of hcws was followed up during four months, twice a week, for the detection of respiratory symptoms. rv was diagnosed by direct immunofluorescent assay (dfa) and real time pcr in symptomatic hcws. influenza a was detected in five episodes of respiratory symptoms ( . %) and other rv in ( . %) episodes. the incidence density of influenza and other rv was . and . episodes per hcw-month, respectively. the educational nature of the present study may persuade hcws to develop a more positive attitude to influenza vaccination. the compliance with influenza vaccination has been historically poor among health care workers (hcws) varying from to % around the world [ ] [ ] [ ] [ ] . a recent review of relevant predictor studies of self-reported reasons for accepting or rejecting influenza vaccination showed that the two major reasons for rejecting are misconceptions or lack of knowledge about influenza infection; and a lack of convenient access to vaccine. on the other hand, hcws compliant to seasonal vaccination are generally older, believe in vaccine efficacy, take the vaccine for self-protection, and have been previously vaccinated [ ] . at hospital das clinicas, university of sã o paulo school of medical sciences, a previous study showed a % compliance with influenza vaccination among hcws. in the mentioned study, the main reasons for non-compliance were the perception of vaccine inefficacy and the fear of adverse reactions [ ] . respiratory symptoms occurring after vaccination are frequently misinterpreted as vaccine failure which reinforces the hcw's skepticism on vaccine efficacy. to overcome these false beliefs, we proposed a prospective study in a cohort of hcws to demonstrate that influenza vaccine is safe and other respiratory viruses (but not influenza) are generally the cause of respiratory symptoms in the months following influenza vaccination. this study was conducted at hospital das clinicas, university of são paulo school of medical sciences (hc-fmusp) from may to october . the hospital das clinicas is a , -bed tertiary teaching hospital consisting of buildings attached to the university of são paulo. the main building has approximately beds and contains most of the surgical and clinical wards and intensive care units. hospital das clinicas has an estimated , hcws, including permanent and casual staff, employees, students, and volunteers. since , annual influenza vaccination has been offered free of charge to all hcws. vaccination usually takes place at the hospital's immunization center during working hours, from monday to friday. in , as a strategy to increase compliance with influenza vaccination, vaccine was offered at places of easy access during expanded hours, as suggested by % of the interviewed in previous survey [ ] . in addition, an educational campaign was carried out emphasizing the safety and importance of influenza vaccination. detailed information about the educational and vaccination campaign have been published elsewhere [ ] . during vaccination campaign, hcws were invited to participate in the present study which had two steps: ) evaluation of vaccine safety and, ) cohort study to evaluate which respiratory viruses were more frequently detected in hcws presenting respiratory symptoms in the four-month period following vaccination. sample size was estimated taking into account an expected frequency of % of adverse events in adult population. considering an acceptable frequency rate of up to %, we estimated to enroll at least hcws (epiinfo version ). three hundred and ninety eight vaccinated hcws were surveyed for adverse events occurring within the first h after influenza vaccination. a subset of hcws participated in the follow-up phase of the study. to assure that all hospital sectors were represented, the cohort was defined during the assessment of adverse events which was performed by a hospital epidemiologist nurse, through visits in all hospital floors and sectors. afterward, these hcws were actively surveyed twice a week, at work place, during four months, to check for the occurrence of respiratory symptoms and nasal wash sampling which was done in of the participants. figure shows the algorithm of the study. a followup time of four months was proposed taking into account the period when serum antibodies elicited by influenza vaccine are expected to maintain protective levels. the following adverse events were actively surveyed: fever, headache, malaise, myalgia, local pain, local edema and allergic reaction. other adverse events spontaneously reported were also registered. during follow-up visits, participants were asked about the presence of the following symptoms: fever, coryza, blocked nose, sneeze, cough, watery eyes, headache, myalgia, sore throat, hoarseness, sibilance, and dyspnea. allergy was ruled out in those with sneezing as the only symptom. influenza like illness (ili) was defined by the presence of fever and cough and/or sore throat according to the cdc definition [ ] . in the presence of any of the above mentioned symptoms, a nasal wash sample was taken according to englund et al, kept at uc to uc and processed at the virology laboratory within four hours from sampling [ ] . nasal washes were taken from hcws who consent with sampling and whose duration of symptoms did not exceed three days. respiratory syncytial virus (rsv), influenza (inf) a and b, adenovirus (adv) and parainfluenza virus (piv) were diagnosed by direct immunofluorescent assay (dfa) according to the manufacturer's instructions (imagenh dako, cambridgeshire, uk). aliquots of nw samples were stored at uc for later pcr and real time pcr processing. pcr was used to detect coronavirus and picornavirus. rt-pcr products for picornavirus were subsequently sequenced to differentiate rhinovirus from enteroviruses. real time pcr (taqman assay) was used to diagnose human metapneumovirus (hmpv). to increase the sensitivity of influenza diagnosis, a real time pcr (taqman assay), was added to the diagnostic tools. similarly, a nested adenovirus pcr was used along with dfa due to the low sensitivity of the latter in diagnosing adv. the pcr protocols used in the present study have been published elsewhere [ ] [ ] [ ] [ ] . hcws were informed about the results of the dfa up to h after sampling. spss . (spss inc., chicago, il) was used with the x test or fisher's exact test for discrete variables, and student's t test or the mann-whitney u test for continuous variables. tests of significance were two sided, and p, . was considered to be statistically significant. incidence density (id) of respiratory symptoms, influenza virus infections and other respiratory virus infections were calculated by the formula described below. id results were expressed per hcw-month [ ] . the interviews for adverse events occurring within h of vaccination were made from one to days after vaccination. the majority of the participants ( . %) were surveyed within the first week of vaccination. all hospital sectors were represented (table ) . one hundred and twenty of the hcws ( . %) reported at least one adverse event (ae). table shows the occurrence of adverse events according to the demographic characteristics of the vaccinees. sector of work was the only variable associated with the presence of adverse events (p = . ). the sectors with highest frequency of adverse events were the virology laboratory ( . % of the subjects), burn unit ( . %), nephrology ( . %) and pneumology ( . %). in the remaining sectors, ae were reported by less than % of the subjects. those surveyed in the first five days after vaccination were more likely to report such events [ ( . %) versus ( . %); p, . ]. local ae were reported by . % of the participants, systemic ae by . %, and % of the participants reported both local and systemic aes. headache, myalgia and malaise were more frequently reported ( %, . % and %, respectively). local pain and local edema was reported by . % and % of the hcws. no severe adverse event was observed. during the -month period following influenza vaccination, respiratory symptoms were evaluated in hcws. a total of , follow-up visits were performed (median per hcw, ranging from one to visits). one hundred and twenty-one hcws ( %) developed episodes of respiratory symptoms. coryza, cough, sore throat and myalgia were reported by . %, %, . % and . % of the participants, respectively. seventy-one of them ( . %) presented more than one episode suggestive of upper respiratory infection (uri). ili was observed in of the episodes ( . %). mean time to the occurrence of respiratory symptoms was . ( . to . ) months. the incidence density of respiratory symptoms was . episodes per hcw-month. nasal washes were taken in of the episodes of uri. in episodes ( . %) no respiratory virus was found, even though % had coryza, % had cough and % had sore throat. the frequency of ili was similar among hcws who agreed with sampling and those who did not agree ( . % versus . %, p = . ) ( misconceptions about influenza vaccine, be it about its safety or its effectiveness, have been identified in all studies included in a recent review of attitudes and predictors of influenza vaccination among hcws, highlighting the importance of education efforts [ ] . initial symptoms of rv infections are often unspecific such as fever, malaise, or myalgia. as influenza vaccine is offered when other rv are circulating (e.g., rsv), vaccinated hcws developing symptoms within h of vaccination misinterpret those signs as vaccine adverse events. in addition, the occurrence of respiratory symptoms in the months following vaccination is mistaken as vaccine failure. other respiratory infections as the cause of such symptoms are hardly ever considered. to diminish the arguments of fear of adverse events or perception of vaccine inefficacy, this prospective study was conducted to demonstrate to a subset of hcws from our hospital, that severe adverse events following influenza vaccination are rare and the episodes of respiratory symptoms occurring in the first four months after vaccination are generally caused by other respiratory viruses and not by influenza virus. as expected, no severe adverse event was observed in the present study, and the events more frequently reported, such as headache, myalgia and malaise could be related to influenza vaccine itself as well as to other causes, given their unspecificity. in adults, the adverse event more frequently reported after intramuscular administration of inactivate vaccines is local pain, affecting % to % of the vaccinated [ ] [ ] [ ] . in the present study, . % of the participants reported local pain. systemic reactions like fever, malaise and myalgia can also occur after inactivate vaccines. in the present study, the frequency of systemic aes (over %) was higher than reported in previous studies. recent publications have shown rates of systemic adverse events ranging from % to % in hwcs [ , ] . ideally, the subjects should have been surveyed within the first four days of vaccination. as we preferred to apply the questionnaire personally, rather than by mail or phone calls, only . % of the participants were interrogated up to the fourth day, due to the great number of interviews. thus, the high rate of systemic adverse events observed in the present series may be either an overestimation by the subjects or a consequence of the survey method applied. a recent study evaluating vaccine coverage in korea has demonstrated that interview surveys provide more reliable information than telephone surveys, showing lower missing rates and % of agreement with the immunization registry record [ ] . anaphylaxis and neurological reactions are rare [ , ] . the frequency of adverse events observed in the present study may be overestimated taking into account the subjectiveness of selfreported unspecific symptoms. as hcws are aware of vaccine adverse events and fear its consequences, it is comprehensible that these events will be more frequently reported by them than by general population. another study conducted in the same hospital demonstrated that hcws reported significantly more adverse events ( . %) than the elderly ( . %) [ ] . the higher frequency of adverse events reported by hcws surveyed in the first five days of vaccination, as compared with those surveyed after the fifth day, may suggest that people may be more predisposed to remember any symptom possibly associated with the vaccine if inquired within the first days of vaccination. on the other hand, we believe that if the adverse events were severe or important, they would not be missed if inquired after to days. interestingly, we observed that some sectors showed significantly higher rates of ae than others, supporting the subjectivity of the information. also, this data may suggest a mouth to mouth effect among sector coworkers influencing the self-report of ae. among hcws, the belief that coworkers take influenza vaccine influences the vaccine uptake. thus, it is possible that the same occurs concerning to adverse events. continued education of health professionals is essential to highlight not only the epidemiological importance of the vaccine, but also its safety and the low risk of severe adverse events. our study also demonstrated that the respiratory symptoms occurring in the months following influenza vaccination were more frequently caused by other respiratory viruses and generally do not mean vaccine failures. one limitation of our study is that in only of the episodes of respiratory symptoms ( . %) the subjects agreed with nw sampling. nw sampling is a simple but uncomfortable procedure and this fact may explain why some hcws preferred not to get tested during working hours. one could argue that influenza cases could be missed among those not tested. however, we believe that this loss has not affected our results as the frequency of ili was similar between those who agreed with sampling and those who did not ( table , p = . ). the incidence density of other respiratory viruses was . times greater than incidence density of influenza. probably, this difference would be even greater if real time pcr was also performed to increase the sensitivity of the diagnosis of other respiratory viruses as well. in addition, more cases of other rv infections would be diagnosed if a larger number of professionals were tested, increasing the difference between the incidence density of influenza and other rv. influenza infection is characterized by the abrupt occurrence of fever, headache, myalgia, and dry cough. during influenza season, the presence of these symptoms is highly predictive of influenza infection and summarizes the case definition of influenza-like illness (ili), which has been used worldwide for influenza surveillance purposes. however, the sensitivity and positive predictive value of such definition can vary greatly depending on the co-circulation of other respiratory viruses in the community [ ] . indeed, bellei et al. have recently reported that % of ili cases in the city of são paulo were caused by other agents, mainly rhinovirus, which peaks along with influenza [ ] . similar results have been previously published by other authors [ ] . in our series, influenza cases in vaccinated hcws were mild and occurred significantly earlier following vaccination in comparison to other respiratory viruses. this finding may be explained by the marked seasonality of influenza in são paulo city as reported previously [ , ] , peaking in early winter and coinciding with the initial period of the study. the effectiveness of influenza vaccines is related predominantly to the age and immune competence of the vaccinee and the degree of similarity between the viruses in the vaccine and those in circulation. vaccine effectiveness in preventing laboratory-confirmed influenza illness when the vaccine strains are well matched to circulating strains is - % in randomized, placebo-controlled trials conducted among children and young healthy adults, but is lower among elderly or immunocompromised persons [ ] . in adults $ years old, the efficacy of influenza inactivate vaccine varies from % to % [ ] . trials that measure laboratory-confirmed influenza virus infections as the outcome are the most persuasive evidence of vaccine efficacy [ ] . in the present study, only five of the vaccinated hcws ( . %) acquired influenza. in accordance with the educational nature of our study, we considered all cases of influenza as vaccine failures, since vaccinated health personnel look forward to be protected against influenza. molecular characterization of influenza cases was not performed to check for possible mismatches between circulating viruses and vaccine strains, which could possibly justify those failures. our study demonstrated that the fear of severe adverse events seems unjustified as well as the perception of vaccine inefficacy. uri following influenza vaccination were generally caused by other respiratory viruses and not by influenza. in times of pandemic influenza a h n and widespread vaccination, healthcare and emergency medical services personnel are among the priority groups recommended to receive the h n influenza vaccine. it is time to overcome definitively the misconceptions about the vaccine as well as the fear of adverse events. so far, the vast majority ( %) of adverse events reported to vaers after receiving the trivalent - influenza vaccine, were classified as ''non serious'', e.g., soreness at the vaccine injection site [ ] . we believe that the educational nature of the present study may persuade hcws to develop a more positive attitude to influenza vaccination. influenza vaccination among medical residents in a teaching hospital influenza vaccination rates and motivators among healthcare worker groups influenza immunisation: attitudes and beliefs of uk healthcare workers attitudes of health care workers to influenza vaccination: why are they not vaccinated? influenza vaccination of health care workers in hospitals-a review of studies on attitudes and predictors intervention to increase influenza vaccination rates among healthcare workers in a tertiary teaching hospital in brazil * update: influenza activity-united states rapid diagnosis of respiratory syncytial virus infections in immunocompromised adults detection of human rhinovirus rna in nasal washings by pcr polymerase chain reaction for rapid diagnosis of respiratory adenovirus infection frequency of human metapneumovirus infection in hematopoietic sct recipients during consecutive years simultaneous detection of influenza viruses a and b using real-time quantitative pcr measures of disease frequency effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial frequency of adverse reactions after influenza vaccination the effectiveness of vaccination against influenza in healthy, working adults immunogenicity of a monovalent pandemic influenza a h n vaccine in health-care workers of a university hospital in japan adverse events associated with the h n influenza vaccination and the vaccination coverage rate in health care workers adverse reactions to influenza vaccine in the elderly occurrence of early adverse events after vaccination against influenza at a brazilian reference center predicting influenza infections during epidemics with use of a clinical case definition acute respiratory infection and influenza-like illness viral etiologies in brazilian adults low mortality rates related to respiratory virus infections after bone marrow transplantation use of oseltamivir to control influenza complications after bone marrow transplantation prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices (acip) the efficacy of influenza vaccine in elderly persons. a meta-analysis and review of the literature summary of - trivalent influenza vaccine data from the u.s. vaccine adverse event reporting system the authors thank the infection control group of hospital das clínicas, school of medical sciences, university of são paulo. key: cord- -nkr x authors: yokomichi, hiroshi; tanaka-taya, keiko; koshida, rie; nakano, takashi; yasui, yoshinori; mori, masaaki; ando, yuka; morino, saeko; okuno, hideo; satoh, hiroshi; arai, satoru; mochizuki, mie; yamagata, zentaro title: immune thrombocytopenic purpura risk by live, inactivated and simultaneous vaccinations among japanese adults, children and infants: a matched case–control study date: - - journal: int j hematol doi: . /s - - - sha: doc_id: cord_uid: nkr x this case–control study investigated immune thrombocytopenic purpura (itp) risk following live, inactivated, and simultaneous vaccination, with a focus on infants aged < years. we matched case patients with itp to one or two control patients with other diseases by institution, hospital visit timing, sex, and age. we calculated mcnemar’s pairwise odds ratios (ors [ % confidence interval]) with case–control pairs. the case group had ( %) males and ( %) infants, and the control group included ( %) males and ( %) infants. for all age groups, the mcnemar’s or for itp occurrence was . ( . – . , p = . ) for all vaccines. among infants, these were . ( . – . , p = . ) for all vaccines, . ( . – . , p = . ) for live vaccines, and . ( . – . , p = . ) for inactivated vaccines. sex-adjusted common ors for simultaneous vaccination were . ( . – . , p = . ) for all vaccines, . ( . – . , p = . ) for inactivated vaccines only, and . ( . – . , p = . ) for mixed live and inactivated vaccines. in infants, these were . ( . – . , p = . ), . ( . – . , p = . ) and . ( . – . , p = . ), respectively. these limited data suggest no significant itp risk following vaccinations or simultaneous vaccination in any age group, including infants. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. immune thrombocytopenic purpura (itp) is a haemorrhagic disorder characterised by thrombocytopenia, a purpuric rash, normal bone marrow and the absence of signs of other identifiable causes of thrombocytopenia [ ] [ ] [ ] [ ] [ ] . previous studies have shown that itp risk increases after measles, rubella, chickenpox and influenza infection [ , [ ] [ ] [ ] . recently, live measles-mumps-rubella (mmr) [ ] [ ] [ ] [ ] and varicella [ ] vaccines have been reported to potentially increase the risk for itp. studies have also suggested that inactivated hepatitis b [ ] and diphtheria-tetanus-acellular pertussis (dtap) [ ] vaccines may increase itp risk. evidence suggests that itp risk after vaccination increases through the same mechanism as that by which microbial infections induce antiplatelet autoantibodies [ ] . because vaccines are designed to induce protective immunity by mimicking infections in the human body, both live and inactivated vaccinations can theoretically trigger the development of itp [ ] . researchers have investigated associations between multiple vaccinations and itp risk, but findings regarding inactivated vaccinations were inconsistent [ ] [ ] [ ] [ ] [ ] . however, because many vaccines are administered to children in infancy, an epidemiological study for vaccine safety conducted some time after a single vaccine dose is difficult to design. therefore, more studies are needed to clarify the itp risk associated with live and inactivated vaccines. a combined vaccine is defined as a single product in which equivalent component vaccines are administered as a single vaccine to prevent more than one disease or to protect against multiple strains of infectious microbes [ ] . for example, mmr, diphtheria-pertussis-tetanus and multivalent pneumococcal conjugate vaccines have been licensed for large-scale supply. the nature of combined vaccines means it is difficult to separately measure the adverse reaction rate of each component. simultaneous vaccination, which is commonly conducted for children in europe [ ] , north america [ , ] and asia [ ] , is defined as administering more than one vaccine at different anatomic sites during the same clinic visit, without combining these vaccines in the same syringe [ ] . early research reported that parents were concerned about the efficacy of simultaneous immunisation [ ] . however, experimental and clinical epidemiological studies provided a scientific basis for the efficacy of this practice [ ] . recently, the focus of interest in simultaneous vaccination has moved from questions of efficacy to questions of safety [ ] [ ] [ ] . if a vaccination has adverse reaction risks, these risks may accumulate in simultaneous vaccination [ ] . however, no research has compared the risks when administering vaccines simultaneously versus separately in the same population. studies conducted in the s indicated rates of adverse reactions were similar between simultaneous and separate vaccine administration [ ] [ ] [ ] . correspondingly, the centers for disease control and prevention issued a guideline recommending that parents use simultaneous vaccination for children younger than years to avoid missing the appropriate vaccination timing [ ] . however, some studies suggested that rates of several adverse reactions may increase with simultaneous vaccination [ , ] . therefore, the risk associated with simultaneous vaccine administration needs to be investigated more comprehensively. in this case-control study, we aimed to determine the itp risk after live, inactivated and simultaneous vaccination in japan. we also examined the risk associated with simultaneous vaccination among subjects aged < years, referred to in this study as infants [ ] , because this age group are frequently immunised using this method. we requested physicians from paediatrics and internal medicine departments at seven university hospitals and regional centre hospitals in japan to recruit inpatients and outpatients for this study. recruitment occurred from october to march . during this period, participating physicians enrolled in all new cases with itp that attended their hospital and met the inclusion criteria for this study. these physicians filled in the study questionnaire with the requested data for the case and control patients. we defined exposure as vaccination within days before the onset of itp. to measure this exposure, participating physicians who treated case (itp) and control (other diseases) patients completed questionnaires covering retrospective information on vaccination history and other characteristics. in japan, vaccination history for infants and preschool children is recorded in the maternal and child health handbook, which is provided by the municipality. vaccination history for other children and adults was captured in a medical interview conducted by physicians or obtained from medical records. additional information was obtained from hospital medical records. in japan, the immunization law defines itp as an adverse event following immunisation that occurs within days after vaccine administration [ ] . based on this law, we considered ≤ days after administration as the duration in which vaccinated people could potentially develop itp as a result of vaccination. the live vaccines investigated were the bacillus calmette-guérin (bcg), rotavirus, varicella, mumps and measles-rubella (mr) vaccines (in japan, mr and mumps vaccines are administered separately). inactivated vaccines were the influenza, diphtheria-pertussis-tetanus-polio (dpt-ipv), hepatitis b, following japanese and american guidelines [ ] [ ] [ ] [ ] , cases with itp were identified when patients met all of the following conditions. ( ) peripheral blood platelet count ≤ , /µl [ ] [ ] [ ] . ( ) without anaemia unless the patient was bleeding as a result of itp. ( ) without deformation of red or white blood cells. ( ) without aplastic anaemia, myelodysplastic syndrome, leukaemia, malignant lymphoma, paroxysmal nocturnal haemoglobinuria, systemic lupus erythematosus, disseminated intravascular coagulation, bone marrow metastasis, myelofibrosis, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome, liver cirrhosis, hypersplenism and megaloblastic anaemia. ( ) without bernard-soulier, wiskott-aldrich, may-hegglin and kasabach-merrit syndromes. ( ) condition was not pseudo-thrombocytopenia due to ethylenediaminetetraacetic acid. ( ) condition was not thrombocytopenia caused by pharmacological agents, radiation or measles. because this study included patients with new onset itp, all itp cases were considered to be as acute [ ] . each patient with itp (case) was matched with one or two control patients [ , ] . participating physicians matched controls with case patients by the institution, timing of hospital visit (within a -month difference), sex and age. in the matched study design, we permitted overlapping use of case patient datum to be paired with two different control patient data; within an institution, one control datum was paired with two different case patient data. we requested that participating physicians reduced the difference in timing of hospital visit between case and control patients to within weeks where possible. age was matched as age in months for case patients aged under year, and within years for case patients aged - years. for case patients aged ≥ years, age was matched within years where possible, with a maximum difference of years. all participating patients were of asian ethnicity. sex, age at hospital visit and consulted department were measured; height and body weight were not measured. to exploit the matched study design, we calculated mcnemar's odds ratios (ors) and their % confidence intervals (cis) [ ] for the primary outcome. mcnemar's or is suitable for matched case-control design. briefly, in this calculation method, vaccination histories for case-control pairs were grouped into four profiles: ( ) vaccination ( +) for a patient with immune thrombocytopenic purpura (case) and vaccination ( +) for a patient with other diseases (control); ( ) vaccination ( +) for case and vaccination ( −) for control; ( ) vaccination ( −) for case and vaccination ( +) for control; and ( ) vaccination ( −) for case and vaccination ( −) for control. in calculating mcnemar's ors, only two of these profiles ( and ) were used based on an assumption of the binary distribution. for example, if the number of the case-control vaccination profile equalled that of profile , mcnemar's or = (null hypothesis) [ ] . if the former number of profile doubled the latter number of profile , mcnemar's or = . this calculation method originated when mcnemar's or was developed to evaluate the results of a matched case-control study. subsequently, conditional logistic regression was developed to further adjust for covariates. we also calculated mcnemar's ors stratified by age group. because vaccination for measles, rubella and varicella are known risk factors for itp onset [ ] [ ] [ ] [ ] [ ] , we calculated those ors as the reference values. tests for p values were based on a binary distribution with the null hypothesis being the same pair of numbers between the two vaccination history profiles, which is usually used in calculating ncnemar's or [ ] . we also calculated common ors to exploit all available data for unmatched case and control patients. data for those patients whose paired partner was excluded from the matched data analysis were included in the unmatched analysis. common ors were the secondary outcome. we aimed to measure confounders of history of infection with helicobacter pylori [ , ] , other viruses and bacteria, but only obtained these data for a subset of patients. therefore, in estimating common ors, we only adjusted for sex [ , , ] , and calculated ors stratified by age group. the age groups were < , - , - and ≥ years, based on the vaccination schedule for children, adults and older adults recommended by the japan pediatric society and the infectious disease surveillance center (english versions) [ , ] . because the risk associated with simultaneous vaccination could not be assessed in the matched analysis because of the small sample size, this risk was only assessed in the unmatched analysis. we calculated sex-adjusted common ors for itp occurrence in the simultaneous administration of two or more vaccines. we performed all statistical analyses using sas version . (sas institute, cary, nc, usa). all reported p values were two-sided, and p < . was considered significant. in total, pairs were included in the matched analyses, and patients in the unmatched analyses. most patients with itp were enrolled from paediatrics departments. in the itp case and control groups, varied infectious diseases were reported month before the hospital visit. there were no underlying diseases involving an immunocompromised status, but there was an epilepsy case in the itp case group and an asthma case in the control group. table shows the characteristics of the matched case and control patients. in total, participants ( . %) were under years of age, ( . %) were aged - years and ( . %) were male. for the cases on whom data was provided by their physicians, the mean (standard deviation) of duration from vaccination to itp onset was . ( . ) days. among case patients, there were cases of purpuras, three of bleeding in the oral cavity and difficulty stopping bleeding, three of hypermenorrhoea and one of haematochezia. diagnoses recorded for hospital visits among control patients included respiratory tract infections, nine digestive tract infections, three urinary tract infections, nine allergic diseases and four malignant neoplasms. there were positive results for any helicobacter pylori test in the case group, but no positive results in the control group. figure presents a histogram of the ages of case patients. most case patients with itp were aged < - years. for simultaneous vaccination, we investigated children aged months to years: six children had two vaccines, four had three vaccines, two had four vaccines and one had five vaccines. table shows the sex-adjusted common ors for itp occurrence in the simultaneous administration of two or more vaccines. the mcnemar's and common ors for itp occurrence for all, live and inactivated vaccines ranged from almost null to more than among people of all ages, children aged < years and children aged < years, but these results were not statistically significant. the common ors for simultaneous administration of two or more vaccines were greater than for all, live and inactivated vaccines; these results were not statistically significant. previous research suggests that people may develop itp as an immune reaction to vaccination in combination with a genetic predisposition [ , [ ] [ ] [ ] [ ] [ ] . because vaccines are designed to mimic real infections and trigger immune reactions, clinicians have been concerned that vaccinationparticularly the administration of live vaccines-may cause autoimmune disease [ ] . mmr-associated acute itp has been frequently investigated in studies on this topic [ , [ ] [ ] [ ] . in , the united states institute of medicine acknowledged that evidence had established a causal relationship between mmr vaccination and thrombocytopenia [ ] . in our study, the common or for mr vaccination was . , although this result was not statistically significant (supplementary table ). in summary, the present study did not find many significant effects, but the mcnemar's and common ors estimated for live vaccination ranged from null to high across age groups. itp risk associated with inactivated vaccination has not been sufficiently investigated in previous studies. a postlicensure retrospective study in the united states did not find any itp cases among -month-old infants vaccinated with the dtap-ipv/hib or other dtap-containing vaccine from october to july [ ] . a canadian surveillance study ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) identified eight itp cases after dtp or dtap ± ipv ± hib vaccinations, three after hepatitis b vaccination and two after influenza vaccination in paediatric hospitals [ ] . an italian post-licensure prospective study involving a large number of older adults conducted from to reported cases of itp after seasonal influenza vaccinations [ ] . a study using a taiwanese national database found an incidence rate ratio for itp of . ( % ci . - . ) following pandemic influenza (h n ) monovalent vaccination without adjuvant versus non-vaccination among people aged - years, and of . ( % ci . - . ) among children [ ] . the united states vaccine adverse event reporting system database reported that from to , influenza vaccination had a proportional reporting ratio (an index of identifying unexpectedly frequent reports) for thrombocytopenia occurrence of . ( cases, lower bound of % ci of the empirical bayesian geometric mean < . ) [ ] . however, there is a lack of consistent evidence about the itp risk associated with inactivated vaccines. in our study, the estimated mcnemar's ors for inactivated vaccines varied from under to over , and were not statistically significant in the examined age groups. calculation of mcnemar's ors used discordant case-control pairs in terms of vaccination history; therefore, calculating mcnemar's ors required a much larger sample size than would have been required to calculate common ors [ ]. because of insufficient power, we were unable to clarify whether itp risk accompanied inactivated vaccination. care should be taken in the interpretation of the ors reported for inactivated vaccines in this study. in the context of japan, many inactivated vaccinations are scheduled for children aged < year [ ] , meaning that infants of this age have a high chance of being immunised with inactivated vaccines. previous research suggests that among japanese children, the peak age of itp onset is < years [ ] . the ors for inactivated vaccination could, therefore, be overestimated in this study because most data used for their estimation included data for infants aged < year, who frequently receive inactivated vaccines and have a relatively high incidence of itp. therefore, we interpreted the mcnemar's or of . (table ) and common or of . (table ) among children aged < years as indicating that this study did not detect itp risk in inactivated vaccination. vaccination is frequently criticised in the media [ , ] . however, vaccination has three types of benefits: direct effects (immunity of the vaccinated person), indirect effects (herd protection of non-vaccinated people) and reduction in the risk for developing itp caused by infection with viruses or bacteria. the third type of benefit could be rephrased as the observation that the incidence of itp following vaccination is lower than the incidence of itp after infection with wild viruses [ ] . the incidence of itp development in children immunised with mmr is reportedly around one in , , whereas it is approximately one in following natural rubella infection and approximately one in following measles infection. another report suggested that the incidence of itp caused by mmr vaccination is - times lower than the incidence of itp following natural infection [ ] . as is inherent with a single outcome (in this case, the development of itp), the present findings of ors greater than do not consider the third type of vaccination benefit. in other words, it is difficult to investigate the long-term effect of vaccination on preventing itp development from the perspective of the third type of benefit-if it exists-in cohort or case-control studies. the present study is notable for investigating itp risk following simultaneous vaccination. although we did not find statistically significant results, the sex-adjusted ors were relatively high (or . among children aged < years and . among children aged < years; table ). the point estimate of the or was larger than that of single vaccination ( . among children aged < years and . among children aged < years; table ) in children of each age group. few studies have investigated the risks associated with simultaneous vaccination. a randomised controlled trial involving people receiving simultaneous influenza vaccination reported increased haemagglutinin inhibition titre, seroconversion and seropositivity rates, suggesting that the immune response was boosted [ ] . because vaccine efficacy and immune-related adverse reactions have the same origin [ ] , the rate of itp development may increase depending on the administration method. table suggests that there is potential for a relatively higher risk for itp with simultaneous vaccination compared with separate vaccination. however, further analyses using large databases are needed to confirm this finding. there are several limitations inherent to this study. first, the sample size meant the study was underpowered because we adopted a matched design to adjust for several confounders between cases and controls. this sample size also made it difficult to estimate ors separately by age group. to compensate for this limitation and present additional results, we calculated common ors using all available data, although adjustment for confounders might have been insufficient for this analysis. second, we could not adjust for infection history as a confounder. although we aimed to measure infection history in the questionnaire, we did not obtain sufficient data. third, because the investigation depended on the voluntary replies of physicians by post, reporting bias might have occurred. physicians who were interested in potential adverse events might have been more likely to participate in this study, which could have led to an overestimation of the ors. a national surveillance system of adverse events following vaccinations in japan is needed in an era when people are concerned about drug-induced diseases. fourth, each case was matched to one or two controls. this method might have resulted in an imbalance in the weight of samples for the primary outcome. because several matching factors may restrict selecting potential control patients, we chose a design to counter this limitation. in terms of study strengths, the detection of itp cases by physicians was a main advantage of the present study. the use of physician-registered cases enhanced the internal validity of this investigation. this validity would not be possible in a large database study. second, the data were gathered from hospitals across japan. the reported itp risks, therefore, reflect a broad area, suggesting relatively high external validity. third, the analyses included detailed results stratified by age group and type of vaccine. this information will be informative for researchers and clinicians seeking to assess the potential risks for adverse events for their patients. based on the limited data available in this study, high itp risk was not found following inactivated or simultaneous vaccination. future investigations of itp risk should include analyses using large databases. idiopathic thrombocytopenic purpura recurrent immune thrombocytopenia after influenza vaccination: a case report prediction of response to first-line therapy with itp by flow cytometric analysis of bone marrow lymphocyte phenotypes diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (ttp) in japan glucocorticoids promote response to thrombopoietin-receptor agonists in refractory itp: a case series the itp syndrome: pathogenic and clinical diversity virus-associated immune thrombocytopenic purpura in childhood association between drug and vaccine use and acute immune thrombocytopenia in childhood vaccine administration and the development of immune thrombocytopenic purpura in children risk of immune thrombocytopenic purpura after measles-mumps-rubella immunization in children mmr vaccine and idiopathic thrombocytopaenic purpura immune thrombocytopaenic purpura: an autoimmune cross-link between infections and vaccines thrombocytopenia reported in association with hepatitis b and a vaccines consequence or coincidence?: the occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines immune thrombocytopenic purpura (itp) associated with vaccinations: a review of reported cases thrombocytopenia after vaccination: case reports to the us vaccine adverse event reporting system safety of dtap-ipv/hib vaccine administered routinely to infants and toddlers thrombocytopenia after immunization of canadian children safety of mf -adjuvanted influenza vaccination in the elderly: results of a comparative study of mf -adjuvanted vaccine versus nonadjuvanted influenza vaccine in northern italy safety of pandemic (h n ) monovalent vaccines in taiwan: a self-controlled case series study best practices guidance of the advisory committee on immunization practices (acip) vaccination schedules for individual european countries and specific age groups advisory committee on immunization practices recommended immunization schedule for children and adolescents aged years or younger-united states canada's provincial and territorial routine (and catch-up) vaccination routine schedule programs for infants and children. . public health agency of canada vaccination schedule recommended by the japan pediatric society addressing parents' concerns: do multiple vaccines overwhelm or weaken the infant's immune system? simultaneous administration of childhood vaccines: an important public health policy that is safe and efficacious children who have received no vaccines: who are they and where do they live? the pandemic influenza a (h n ) vaccine does not increase the mortality rate of idiopathic interstitial pneumonia: a matched case-control study safety of the influenza a (h n ) vaccine in chronic obstructive pulmonary disease: a matched case-control study additive, multiplicative, and other models for disease risks simultaneous administration of measles-mumpsrubella vaccine with booster doses of diphtheria-tetanus-pertussis and poliovirus vaccines safety, tolerability, and immunogenicity of concurrent administration of haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) with either measles-mumps-rubella vaccine or diphtheriatetanus-pertussis and oral poliovirus vaccines in -to -monthold infants immune response to simultaneous administration of a recombinant dna hepatitis b vaccine and multiple compulsory vaccines in infancy reactions following administration of influenza vaccine alone or with pneumococcal vaccine to the elderly centers for disease control and prevention ministry of health, labour and welfare consensus guideline for diagnosis and treatment of childhood idiopathic thrombocytopenic purpura epidemiology of primary immune thrombocytopenia in children and adults in japan: a population-based study and literature review standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group chinese guidelines for treatment of adult primary immune thrombocytopenia reference guide for management of adult immune thrombocytopenia in japan: revision thromboembolism in patients with immune thrombocytopenia (itp): a meta-analysis of observational studies : the analysis of case-control studies the mcnemar test for binary matched-pairs data: mid-p and asymptotic are better than exact conditional high-dose dexamethasone therapy as the initial treatment for idiopathic thrombocytopenic purpura risk of immune thrombocytopenic purpura after measles-mumps-rubella immunization in children. child care health dev a nationwide survey of newly diagnosed childhood idiopathic thrombocytopenic purpura in japan routine/voluntary immunization schedule in japan vaccination and autoimmune disease: what is the evidence? idiopathic thrombocytopenic purpura and mmr vaccine recurrent thrombocytopenic purpura after repeated measles-mumps-rubella vaccination effect of live measles vaccine on the platelet count persistent changes in circulating white blood cell populations after splenectomy adverse events associated with childhood vaccines other than pertussis and rubella: summary of a report from the institute of medicine on the sample size for studies based upon mcnemar's test safety and immunogenicity of a pandemic influenza a h n vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the - influenza season: a multicentre, randomised controlled trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to express our deep gratitude to the participating patients. for their cooperation as physicians in this study, we would also like to thank dr. katsuko maeda, yamagata city hospital saiseikan; dr. yuya sato, dokkyo medical university hospital; dr. noritaka furuya, saitama citizens medical centre; dr. yoshinori kobayashi, national hospital organization yokohama medical centre; conflict of interest tn received honoraria from daiichi sankyo co., sanofi k.k. and mitsubishi tanabe pharma corporation. mmochizuki received honoraria from pfizer inc. mmori's department received unrestricted research grants from abbvie gk; ayumi pharmaceutical corporation; chugai pharmaceutical co., ltd.; csl behring k.k.; japan blood products organization; nippon kayaku co., ltd.; ucb japan co., ltd.; and asahikasei pharmaceutical corporation. the other authors have no conflicts of interest to declare. the study protocol was reviewed and approved by the ethics committee of the national institute of infectious diseases (the principal institution of this project) in accordance with the ethical guidelines and regulations of the declaration of helsinki (approval number: h - ).informed consent physicians in hospitals explained the study to their patients and obtained written informed consent from the parent(s) or legal guardian(s) of each child and/or assent by the child (when applicable) before initiating medical interview and record review. hiroshi yokomichi · keiko tanaka-taya · rie koshida · takashi nakano · yoshinori yasui · masaaki mori · yuka ando · saeko morino · hideo okuno · hiroshi satoh · satoru arai · mie mochizuki key: cord- -k ad qgu authors: kabir, k. m. ariful; tanimoto, jun title: modelling and analysing the coexistence of dual dilemmas in the proactive vaccination game and retroactive treatment game in epidemic viral dynamics date: - - journal: proc math phys eng sci doi: . /rspa. . sha: doc_id: cord_uid: k ad qgu the dynamics of a spreadable disease are largely governed by four factors: proactive vaccination, retroactive treatment, individual decisions, and the prescribing behaviour of physicians. under the imposed vaccination policy and antiviral treatment in society, complex factors (costs and expected effects of the vaccines and treatments, and fear of being infected) trigger an emulous situation in which individuals avoid infection by the pre-emptive or ex post provision. aside from the established voluntary vaccination game, we propose a treatment game model associated with the resistance evolution of antiviral/antibiotic overuse. moreover, the imperfectness of vaccinations has inevitably led to anti-vaccine behaviour, necessitating a proactive treatment policy. however, under the excessively heavy implementation of treatments such as antiviral medicine, resistant strains emerge. the model explicitly exhibits a dual social dilemma situation, in which the treatment behaviour changes on a local time scale, and the vaccination uptake later evolves on a global time scale. the impact of resistance evolution and the coexistence of dual dilemmas are investigated by the control reproduction number and the social efficiency deficit, respectively. our investigation might elucidate the substantial impacts of both vaccination and treatment in the framework of epidemic dynamics, and hence suggest the appropriate use of antiviral treatment. the dynamics of a spreadable disease are largely governed by four factors: proactive vaccination, retroactive treatment, individual decisions, and the prescribing behaviour of physicians. under the imposed vaccination policy and antiviral treatment in society, complex factors (costs and expected effects of the vaccines and treatments, and fear of being infected) trigger an emulous situation in which individuals avoid infection by the pre-emptive or ex post provision. aside from the established voluntary vaccination game, we propose a treatment game model associated with the resistance evolution of antiviral/antibiotic overuse. moreover, the imperfectness of vaccinations has inevitably led to anti-vaccine behaviour, necessitating a proactive treatment policy. however, under the excessively heavy implementation of treatments such as antiviral medicine, resistant strains emerge. the model explicitly exhibits a dual social dilemma situation, in which the treatment behaviour changes on a local time scale, and the vaccination uptake later evolves on a global time scale. the impact of resistance evolution and the coexistence of dual dilemmas are investigated by the control reproduction number and the social efficiency deficit, respectively. the appearance of epidemiological dynamics in the mechanism of pre-emptive voluntary vaccination has been studied in various contexts [ ] , such as perfect and imperfect vaccination [ , ] , dynamical behaviour of vaccination [ ] , vaccination with information spreading [ ] , metapopulation migration modelling [ ] and heterogeneous networks [ ] . furthermore, chen & fu [ ] studied an effective antiviral treatment with prescribing behaviour and resistance evolution. remarkably, influenza-like illnesses, oseltamivir (tamiflu) [ ] is a widely used ex post treatment originally administered against influenza a and b viruses. however, over the years, the societal benefits of antiviral treatment have lessened with overuse, leading to treatment resistance. these trends are evidenced by the interplay between prescription behaviour and resistance evolution. here, the theoretical studies of vaccination and treatment strategies have considered different effectiveness, associated costs, payoff structures and time scales. previously, compartment models with the mean-field approximation, such as the si [ ] , sis [ ] , sir [ ] , seir [ ] and seiqr [ ] models, are exhibited by dividing the population into several distinct groups. in these designations, s, i, r, e and q represent the proportions of susceptible, infected, recovered, exposed and quarantined individuals, respectively. recently, kabir et al. extended the simple sir model by introducing an awareness effect on epidemic spreading and implemented a two-layer sir-ua model on well-mixed [ ] and heterogeneous networks [ ] . additionally, treatment is an important compartmented state that reduces the disease after infection. treatments such as antibiotics, quarantine and isolation have been theoretically investigated by many researchers [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the consequences of vaccination and treatment on an epidemic model were investigated in an influenza model with age structure by qiu & feng [ , ] and feng et al. [ ] , an sivs model with vaccination age by li et al. [ ] , an sir epidemic model with optimal control theory by zaman et al. [ ] and a pandemic influenza model by towers et al. [ ] . all these works presumed that vaccination, quarantine or treatment would reduce epidemic infection in a simple dynamical situation on local time scales and with no game aspect. by contrast, the present study aims to establish a theoretical epidemic model encompassing both vaccination and treatment as an evolutionary game approach. the human decision-making process is affected by the cost and risk of the vaccine, selfopinion, networks and neighbours' decisions; therefore, how vaccine acquiescence is influenced by various factors must be investigated [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . according to prior studies, a game approach to epidemiological vaccination can fairly predict the infection risk in both vaccinated and nonvaccinated individuals [ ] [ ] [ ] [ ] . such voluntary vaccination game approaches have been studied theoretically and in multi-agent simulations (mas). to elucidate the mechanism of infectiousdisease control, these approaches incorporate a two-layer time scale: a local time scale (epidemic season) of epidemic diffusion and a global time scale on which the strategy updates at the end of the season (at local equilibrium), followed by repeated seasons. kuga & tanimoto [ ] developed a theoretical model of imperfect vaccination on local and global time scales and validated it by mas. however, kabir & tanimoto [ ] claimed that an individual's decision to take a vaccination after social learning (dynamical behaviour) also occurs on local time scales, so this strategy should be updated instantly. accordingly, it seems that the voluntary vaccination game approach can be implemented into the local time scale while maintaining the framework on the global time scale (strategy update at the end of each season). in the same context, antiviral treatment depends on the local time scale, antiviral resistance and prescribing behaviour. to shed light on this complex phenomenon, we newly propose the dual-dilemma game structure that considers the roles of both the proactive vaccination and retroactive treatment games. this approach admits different strategy update rules and different time scales of the two provisions. in most of the previous studies [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , the proactive vaccination permits an individual to accept or decline a vaccination at the end of every epidemic season. this repeated choice is made on global time scales. on the other hand, the retroactive treatment prescribes the behaviour and the antiviral resistance of a certain individual only when s/he is actually infected at a certain time in an epidemic season, which occurs on local time scales. an excessive antiviral treatment may also trigger another viral resistant strain; this behaviour is an expected social problem concerning seasonal influenza in japan [ ] . in this case, the so-called vaccination dilemma modelled by the vaccination game is joined by another dilemma, whereby an individual seeking to use public goods (i.e. accepting the antiviral) induces another viral strain with devastating consequences for others. using our novel idea backed by the theoretical game approach, we quantify the impact of the pre-emptive vaccination game (before the disease spreading) and the treatment game (after the infection), which includes the prescribing behaviour as an ex post provision. both games are influenced by vaccine effectiveness, treatment efficacy, treatment cost and vaccination cost. such a double social dilemma situation, perhaps quite ubiquitous in the real world, has not been considered in related previous studies. the vaccination game in the double-dilemma scenario occurs on a larger time scale (over repeated seasons) than the treatment game, which occurs on a day-by-day basis. therefore, a coevolutionary process can be plausibly modelled in the present study. we employ a pre-emptive control measure that prevents the breakout of infection at an early stage based on an individual's decision. meanwhile, the ex post treatment can be regarded as a fail-safe provision implemented after infection. owing to the imperfections of vaccines and the unwillingness to take vaccines as a pre-emptive provision, people probably consider a retroactive treatment as the 'ultimate weapon' against disease dispersion. however, overuse of antiviral treatment and prescribing behaviour can trigger the emergence of resistant strains, encouraging more ex post provision activity by individuals. to handle these two provisions working on different time scales, our model implants the second social dilemma incurred by the antiviral treatment rather than the so-called vaccination dilemma acquired by the proactive provision. to our knowledge, no previous theoretical analysis has considered two provisions in the same context of the evolutionary game process. we also develop another new concept called the social efficiency deficit (sed). such a framework can explicitly elucidate the social dual-dilemma on both global (vaccination) and local (treatment) time scales. in our model, the retroactive antiviral treatment targets the individuals harbouring a sensitive or resistant strain that is controlled by the treatment (antiviral/antibiotic) potency (efficacy). the resistant strain incurs a high medical cost, mortality and the risk of antiviral/antibiotic use, which increases when the demand for antiviral use is driven by the individual's self-interest and overprescribing. here, we emphasize the social learning behaviour for prescription of antiviral treatment under the evolutionary dynamics of resistance that can uphold the optimal use of the treatment. to explore this evolutionary process of vaccination and treatment, we impose three strategy update rules: individual-based risk assessment (ib-ra), society-based risk assessment (sb-ra) and direct commitment (dc). these rules govern the individual's connection with society. moreover, we derive the control reproduction numbers of the sensitive and resistant strains, and hence analyse the disease-free equilibria situations in an epidemic. the remainder of this paper is organized as follows. the 'methods and model' section introduces the new model of epidemic vaccination with the antiviral treatment model and demonstrates it schematically. the 'results and discussion' section validates the proposed model in numerical simulations. finally, the 'conclusion' section summarizes and further discusses our findings. to model the social dual-dilemma as a two-stage game, the pre-emptive vaccination and ex post treatment are developed in the framework of sir epidemic dynamics in a well-mixed population (figure ). in stage , the individuals make their vaccination decisions (yes or no) that will control their infection risk during the pandemic season. in stage , the infected people with either the sensitive strain or resistant strain decide their treatment provision (treated or untreated) on the local time scale. the antiviral (antibiotic) treatment case incorporates a feedback loop between the prescription behaviour and resistance evolution. to model the disease diffusion in a single season, the initially susceptible people are compartmentalized into vaccinated and nonvaccinated groups. the individuals in the susceptible state can be infected with either sensitive or resistant strains, then seek treatment at an overall treatment rate (treatment probability) denoted as ωp , where p is the prescribing rate and ω determines the probability at which infected people accept treatment from the prescribing individuals. consequently, the individuals can recover in two ways: natural recovery with no antibiotic/antiviral treatment or recovery after treatment. the epidemiological dynamics are described by the following system of ordinary differential equationsṠ here, the fractions of vaccinated plus non-vaccinated individuals infected with the sensitive and resistant strains are denoted by i u sen and i u res , respectively. t denotes the fraction of infected individuals receiving treatment and r represents the fraction of individuals who have recovered from infection by a sensitive or resistant strain. in addition, β s and β r (γ s and γ r ) are the disease transmission rates (infection recovery rates) for the sensitive and resistant strains, respectively and γ t is the recovery rate of infected individuals receiving treatment. finally, μ s and μ r are the mutation rates of the sensitive and resistant strains, respectively. without mutation, the coexistence of sensitive and resistant strains is forbidden by the competitive exclusion principle. the portion of vaccinated individuals is separated into perfectly immune and nonimmune individuals, distinguished by the vaccine's effectiveness e( ≤ e ≤ ). the treatment efficacy ε controls the treatment efficiency of the sensitive and resistant strains. when ε = , the treatment is far less beneficial against the resistant strain than against the sensitive strain. on the other hand, when ε = , the higher number of people in the resistant state is now taking the highest benefit of treatment and is ineffective against the sensitive strain. the basic reproduction number (ratio) r is the estimated number of infected individuals instigated by a susceptible individual (r = β/γ ). in particular, if r < , the disease will eventually die out, whereas if r > , the disease will spread through the population. in this case, we presume separate control reproduction numbers r s and r r for the sensitive and resistant strains, respectively. to evaluate the control reproduction numbers, we initially set let us express the model dynamics as we can write similarly, we have as mentioned above, the control reproduction number must reflect the stability of the diseasefree equilibrium state. according to equations ( . ) and ( . ), the control reproduction numbers of both sensitive (r s ) and resistant (r r ) strains act like a decreasing function of p and x; both ranging from to displayed in figure in panels (a-ii) and (a-iii), we can find the critical treatment probability p c at which the treatment probabilities of the sensitive and resistant strains are equal. when < p < p c , the sensitive strain is more prevalent than the resistant strain (i.e. r s > r r ). however, when p > p c , the resistant strain will outperform against the sensitive strain. at the social optimum, the critical treatment probability p c specifies the maximum treatment control under which resistant strains will not emerge. assuming r s = r r in equations ( . ) and ( . ), p c is calculated as . we incorporate two-game aspects (treatment and vaccination) in a single epidemiological game model. this model reproduces the coevolutions of accepting a vaccination at the beginning of every season and receiving treatment after becoming infected in a season. in the treatment game, the individual decision to receive or decline treatment against the infectious sensitive and resistant strains occurs on the local time scale. in the vaccination game, the individuals can consent to alter their strategy (accept or decline vaccination) based on the progress of the last pandemic season, which occurs on the global time scale. based on a feedback loop between the resistance evolution and prescription norm, the game approach establishes a social learning dynamical process that somehow controls the optimum use of the antiviral treatment. to quantify the evolutionary decision dynamics of treatment versus non-treatment (prescribing versus non-prescribing), we specify the relative treatment cost c t visà-vis the infection cost c i = . we also introduce the benefit b t of treating the sensitive strain (the resistant strain is excluded, because it is much more difficult to treat than the sensitive strain, so b t is always positive). this idea is formulated as a two-strategy game in table . the fractions of individuals infected with the sensitive and resistant strains are, respectively, given by the expected payoffs of the treated and untreated individuals are, respectively, given by and to model the two-strategy game, we presume the dc strategy update rule presented in iwamura & tanimoto [ ] . this rule is designed by comparing the expected payoffs of the treated π t and untreated π u individuals. in the present study, the strategy updates (in both the treatment and vaccination games (see later)) apply the mean-field approximation. the modified fermi function of dc is given by where π i and π j are the mean payoffs of the focal portion of individuals and the opponent strategy (fraction), respectively. here, we consider pairwise comparison between two groups; which depends on the payoff difference π j − π i . because, the pairwise fermi has been wellaccepted strategy-updating procedure that stochastically comparable to the real-world human decision-making process. the probabilities of the population transiting from untreated to treated and from treated to untreated are, respectively, calculated as and consequently, the treatment game is expressed by the following dc dynamics: considering the defined payoff structure and the portion of individuals presented in table , the social average payoff π , expected value of vaccinators π c and expected value of nonvaccinators π d are, respectively, given by to formulate the evolutionary process, we consider two types of strategy adaptation procedures [ ] ; ib-ra and sb-ra. in the case of ib-ra, an individual can update strategy by observing a neighbour's strategy. the update is governed by the transition probability prob(s i ← s j ) taken from the pairwise fermi function [ ] . alternatively, in an sb-ra, an individual relies on the mean payoff of all opposite neighbours [ ] . we apply the mean-field approximation to formulate the adaptation dynamics in both the ib-ra and sb-ra rules. here, we replace the first row by the actual transition probabilities in the second row of table . to establish the dynamical system at the end of each epidemic season, we formulate ib-ra and sb-ra as mathematical models that modify the fraction of vaccinators x. the evolutionary dynamics of the ib-ra and sb-ra are, respectively, given by individual-based risk assessment (ib-ra) society-based risk assessment (sb-ra) we have now established all mathematical frameworks in both the vaccination and treatment cases. the above set of equations is numerically solved by the explicit finite difference method. the calculation results affected by the two-stage process (the sitr/v dynamical model and treatment update) are together obtained in a single season (local update) at equilibrium, and the vaccination strategy is adopted at the end of every season (global update). the initial values were set as v( the results are presented in two-dimensional ( d) phase diagrams. the strategy update rules of the vaccination game (ib-ra or sb-ra) and the dc were applied on the global and local time scales, respectively (where the dc depicts the prescribing behaviour of the treatment policy). the coalescing impact of proactive vaccination and the retroactive treatment policy based on human behaviour was formulated by the conventional mean-field approximation. the simultaneous changes of two coevolutionary decision-making processes were globally demonstrated in two cases. we first explored the phase diagram of the final epidemic size (fes), vaccination coverage (vc), fraction of treated people (ftr) and the average social payoff (asp) while varying two parameters: the vaccination effectiveness e and the treatment efficacy ε, maintaining sensible fixed values of the other parameters. in the second case, we introduce sed that explicitly reveals the as shown in figure , the fes increased (higher infection region) with increasing vaccination cost c r and treatment cost c t . reducing the cost of both vaccination (c r = . ) and treatment (c t = . ) improved the fes (lowered the infection region) ( figure (a-i) , both panels). furthermore, reducing the costs (c r , c t < . ) more effectively benefitted the fes (in terms of the critical borderline between infection breakout and diminution) in ib-ra than in sb-ra (cf. panel sets a and b); the reverse tendency was found at higher costs (c r , c t ) as analogously reported by fukuda et al. [ ] . when the costs are relatively low, vaccination is more encouraged in sb-ra than in ib-ra, which hampers the reduction in the infected number of individuals in the early stage of each season. thus, based on the human decision-making of whether to accept or decline both vaccination and treatment, the changing propensity of the fes can be significantly enhanced by the vaccination effectiveness, treatment efficacy and their corresponding costs. as indicated in figure , lowering the vaccination cost and increasing the reliability (effectiveness) of the vaccine enticed the individuals to accept more vaccines. this tendency was more marked in the sb-ra than in the ib-ra, and enhanced the vaccination acceptance when the post-infection treatment cost was high (c t = . ) on the local time scale. however, the portion of individuals making treatment provision (ftr) diminished at higher treatment costs (c t = . ) in both schemes (panels (*-iii) in figure ). a small treatment cost attracts individuals to the treatment provision, whereas a higher cost hampers the treatment-seeking behaviour (lowers the ftr). therefore, either lowering the vaccination cost or improving the vaccination effectiveness to explore the dual-dilemma structure on an epidemiological model, we considered the joint impact of vaccination and treatment games in the same context. a typical scenario is demonstrated in figure . our idea was motivated by the endorsement of social dilemma situations in the strategies of evolutionary game theory, in which the players are all individuals in a well-mixed population. in a coevolutionary adaptation process, it is important to know whether the social dual-dilemma exists under certain combinations of the model parameters, such as the vaccination effectiveness, treatment efficiency and their associated costs. unlike simple by games in which the so-called dilemma strength (ds) can be explicitly defined [ ] , a real social dilemma typically observed in the vaccination game [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , traffic flow [ ] [ ] [ ] [ ] [ ] [ ] [ ] and others may have a time-variable game structure. in the vaccination and traffic games, this structure is mainly influenced by the disease-spreading and traffic flow dynamics, respectively. the timevariable game structure is too complex to represent by the payoff matrix in a × game or the time-constant payoff structure function in the -strategy and n-player game. thus, the ds is difficult to determine in advance even when the mathematical model is well defined. our new sed concept (defined above and mathematically formulated blow) was inspired by the seminal idea of traffic flow analysis (e.g. [ ] [ ] [ ] [ ] [ ] [ ] [ ] ). the ds indicates the existence or absence of a social dilemma (behaving as a prognostic index), whereas the sed provides an 'ex post' or diagnostic index. here, let us define sed as the gap between the result of the evolutionary trail (which can be evaluated by the nash equilibrium (ne)) and the optimum solution (ideal result from a social-welfare standpoint [ ] ). the payoff at the ne can always be observed by taking an evolutionary game approach, whereas the optimal social payoff is observable in a model of any complexity. therefore, one can evaluate the sed in any context, and hence predict the occurrence of a social dilemma (if the sed is positive, the gap exists; if it is zero, the evolutionary trail matches the optimum). thus, the sed indicates that the payoff can be improved from that at the ne. mathematically, the sed is given by sed = (social optimal payoff) − (payoff at nash equilibrium) ( again, let us reiterate that sed = implies no social dilemma, while any social dilemma causes a positive sed. according to the abovementioned conceptual definition, sed in the current model (which deals with both vaccination and treatment games) is given by meanwhile, the asp is the quantity of payoff. the superscript 'opt' and subscript 'social' together indicate the social optimal. the c i was taken as the standardizing denominator as previously defined as . the seds in the vaccination and treatment game of the present model are, respectively, defined as follows: social reflect the fact that the maximum asp is obtained for varying x ranging from to (for fixed p k ) and varying p from to (for fixed x l ), respectively. figure presents the stepwise procedure of finding sed and quantifying the dual dilemma in the proposed method. step . construct the asp phase diagram based on the evolutionary game approach (figure (i)). to this end, implement both the vaccination and treatment games and obtain the appropriate asp at the ne, along with a certain vaccine effectiveness (e) and treatment efficacy (ε). the asp associated with the fraction of vaccinators and probability of treatment (x l , p k ) at the ne can also be observed for a precise (e i , ε j ). step . for this fixed (e i , ε j ), evaluate asp to address whether a dual dilemma exists in the vaccination and treatment games, we plot the sed diagrams in the vaccination effectiveness (e) versus treatment efficacy (ε) planes at different costs. panels a and b of figure are plotted under the strategy update rules ib-ra and sb-ra, respectively, and plots (a-*) and (b-*) present the seds in the vaccination game sed v and the treatment game sed t , respectively. moreover, the combined vaccination and treatment costs (c r , c t ) were varied as ( . , . ), ( . , . ), ( . , . ) ( . , . ), and ( . , . ) in plots (*-i), (*-ii), (*-iii) and (*-iv), respectively. as demonstrated in the above sed formulation, the dilemma situation (non-white areas in the plots) appeared in all cases, but interestingly depended on e and ε. nodilemma regions, in which either the vaccination or treatment game became trivial, were also observed. now, comparing panels (a-i) and (a-ii) for c r = . with panels (a-iii) and (a-iv) for c r = . , one finds that the non-dilemma region (whiteout region) expanded with increasing vaccination cost. at the smaller vaccination cost (c r = . ), the region of larger sed appeared at a relatively low vaccination effectiveness (around e = . ; dotted red box in panel (a-i)). the huge gap between ne and the social optimal results from the lower ne due to a lower efficiency which makes fewer people commit vaccination when compared with a situation allowing a relatively higher efficiency which makes much more people commit. by contrast, a relatively high vaccination efficiency entices people to vaccinate, thus increasing the ne. meanwhile, increasing the vaccination cost (c r = . ) shifted the region of reasonably high sed to the maximally high vaccination effectiveness (dotted blue box in panel (a-iv)). this occurred because despite the high vaccination effectiveness, low vaccination efficiency hampers the commitment to vaccination. reliable vaccination provides a high commitment incentive, but high cost encourages free-riding on the herd immunity of the devoted others. in summary, we have numerically demonstrated that the sed precisely and easily detects the social dilemma in our dual-dilemma coevolutionary model. this paper developed an sitr/v epidemic model that combines the effects of proactive vaccination and retroactive treatment on the control and prevention of infectious viral diseases. the model building and its investigation were presented in this work. the most important contribution is that our new model gives a brand-new framework in which both pre-emptive vaccination and treatment as an ex post provision having different evolutionary time scales, which dovetails the ideological dynamics with the dynamics of the human decision-making process. this concept has been never studied. also, our model gives a clear procedure to quantify the social dilemmas, respectively, entailed by 'vaccination game' and 'treatment game'. the most novel aspect of our model is the simultaneous implementation of two social dilemma games: the antiviral treatment game and the vaccination game, which none of the previous work has tried to implement. the vaccination game implements on the global time scale under two strategy adaptation rules: ib-ra and sb-ra, assuming an infinite and well-mixed population. meanwhile, the treatment game describes the behaviour of antiviral administration with resistant-strain emergence. the treatment game is updated on the local time scale by presuming the dc rule, and precisely integrating a feedback loop between the sensitive and resistant strains. the outcome of antiviral and vaccination use depends on the effectiveness of the vaccine, the efficiency of treatment and their corresponding costs. increasing the effectiveness of the vaccine and lowering its administration cost reduced the final epidemic size (increased vaccination coverage). lowering the treatment cost and enhancing the treatment efficacy exerted a similar effect. thus, by applying retroactive antiviral use with pre-emptive vaccination, we can deeply understand and investigate individual decisions regarding vaccination and implement proper strategies that lessen the diffusion of infection or recommend appropriate and careful administration of both antivirals and vaccination. we also introduced the social optimum point p c that distinguishes the conditions under which treatment resistance emerges under antibiotic overuse and its associated factors. besides evolving the voluntary vaccination game, our model introduces a new game aspect with two provisions: vaccination as a proactive measure and treatment as a retroactive measure. presuming seasonal influenza-like diseases, the (pre-emptive) vaccination works over repeated seasons on global time scales, whereas the ex post treatment works seasonally on local time scales and depends on the antiviral cost, prescription behaviour and resistant-strain emergence. in the present model, we successfully established a 'double-layer' game structure of pre-emptive vaccination and ex post treatment. unlike the vaccination game model, which only considers whether the vaccine is accepted or declined, and whether an ex post provision is taken in a single season, the treatment game includes an aspect that depends on the antiviral resistance evolution and prescribing behaviour. to explicitly prove the dual-dilemma situation in the 'double-layer' game, we proposed the sed indicator, which quantifies whether the dynamics develop a social dilemma structure. this indicator is measured by the gap between the ne and the social optimal state. the dilemma strength [ ] [ ] [ ] , which explains the dilemma structure in simple two-player and two-strategy ( × ) games, is too simplistic for realistic dilemma games with substantially complex and time-dependent structures, such as vaccination games and traffic flow analysis. however, sed can quantify whether a game intrinsically has a social dilemma or not. we applied the sed to the present social dual-dilemma game, in which both vaccination and treatment dilemmas are inevitable. data accessibility. this article has no additional data. the supplementary material provides the basic code of our study. fundamental of evolutionary game theory and its applications risk assessment for infectious disease and its impact on voluntary vaccination behavior in social network imperfect vaccine and hysteresis dynamical behavior of a stochastic svir epidemic model with vaccination effect of information spreading to suppress the disease contagion on the epidemic vaccination game evolutionary vaccination game approach in metapopulation migration model with information spreading on different graphs impact of imperfect vaccination and defense against contagion on vaccination behavior in complex networks social learning of prescribing behavior can promote population optimum of antibiotic use tamiflu report comes under fire a contribution to the mathematical theory of epidemics dynamics of stochastically perturbed sis epidemic model with vaccination dynamic behaviors of a modified sir model in epidemic diseases using nonlinear incidence and recovery rates global stability for the seir model in epidemiology a delayed seiqr epidemic model with pulse vaccination and the quarantine measure analysis of sir epidemic model with information spreading of awareness analysis of epidemic outbreaks in two-layer networks with different structures for information spreading and disease diffusion a brief history of the antibiotic era: lessons learned and challenges for the future emergence of drug resistance: implications for antiviral control of pandemic influenza emergence of drug-resistant influenza virus: population dynamical considerations a delay differential model for pandemic influenza with antiviral treatment a population-dynamic model for evaluating the potential spread of drug-resistant influenza virus infections during community-based use of antivirals prophylaxis or treatment? optimal use of an antiviral stockpile during an influenza pandemic impact of emerging antiviral drug resistance on influenza containment and spread: influence of subclinical infection and strategic use of a stockpile containing one or two drugs potential impact of antiviral use during influenza pandemic antiviral resistance and the control of pandemic influenza transmission dynamics of an influenza model with vaccination and antiviral treatment transmission dynamics of an influenza model with age of infection and antiviral treatment modeling the effects of vaccination and treatment on pandemic influenza stability and bifurcation of an sivs epidemic model with treatment and age of vaccination optimal strategy of vaccination and treatment in an sir epidemic model antiviral treatment for pandemic influenza: assessing potential repercussions using a seasonally forced sir model swarm intelligence inspired cooperation promotion and symmetry breaking in interdependent networked game /journal/rspa proc. r. soc information cascades in complex networks incorporating latent constraints to enhance inference of network structure statistical physics of vaccination vaccination and the theory of games can influenza epidemics be prevented by voluntary vaccination? three-strategy and four-strategy model of vaccination game introducing an intermediate protecting measure to vaccinate or not to vaccinate: a comprehensive study of vaccination-subsidizing policies with multi-agent simulations and mean-field modeling influence of breaking the symmetry between disease transmission and information propagation networks on stepwise decisions concerning vaccination investigation of epidemic spreading process on multiplex networks by incorporating fatal properties suppression of epidemic spreading process on multiplex networks via active immunization discerning influential spreaders in complex networks by accounting the spreading heterogeneity of the nodes coevolution of vaccination opinions and awareness affecting the spread of epidemics virus propagation and patch distribution in multiplex networks: modeling, analysis, and optimal allocation community detection in temporal networks via a spreading process coupled disease-behavior dynamics on complex networks: a review effects of stubborn decision-makers on vaccination and disease propagation in social network effect of noise-perturbing intermediate defense measures in voluntary vaccination games realistic decision-making processes in a vaccination game effect of intermediate defense measures in voluntary vaccination games which is more effective for suppressing an infectious disease: imperfect vaccination or defense against contagion? dynamical behaviors for vaccination can suppress infectious disease-a game theoretical approach oseltamivir-resistant influenza a viruses circulating in japan dilemma game structure observed in traffic flow at a -to- lane junction dilemma game structure hidden in traffic flow at a bottleneck due to a into lane junction /journal/rspa proc. r. soc dangerous drivers foster social dilemma structures hidden behind a traffic flow with lane changes social dilemma structures hidden behind a traffic flow with lane changes social dilemma structure hidden behind traffic flow with route selection complex traffic flow that allows lane-changing and hampering intrinsically contains social-dilemma structures improvement of traffic flux with introduction of a new lane-change protocol supported by intelligent traffic system localized prosocial preferences, public goods, and common-pool resources relationship between dilemma occurrence and the existence of a weakly dominant strategy in a two-player symmetric game universal scaling for the dilemma strength in evolutionary games scaling the phase-planes of social dilemma strengths shows gameclass changes in the five rules governing the evolution of cooperation acknowledgements. we would like to express our gratitude to the funders. key: cord- -ijncfuxi authors: wang, yuheng; cheng, minna; wang, siyuan; wu, fei; yan, qinghua; yang, qinping; li, yanyun; guo, xiang; fu, chen; shi, yan; wagner, abram l.; boulton, matthew l. title: vaccination coverage with the pneumococcal and influenza vaccine among persons with chronic diseases in shanghai, china, date: - - journal: bmc public health doi: . /s - - - sha: doc_id: cord_uid: ijncfuxi background: adults with chronic conditions such as heart disease, diabetes, or lung disease are more likely to develop complications from a number of vaccine-preventable diseases, including influenza and pneumonia. in this study, we use the data from a chronic disease management information system in shanghai to estimate vaccination coverage and characterize predictors of seasonal influenza and -valent pneumococcal polysaccharide vaccine (ppsv ) vaccination among people with chronic disease in shanghai. methods: the shanghai centers for disease control and prevention have information systems related to chronic disease management, hospital records, and immunizations. data from individuals with hypertension, diabetes and chronic obstructive pulmonary disease (copd) were abstracted during july . the main outcome was coverage of pneumococcal and influenza vaccination. vaccination coverage was calculated across demographic groups. significance in bivariate associations was assessed through pearson’s chi-square tests, and in multivariable models through logistic regression models with a forward stepwise method to select variables. results: in the sample of , , individuals ≥ years, . % were vaccinated for pneumonia from january to july , and the vaccination coverage of influenza in the / influenza season was . %. vaccination coverage was highest in those – and lowest in those younger than . compared to urban areas, uptake in rural areas was higher for pneumonia vaccination (or: . , % ci: . , . ), but lower for influenza vaccination (or: . , % ci: . , . ). having a greater number of chronic diseases was associated with higher likelihood of pneumonia vaccination ( vs : or: . , % ci: . , . ), but this relationship was not statistically significant for influenza vaccination. conclusions: we found low levels with of pneumococcal vaccination, and extremely low uptake of influenza vaccination among individuals with high risk conditions in shanghai who should be priority groups targeted for vaccination. interventions could be designed to target groups with low uptake – like younger adults, and individuals who have not yet retired. adults with chronic conditions such as heart disease, diabetes, or lung disease are more likely to develop complications from certain vaccine-preventable diseases, especially pneumonia and influenza. these complications can include long-term illness, hospitalization, and even death [ ] . persons with diabetes or chronic obstructive pulmonary disease (copd) often have immune system impairment sometimes leading to greater morbidity or mortality following infection with influenza compared with healthy adults of the same age. these individuals also have an influenza-related hospitalization and excess mortality rate significantly higher than those without chronic disease [ ] [ ] [ ] . one study showed diabetics had . times higher odds of developing serious complications from the influenza compared to non-diabetics ( % confidence interval (ci): . , . ) [ ] . in one systematic review of avian influenza, people with diabetes had . times the odds of hospitalization with influenza compared to healthy people ( % ci: . , . ) and those with copd had . times ( % ci: . , . ), . times ( % ci: . , . ) and . times ( % ci: . , . ) higher odds of hospitalization, being admitted to the icu, and requirement ventilator assistance, respectively [ ] . several studies have found a benefit of administering pneumococcal polysaccharide and seasonal influenza vaccines to people with chronic illness [ ] [ ] [ ] . simultaneous vaccination of pneumococcus and influenza in elderly copd patients could reduce pneumonia hospitalization by % and overall mortality by % [ ] . influenza vaccination could substantially reduce hospitalization and mortality among diabetic patients and was well tolerated during an influenza season [ ] . the combination of seasonal influenza and pneumococcal vaccine (including valent pneumococcal polysaccharide vaccine (ppsv )) significantly reduced the hospitalization rate and mortality of influenza, pneumonia and other diseases such as respiratory disease, copd and congestive heart failure among the elderly compared to the uptake of influenza or pneumococcal vaccine alone [ , ] . co-administering these vaccines could significantly reduce the rate of intensive care and prolong the survival period of elderly patients with chronic diseases [ ] , and has been shown to be cost-effective [ ] . the elderly and patients with chronic disease including diabetes, copd and heart disease are recommended to be priority groups for pneumococcal and influenza vaccination by the world health organization (who) [ , ] and by the us centers for disease control and prevention (cdc) [ ] . according to chinese guidelines for vaccination, adults with these chronic diseases are recommended to receive the seasonal influenza and ppsv vaccines [ , ] . pneumococcal vaccines (ppsv and -valent pneumococcal conjugate vaccines) are also available to children for a fee. according to the manufacturer's instructions, children and younger adults with certain chronic conditions (cardiovascular disease, lung disease, diabetes, cirrhosis, spleen dysfunction, sickle cell disease, chronic renal failure, organ transplants, hiv, cerebrospinal fluid leakage) or who live in certain environments (individuals in long-term care facilities, staff at welfare organizations) are recommended to get the ppsv vaccine. these recommendations are consistent with global guidelines for prevention and treatment of chronic diseases [ , ] . the governments of some cities in china such as beijing, shenzhen, karamay and xinxiang have published policies providing free influenza vaccination to local elderly residents, while some other cities such as chongqing and ningbo implemented subsidies for the influenza vaccine in medical insurance programs for target residents [ ] . shanghai has implemented a government program providing people over years old with a free pneumococcal vaccination (ppsv ) since , but the influenza vaccine is not offered under the government's expanded program on immunization (epi) and is instead administered for a fee. there is a large population of chronic disease patients in shanghai [ ] , but data about pneumococcal and influenza vaccination coverage among patients with chronic disease is absent. a survey from china found that influenza vaccination was actually lower in adults with highrisk health conditions ( . %) than those without ( . %) [ ] . more information is needed about who gets vaccinated. in this study, we use the data from a chronic disease management information system in shanghai to estimate vaccination coverage and characterize predictors of influenza and pneumococcal vaccination among people with chronic disease in shanghai. we assess whether there are differences in coverage in pneumococcal vaccine and influenza vaccine across age groups, urbanicity and chronic disease diagnoses. we hypothesize that influenza vaccine has lower coverage than pneumococcal vaccine due to differentials in price, that uptake of both vaccines is lower in low age groups compared to high age groups, that uptake of both vaccines is lower in rural areas than in urban areas, and that coverage for both vaccines is higher among those with more chronic diseases. this study used a retrospective cohort design. during july , the data were obtained from three distinct sources -( ) the shanghai chronic disease management information system and ( ) the shanghai immunization program information system which are both housed at the shanghai cdc, and ( ) the hospital record system, which is located at the shanghai health commission for hospital records. the individual's personal id was used to link the three information systems. throughout shanghai, patients ≥ years old diagnosed with hypertension and diabetes are asked if they want to be included in a centralized databasethe chronic disease management information system. inclusion in the database means that the patients will receive more standardized management of their disease. an estimated % of individuals with hypertension and diabetes in shanghai are enrolled in this database. the other % include those who do not know they have a chronic disease, who have not gone to visit the doctor, or who are unwilling to be enrolled into the system. general practitioners follow up with patients every months at community health centers and input data related to these visits into the chronic disease management information system. this database contains information on sex, birthdate, township residence, occupation and diagnostic information pertaining to hypertension and diabetes. no other individual-level information was available from the dataset. all patients from the shanghai chronic disease management information system were included in this study. data in the immunization program information system were captured and entered by vaccination providers at community health care centers. data are uploaded daily from these health centers' electronic registries into the immunization program information system. pneumococcal vaccination information from january to july and influenza vaccination information from the / influenza season were obtained from the shanghai immunization program information system. types and dates of vaccination were extracted from the immunization program information system. the shanghai cdc and the shanghai health commission implement regular data quality checks of the immunization program information system. diagnosis of copd was obtained from the hospital record system. the international classification of diseases (icd) was used to define chronic diseases in the chronic disease management information system and the hospital record system. hypertension was defined as i -i , diabetes was defined as e -e and copd was defined as j . the chronic diseases in this study represent those at risk for pneumococcal disease or influenza [ , ] . the american diabetes association recommends individuals with diabetes to have both vaccines [ ] . the global initiative for chronic obstructive lung disease has similar recommendations for those with copd [ ] . hypertension is not thought to be linked to either disease, but individuals with hypertension were still included because they were in the original chronic disease management information system and because many are older, and thus may be age-eligible for a free ppsv in shanghai. urbanicity was defined by characteristics of the township where participants resided. residency status refers to locals vs. non-locals, with locals defined as registered permanent residents of shanghai, and non-locals as migrants from other cities who have moved into shanghai for over months. urban areas are those where ≤ % of locals and ≤ % of non-locals were engaged in agricultural work; suburban areas had ≤ % of locals but > % of non-locals engaged in agricultural work; and rural areas had > % of locals in agricultural occupations. classification of occupation was defined according to the china national standard [ ] . the main outcome was receipt of pneumococcal and influenza vaccination. vaccination coverage was calculated by sex, age group, urbanicity, occupation, type and number of chronic diseases. pearson's chi-square test was used to compare the vaccination coverage among the different subgroups. we also analyzed the relationship between predictor variables (sex, age group, urbanicity, occupation, type and number of chronic diseases) and the outcomes using logistic regression models through a forward stepwise method (variable included at p-value of . , excluded at p-value of . , with α = . ). data were analyzed using spss version . vaccination status by township was mapped with qgis . (qgis geographic information system. open source geospatial foundation project). the shapefile map was obtained from shanghai surveying and mapping institute (https://www.shsmi.cn/info/ilist.jsp?cat_id= ). the sample of , , patients from the chronic disease management information system included a majority of females ( . %), more individuals above years ( . %) than other age groups, more urban residents than other locales ( . %), and most individuals were retired ( . %). the majority of patients had hypertension ( . %) with fewer diagnosed with diabetes ( . %) and copd ( . %); a very low proportion had been diagnosed with all three ( . %) ( table ) . only . % patients were vaccinated for pneumococcal from january to july , and vaccination coverage of influenza in / influenza season was exceedingly low at . %. vaccination coverage differed significantly across most socio-demographic characteristics. for both pneumonia and influenza vaccinations, coverage was highest in those - years ( . and . %, respectively) compared to other age groups (p < . ). pneumococcal vaccination was highest in rural areas ( . % compared to . % in urban areas, p < . ) whereas influenza vaccination was highest in urban areas ( . % compared to . % in rural areas, p < . ). for both pneumococcal and influenza vaccination, coverage was highest among those with copd ( . and . %, respectively), compared to those with hypertension ( . and . %, respectively) or diabetes ( . and . %, respectively) (p < . , respectively). there was a dose-response relationship between number of chronic diseases and vaccination coverage; pneumococcal vaccination uptake was . % among those with three conditions, compared to . and . % for those with or only condition (p < . ). influenza vaccination coverage was . , . and . % for those with , , or conditions (p < . ). vaccination coverage also varied geographically, with pneumococcal vaccination coverage highest in jiading and songjiang, at the periphery of shanghai, and was relatively low in the inner districts of huangpu, jing'an, hongkou, and yangpu (fig. ) . influenza vaccination coverage was comparatively low across all districts, ranging from . % in fengxian to . % in xuhui. table shows the multivariable logistic regression models. these models are largely in line with the unadjusted results from table . individuals aged - had . times higher odds of pneumococcal vaccine uptake compared to individuals in their s ( % ci: . , . ). individuals in rural areas and suburban area had higher odds of pneumococcal vaccine uptake compared to individuals in urban areas. patients with and chronic diseases had respectively . ( % ci: . , . ) and . ( % ci: . , . ) times higher odds of vaccination compared to patients with chronic disease. all subjects were included in the multivariable analysis. in the adjusted model of influenza vaccination, patients aged - and above had . ( % ci: . , . ) and . ( % ci: . , . ) times higher odds of vaccination, respectively, compared to patients aged - . compared to patients in urban area, patients in suburban and rural areas had, respectively, . ( % ci: . , . ) and . ( % ci: . , . ) times the odds of influenza vaccination. patients with chronic diseases had . times the odds of uptake influenza vaccine compared to patients with kind of chronic disease ( % ci: . , . ), but there was no significant difference in those with vs chronic diseases. patients with a dose of pneumococcal vaccine had . the odds of receiving the influenza vaccine compared to those with no pneumococcal vaccine ( % ci: . , . ). influenza and pneumococcal vaccination are important for preventing illness and the elderly with chronic diseases [ ] [ ] [ ] . in a large sample of individuals with chronic diseases residing in shanghai, china, we found low pneumococcal vaccination coverage over a -year study period and even lower influenza vaccine coverage. uptake of both vaccines increased in those with more chronic diseases and with older age. chronic disease patients should be targeted for attaining high vaccination coverage compared to the remaining population. there are several overriding factors for exceptionally low coverage of pneumococcal and influenza vaccination among chronic disease patients in shanghai community: ( ) studies have found that individuals lack awareness of pneumococcal and influenza vaccine [ , ] , and physicians do not often recommend vaccinations. ( ) vaccination for adults is not convenient. community health care centers were responsible for implementing vaccinations in shanghai. most centers only provide or half days available for adult vaccination per week, while half days are available for childhood vaccination. ( ) some adverse news related to vaccines have made people reduce their trust in vaccination programs [ , ] . people with chronic disease and the elderly should have priority to take these vaccines due to their risk factors, but their chronic diseases may lead them to believe they have a higher risk for adverse reactions. ( ) there is a limited supply of influenza vaccine. these reasons were not assessed in the current study, but could be explored in future research. pneumococcal vaccination coverage among adults - years at increased risk for pneumococcal disease was . % in in the united states although it was much higher at . % among adults over years old [ ] . this is consistent with a study from spain showing a higher proportion of adults over years had received the pneumococcal vaccine ( . %) [ ] and demonstrating that vaccination levels in both young and elderly chronic disease patients in shanghai are substantially lower than those found in the us or spain. because residents over years of age in shanghai are provided with free pneumococcal vaccination, the coverage in this age groups was not surprisingly higher than younger age groups and approaching that seen in those over years in hong kong in ( %) [ ] which also offers free pneumococcal vaccination to the elderly [ ] . in our study, less than % of individuals received an influenza vaccine, which is far lower than in other countries, many of which provide free vaccine through government-sponsored or private insurance programs. similar studies have shown higher influenza vaccination coverage in the united states ( . %, among adults over years, / season) [ ] , uk ( . %, chronic disease patients, / season) [ ] , poland ( . %, chronic disease patients, / season) [ ] , korea ( . %, over years, ) [ ] , and hong kong ( %, over years, ) [ ] . our findings were relatively consistent with prior studies in china showing an average national vaccination coverage ranging between . and . % in and [ ] . the coverage among patients over years was significantly higher vs younger age groups below which was almost non-existent (i.e. close to %). one previous study found that elderly individuals who live with other family members are more likely to get vaccinated [ ] , perhaps as a result of other family members thinking the elderly, but not younger adults, need to get vaccinated or elderly individuals wanting to protect themselves against influenza as they care for their grandchildren. we found that pneumococcal vaccination coverage was higher in rural areas which distinctly contrasted with influenza vaccination coverage which was lowest in rural areas. for influenza vaccinationwhich requires payment, individuals in urban area might be more able to afford the cost of influenza vaccine while patients in rural area might not [ ] . higher pneumococcal vaccination coverage in rural areas may result from individuals trusting health care workers more [ ] . the study showed that patients with multiple chronic diseases would be more likely to take pneumococcal vaccination than those with only one kind of chronic disease. this association could arise for several reasons. individuals may perceive a greater personal risk of disease as they gain experience with more diseases. or individuals with more co-morbid chronic diseases may have had more opportunities to get immunized through having more healthcare encounters. the overall difference in uptake between influenza and pneumococcal vaccination could also be tied back to experiences and risk perceptions, as influenza could be seen as a nuisance disease that will quickly pass [ ] . the lack of funding to influenza vaccination from the government might be another important reason. pneumococcal vaccine uptake was a strong predictor of influenza vaccine uptake, which indicates that acceptance of one vaccine probably predicts for acceptable of others. since the observation of pneumococcal vaccination was from january to july and the observation of influenza vaccination was only / season, co-administration of both pneumococcal and influenza vaccines could reduce the incidence of various complications, hospitalization and mortality of chronic disease [ , , ] . only . % of total sample had taken both pneumococcal and influenza vaccine in / season, lower than that of hospitalized persons aged over years in victoria ( . %) [ ] . our study looked at vaccination coverage for influenza and pneumococcal disease including predictors for vaccination among community members in shanghai with chronic diseases. interventions or policies like government funding as a potential strategy to encourage vaccination, especially influenza vaccination among chronic disease patients, should be implemented. future studies should further examine differences in uptake of vaccines across different demographic groups. there are several strengths and limitations to this study. a strength of this study is the use of several comprehensive information systems as data sources, and the large number of individuals in the chronic disease management system. this system is opt-in for individuals with certain chronic diseases in the municipality, and an estimated % of individuals with chronic disease participate in it. it is possible that the individuals who participate in the chronic disease management system differ from those who do not. non-participants, for example, likely have lower health-seeking behaviors and so our estimates of vaccination coverage may overestimate trends in the entire population of those with these chronic diseases. future studies could evaluate why and how individuals participate in this database. in addition, limitations include a lack of information on key variables, like education and income. we only have data of pneumococcal vaccination coverage from onward and season of influenza vaccination coverage, and inclusion of additional years would have permitted analysis of trends over time. the very low vaccination coverage, particularly for influenza vaccination, limits our ability to make recommendations beyond a general recommendation to increase coverage. we found very low levels of both pneumococcal and influenza vaccination among individuals with chronic diseases residing in shanghai. these individuals should be prioritized for vaccination with both vaccines. concomitantly, there can be greater ease of access to vaccines, and promotional materials can focus on complications of disease in those with high risk conditions. clinical evaluation of chinese guidelines for community-acquired pneumonia the influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults diabetes and the severity of pandemic influenza a (h n ) infection chronic obstructive pulmonary disease in the absence of chronic bronchitis in china clinical courses and outcomes of hospitalized adult patients with seasonal influenza in korea populations at risk for severe or complicated avian influenza h n : a systematic review and meta-analysis influenza vaccination of elderly persons: reduction in pneumonia and influenza hospitalizations and deaths the additive benefits of influenza and pneumococcal vaccinations during influenza seasons among elderly persons with chronic lung disease influenza vaccine for patients with chronic obstructive pulmonary disease. cochrane database syst rev clinical effectiveness of first and repeat influenza vaccination in adult and elderly diabetic patients additive preventive effect of influenza and pneumococcal vaccines in elderly persons comparison of dual influenza and pneumococcal polysaccharide vaccination with influenza vaccination alone for preventing pneumonia and reducing mortality among the elderly: a meta-analysis. hum vaccines immunother additive benefits of pneumococcal and influenza vaccines among elderly persons aged years or older in taiwan -a representative population-based comparative study costeffectiveness of dual influenza and pneumococcal vaccination in -yearolds world health organization. -valent pneumococcal polysaccharide vaccine. who position paper accessed recommended adult immunization schedule for ages years or older chinese prevention medicine association. technical guideline on application of pneumococcal vaccine in china ( ) technical guidelines for the application of seasonal influenza vaccine in china executive summary: standards of medical care in diabetes-- global initiative for chronic obstructive lung disease. pocket guide to copd diagnosis, management and prevention. global initiative for chronic obstructive lung disease seasonal influenza vaccination in china: landscape of diverse regional reimbursement policy, and budget impact analysis shanghai: shanghai science popularization publishing house influenza vaccination of adults with and without high-risk health conditions in china world health organization. vaccines against influenza who position paper pharmacologic approaches to glycemic treatment: standards of medical care in diabetes global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease gold executive summary chinese general administration of quality supervision inspection and quarantine. classification and codes of occupations knowledge and attitude toward pneumonia and pneumococcal polysaccharide vaccine among the elderly in shanghai, china: a crosssectional questionnaire survey low coverage rate and awareness of influenza vaccine among older people in shanghai, china: a cross-sectional study china's vaccine production scare china vaccine scandal: investigations begin into faulty rabies and dtap shots vaccination coverage among adults in the united states factors associated with pneumococcal polysaccharide vaccination of the elderly in spain: a cross-sectional study. hum vaccines immunother perceptions of seasonal influenza and pneumococcal vaccines among older chinese adults vaccination coverage rates in eleven european countries during two consecutive influenza seasons influenza vaccination coverage rate according to the pulmonary function of korean adults aged years and over: analysis of the fifth korean national health and nutrition examination survey rural migrant workers in urban china: living a marginalised life the free vaccination policy of influenza in beijing, china: the vaccine coverage and its associated factors cross-cultural perspectives on the common cold: data from five populations influenza and pneumococcal vaccine coverage among a random sample of hospitalised persons aged years or more springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we appreciate the work of vaccination providers and primary care physicians in the city of shanghai who contributed data and who work on improving the health of populations with chronic diseases. authors' contributions yw conceived of the study, analyzed the data, and wrote the first draft. mc and cf contributed to study conception revised the manuscript for intellectual content. sw, and fw contributed to data analysis and revised the manuscript for intellectual content. qy , qy , yl, and xg contributed to acquiring data and revised the manuscript for intellectual content. ys, aw, and mb contributed to interpreting the data and revising the manuscript for intellectual content. all authors gave final approval for the study to be published. research was supported by the chinese association of preventive medicine (grant # to yan shi) and the shanghai health commission (grant # to yuheng wang). the funding body had no role in the design of the study and collection, analysis, or interpretation of data. the datasets analyzed for the current study are not publicly available because they contain detailed medical histories of chronic patients, but are available from the corresponding author on reasonable request. the protocol for this research was approved by the ethical review board of the shanghai municipal center for disease control and prevention (scdc). informed consent was exempted because it was limited to analysis of previously de-identified data collected for medical and public health surveillance purposes. not applicable. the authors declare that they have no competing interests. key: cord- -u m x l authors: crupi, robert s.; di john, david; mangubat, peter michael; asnis, deborah; devera, jaime; maguire, paul; palevsky, sheila l. title: linking emergency preparedness and health care worker vaccination against influenza: a novel approach date: - - journal: jt comm j qual patient saf doi: . /s - ( ) - sha: doc_id: cord_uid: u m x l background: health care workers (hcws) can acquire and transmit influenza to their patients and coworkers, even while asymptomatic. the u.s. healthy people initiative set a national goal of % coverage for hcw influenza vaccination by . yet vaccination rates remain low. in the – influenza season, flushing hospital medical center (fhmc; new york) adopted a “push/pull” point-of-dispensing (pod) vaccination model that was derived from emergency preparedness planning for mass vaccination and/or prophylaxis to respond to an infectious disease outbreak, whether occurring naturally or due to bioterrorism. launch of the hcw vaccination program: in mid-september , a two-week hcw vaccination program was launched using a sequential pod approach. in push pod, teams assigned to specific patient units educated all hcws about influenza vaccination and offered on-site vaccination; vaccinated hcws received a identification (id) validation sticker. in pull pod, hcws could enter the hospital only through one entrance; all other employee entrances were “locked down.” a id validation sticker was required for entry and to punch in for duty. employees without the new validation sticker were directed to a nearby vaccination team. after the push/pull pod was completed, the employee vaccination drive at fhmc was continued for the remainder of the influenza season by the employee health service. results: using this model, in two days % of the employees were reached, with % of those reached accepting vaccination. conclusions: this model provides a novel approach for institutions to improve their hcw influenza vaccination rates within a limited period through exercising emergency preparedness plans for infectious disease outbreaks. w ho watches the watchers?" was a phrase rendered from the "satires" of the ancient roman poet juvenal. health care workers (hcws) are supposed to be the watchers of our health, helping ensure that we all stay healthy and that diseases are contained and not spread to others. even though influenza vaccination has been found to be the single most important measure for preventing hospital-acquired influenza, hcws continue to have low vaccination rates. in november the u.s. department of health & human services published a health promotion and disease prevention initiative, healthy people , establishing a goal of a % rate for influenza vaccination of hcws by . yet, the national vaccination rate for hcws remains at unacceptably low levels: % in the - influenza season, % in - , % in - , and % in - . [ ] [ ] [ ] [ ] in , in an attempt to address the failure to improve hcw vaccination rates, the u.s. centers for disease control and prevention (cdc) published recommendations, which focused on three strategies: educating hcws about benefits of vaccination; providing annual, free on-site vaccination; and obtaining signed declination forms for vaccine refusers. , also in , the joint commission established a new infection control standard for influenza vaccination of hcws that included education, on-site access to vaccination, and ongoing program evaluation to improve hcw participation. - * health care institutions have attempted to increase their immunization rates using a variety of methods: education, reminder notices, providing small incentives, establishing easy access to free vaccination, active promotion of vaccination within the workplace, and/or compulsory vaccination as a condition of employment. [ ] [ ] [ ] except for mandatory programs that have achieved vaccination acceptance rates as high as . % article-at-a-glance background: health care workers (hcws) can acquire and transmit influenza to their patients and coworkers, even while asymptomatic. the u.s. healthy people initiative set a national goal of % coverage for hcw influenza vaccination by . yet vaccination rates remain low. in the - influenza season, flushing hospital medi cal center (fhmc; new york) adopted a "push/pull" point-ofdispensing (pod) vaccination model that was derived from emergency preparedness planning for mass vaccination and/or prophylaxis to respond to an infectious disease outbreak, whether occurring naturally or due to bioterrorism. launch of the hcw vaccination program: in mid-september , a two-week hcw vaccination program was launched using a sequential pod approach. in push pod, teams assigned to specific patient units educated all hcws about influenza vaccination and offered on-site vaccination; vaccinated hcws received a identification (id) validation sticker. in pull pod, hcws could enter the hospital only through one entrance; all other employee entrances were "locked down." a id validation sticker was required for entry and to punch in for duty. employees without the new validation sticker were directed to a nearby vaccination team. after the push/pull pod was completed, the employee vaccination drive at fhmc was continued for the remainder of the influenza season by the employee health service. results: using this model, in two days % of the employees were reached, with % of those reached accepting vaccination. conclusions: this model provides a novel approach for institutions to improve their hcw influenza vaccination rates within a limited period through exercising emergency preparedness plans for infectious disease outbreaks. * standard ic . . : the hospital offers vaccination against influenza to licensed independent practitioners and staff. element of performance : the hospital provides influenza vaccination at sites accessible to licensed independent practitioners and staff (ic- -ic- ). the joint commission journal on quality and patient safety under threat of termination, most employment-related programs have achieved only small increases in immunization rates. [ ] [ ] [ ] at our institution, implementing some of these methods resulted in only modest gains in hcw vaccination rates, with an acceptance rate of only % in the - vaccination season. as a result, we decided to employ an emergency preparedness model as the primary means for vaccinating our employees in the - season. interest in the ability to recognize and respond to a bioterrorism or naturally occurring event has intensified during the past years. exercises have focused on problems that hospitals would face with respect to ( ) leadership and decision making, ( ) prioritization and distribution of antibiotics and vaccines, and ( ) applying principles of disease containment, including facility lockdown. recent events, including the emergence of severe acute respiratory syndrome (sars) in november to july , concerns over avian influenza, and, most recently, pandemic h n influenza, have prompted hospitals to reappraise their emergency preparedness plans. however, regular drilling of such plans to challenge their inherent assumptions is often lacking, giving rise to a false sense of security known as the "paper plan syndrome." , modification of emergency preparedness plans through drills and exercises is required to render them more effective. at our institution, the decision to link the hcw influenza vaccination program to exercising our emergency preparedness plan was viewed as an opportunity to enhance the effectiveness of both. in this article, we report on the use of a novel program to increase influenza vaccination rates of hcws at a community hospital by exercising its emergency preparedness plans for mass vaccination and/or prophylaxis for infectious disease outbreaks as a model for improvement of both employee vaccination rates and emergency preparedness. the flushing hospital medical center (fhmc) in flushing, new york, is an urban, -bed, acute care community hospital with , employees, situated in a culturally diverse neighborhood of new york city. in , our full-service emergency department (ed) treated , patients; our outpatient departments saw , patients. in mid-september , we launched our hcw vaccination program with a widely disseminated, facility-based educational campaign about seasonal influenza vaccination that used informational pamphlets, posters, and workshops in a twoweek period. at the campaign's conclusion, we initiated, with no advance notification, influenza vaccination efforts using a sequential "push/pull" point-of-dispensing (pod) approach. the push pod. push refers to actively offering vaccination at locations to which employees are assigned to work. for the purpose of our program, we defined all hospital employees as hcws because we believe that interaction between employees, patients, and visitors places all at potential risk of acquiring and spreading influenza. applying the incident command system (ics) model derived from emergency preparedness planning, vaccination teams established by the nursing department and assigned to specific patient units reported to the command center at : a.m. ( : ) on the day of the push pod. , before deployment, each team was given a -minute focused in-service on dissemination of vaccine information to potential recipients, the use of permission/declination forms, and vaccine administration. on arrival in each clinical unit or office, the vaccination teams briefly educated all hcws about the importance of influenza vaccination and offered on-site vaccination to those who consented. there was no cost to the employee. those who declined vaccine for any reason were required to sign a declination form. only after vaccination or signing the declination form was a validation sticker placed on the hcw's identification (id) badge to easily identify employees already screened. the teams reported back to the command center after all employees present on the assigned units were reached, a process that took about minutes. data for employees reached, vaccinated, or declining vaccination were recorded. assigned push pod teams reported to the command center at : p.m. ( : ) and again at midnight ( : ) to cover all working shifts: all components of the program were repeated. the pull pod. pull refers to the process of actively identifying hcws who were not reached during the push phase the previous day. in this second phase, between : a.m. ( : ) and : a.m ( : ), hcws could enter the hospital only through one entrance. all other employee entrances were "locked down" in compliance with the new york city building fire code regulations. at our institution, all employees-including physicians and management-are required to punch in at the beginning of their shift. electronic time-clock punch-in devices in the facility were disabled except for the one nearest to this open employee entrance. a id validation sticker was required for entry and to punch in for duty. those employees without the sticker were directed to a nearby vaccination team. vaccine was administered or the hcw was required to sign a declination form. only then could the hcw receive an id validation sticker and be allowed entry into the facility. after the two-day program, the data for the number of doses of vaccine administered and declination forms signed were tabulated using microsoft excel . after the push/pull pod was completed, the employee vaccination drive at fhmc was continued for the remainder of the influenza season by the employee health service (ehs). as a result of this two-day exercise, , ( %) of the , total employees of our institution were reached. as shown in table (above), the push pod phase reached of fhmc employees ( %), with ( %) accepting influenza vaccine. during the pull pod, an additional hcws ( %) were reached, of whom ( %) were vaccinated (table ) . together, the two-day push/pull pod drill achieved a vaccination rate of % among the , employees who were reached, representing % ( / , ) of all hcws (table and table [right]). for - , the overall hcw influenza vaccination rate for fhmc was %, which included vaccinations offered by the ehs following the two-day push/pull pod and documented vaccinations received outside fhmc (table ). this rate was significantly higher (p < . ) than the % rate for the - season ( table , right). the push/pull pod plan we have described for influenza vaccination of hcws in - was initially devised as part of our emergency preparedness/drilling for mass immunization/ prophylaxis for infectious disease outbreaks. the linkage of our emergency response plan with improvement in hcw influenza vaccination rates is a unique approach that can enhance the effectiveness of both programs. using components of our emergency preparedness plans, including the ics model, we were able to reach % of hospital employees and vaccinate % of our total workforce in a two-day period, nearly achieving the national average for seasonal influenza vaccination of hcws within that limited time frame. with respect to emergency preparedness planning, the initiative offered an opportunity to organize, execute, and evaluate performance for mass vaccination/prophylaxis in the context of a drill. during the push phase, the incident manager of the ics was able to monitor the deployment and success of vaccination teams in real a novel feature of our program was the facility lockdown in the pull pod. limiting access to the facility as well as restricting access to the device required to clock in for work only to those employees who had been issued id validation stickers during the push pod for either having received or declined influenza vaccine proved to be a successful method for identifying, reaching, and vaccinating additional hcws. the use of mobile vaccination teams is an important and effective method to increase hcw influenza vaccination rates. such teams engage in face-to-face interactions with hcws to specifically address their questions and concerns, potentially resulting in an increased acceptance of influenza vaccination. hcws might also be positively influenced by observing their coworkers accepting vaccination. the process also offered the advantages of employee convenience, avoidance of staffing disruptions, and no cost to the employee. the pull pod phase of our vaccination program, involving a facility lockdown as part of emergency preparedness planning response to infectious disease outbreaks, is to our knowledge and a review of the literature, a novel approach in reaching employees. although our pilot lockdown of ½ hours during a single weekday morning work-shift change was only a brief test, we were successful in reaching employees not encountered in the push pod. although many hcws declined vaccination in this pull phase, vaccination declinations had to be signed to clock in for work. future exercise planning would determine if additional or longer lock-down periods at different shift times can be implemented at our busy urban community hospital. for larger institutions, the manner or feasibility of implementation of the pull pod needs to be considered. our data set only identified whether or not hcws were vaccinated; those who were not vaccinated signed a declination. although this study was not designed to examine vaccine refusal, reasons for declination were obtained. the most common reasons cited were fear of side effects and the belief that the vaccine was ineffective. these findings are consistent with other studies. addressing the reasons for declination would help refine and focus educational efforts to help increase hcw vaccination rates in the future. we did not report on the - vaccination season, given the unusual circumstances of that influenza season. new york state had instituted mandatory influenza vaccination for hcws, only to later suspend the mandate because of disruptions in vaccine supply for both seasonal influenza and mono-valent h n vaccine. some reluctant hcws agreed to be vaccinated because of the original mandate, whereas others withheld their consent while awaiting results of legal challenges. there was also anxiety expressed by some hcws over receiving two vaccinations. in particular, concerns over the "newness" of the h n vaccine and recollections of problems associated with "swine flu" vaccine in might have had a crossover effect in creating or reinforcing negative perceptions about influenza vaccines in general. the challenge of achieving and maintaining high annual hcw influenza vaccination rates in the absence of a requirement for vaccination necessitates a multifaceted approach. mandatory vaccination is increasingly being recommended by professional organizations, including the society for healthcare epidemiology of america, the infectious diseases society of america and the american academy of pediatrics. [ ] [ ] [ ] however, even if such mandates succeeded in achieving high influenza vaccination rates among hcws, there would still be the need to regularly exercise emergency preparedness plans for mass vaccination or prophylaxis in preparation for other potential infectious disease threats. , the emergency preparedness plan as exercised tested our inherent assumptions and succeeded in reaching a majority of our employees over a limited time frame. the plan was executed without altering staffing patterns and allowed for real patients to receive care without interruption. the exercise demonstrated the ability of our ics to successfully deploy multidisciplinary teams and monitor their activities, to rapidly screen hcws, to efficiently distribute vaccine, and to collect measurable data on performance to drive the process. the push/pull pod model derived from emergency preparedness planning is an effective tool for improving influenza vaccination rates among hcws. the addition of our pull pod, that is, the lockdown phase of restricting access to the facility, is a unique strategy that was implemented and found to be successful. this model addresses issues of standards of care and performance improvement for hcw influenza vaccination and emergency preparedness planning and drilling for mass vaccination and prophylaxis. we believe that this model can serve as a dual platform for other institutions to improve their hcw vaccination rates and emergency preparedness planning. the ability to reach and offer influenza vaccination to a majority of hcws early in the influenza vaccination season, and to accomplish such vaccination efficiently, allows for targeted initiatives for those hcws most resistant to vaccination. future studies should explore different approaches to the push/pull model as it relates to duration, frequency, sequencing, or separating its components to create best practices that fit the needs of different institutions. mandatory influenza vaccination of hcws would clearly have the most significant impact on improving acceptance rates but would still not obviate the need to regularly exercise emergency preparedness plans in preparation for other potential infectious disease threats. dr. di john is a speaker for sanofi-pasteur, glaxosmithkline, and novartis. preliminary data from this study were presented by dr. crupi and his colleagues at flushing hospital medical center (fhmc) in a poster at the th annual scientific meeting of the society for healthcare epidemiology of america (shea), march - , , in san diego. the authors express their deep gratitude for the efforts of the departments of nursing, pharmacy, employee health, and security, as well as the hospital administration and all fhmc employees for their cooperation in making this study possible. they also thank jane r. zucker, m.d., m.sc., assistant commissioner, bureau of immunization of the new york city department of health and mental hygiene, for her support, encouragement, and guidance. who watches the watchers star trek the next generation prevention and control of influenza: recommendations of the advisory committee on immunization practices (acip) department of health & human services: healthcare personnel initiative to improve influenza vaccination toolkit national foundation for infectious diseases: call to action: influenza immunization among health care personnel prevention and control of influenza prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices prevention and control of influenza with vaccines: recommendations of the advisory committee on immunization practices (acip) influenza vaccination of health-care personnel: recommendations of the healthcare infection control practices advisory committee (hicpac) and the advisory committee on immunization practices (acip) will carrots or sticks raise influenza immunization rates of health care personnel? joint commission on accreditation of healthcare organizations: new infection control requirement for offering influenza vaccination to staff and licensed independent practitioners requiring influenza vaccination for health care workers influenza vaccination of health care workers in the united states mandatory influenza vaccination of health care workers: translating policy to practice albany judge blocks vaccination rule relationship of influenza vaccination declination statements and influenza vaccination rates for healthcare workers in us hospitals poster presented at the th annual scientific meeting of the society for healthcare epidemiology of america (shea) greater new york hospital association: do you know your incident command system? ensuring effective emergency response and management a plague on your city: observations from topoff designing a disaster plan: important questions disaster planning, part ii: disaster problems, issues, and challenges identified in the research literature terrorism and disaster management medical society of the state of new york: the emergency management institute's compliance courses on national incident management systems (nims) for physicians use of a mobile cart influenza program for vaccination of hospital employees infectious diseases society of america (idsa): idsa policy: mandatory immunization of health care workers against seasonal and pandemic influenza committee on infectious diseases: policy statement-recommendation for mandatory influenza immunization of all health care personnel. pediatrics, in press meeting the challenges of bioterrorism: lessons learned from west nile virus and anthrax pediatric infectious disease infectious diseases, department of internal medicine is administrator, department of emergency medicine key: cord- -m di dpt authors: holm, majbrit v.; blank, patricia r.; szucs, thomas d. title: influenza vaccination coverage rates in europe – covering five consecutive seasons ( – ) in five countries date: - - journal: influenza other respir viruses doi: . /j. - . . .x sha: doc_id: cord_uid: m di dpt objective to understand potential drivers and barriers to influenza vaccination in the general population. methods household surveys were conducted in five european countries between and . results overall influenza vaccination coverage increased over the years and reached · % in / . among the elderly ≥ years, the rate increased significantly to · % ( / ). the most common reason for being vaccinated over the years was the perception of influenza as a serious illness, which people want to avoid. the main reason for not getting vaccinated among those never previously vaccinated was feeling that they were unlikely to catch influenza. a recommendation by the family physician was the most encouraging factor for vaccination. the severity of influenza and the efficacy of vaccination are well documented in the medical literature. , eradication of influenza is impossible but continuous immunization of the population can minimize the impact of the disease. in addition to providing substantial health benefits, vaccination may also be associated with significant economic benefits, not only among the elderly but also among healthy working adults and children. despite this knowledge and ongoing efforts by policy-makers, physicians and other healthcare providers, influenza vaccination rates in the five european countries surveyed remain limited, with the additional effect that manufacturing capacity may be too low for producing a sufficient amount of an appropriate monovalent vaccine when a pandemic occurs. the who states that the risk of a new pandemic is at its highest level since the last pandemic in . this situation might influence the immunization coverage rates in the population. published literature evaluating vaccination coverage rates in europe shows that importance placed on influenza vaccination varies greatly between countries. two recent studies covering several european countries have been published. , this report is an update of the earlier work by szucs and muller. we now have data available for five consecutive influenza seasons which allows us to go beyond the usual cross-sectional approach to analyzing vaccination rates. the main focus of this paper is on high-risk group coverage. a second objective is to understand the determinants for being or not being vaccinated, and to describe the populations' opinions regarding influenza and vaccination. in this context, we examine whether the threat of avian influenza had an impact on recent changes in vaccination coverage in the different countries. this survey is an ongoing assessment of influenza coverage rates in france, great britain, italy, spain, and germany. during [ ] [ ] [ ] [ ] [ ] four target groups were specified. . individuals aged ‡ years . individuals who suffer from a chronic illness . individuals who work in the medical field . combined group of individuals aged ‡ years or who suffer from a chronic illness or who work in the medical field. for example, in germany the group of chronic illness sufferers is defined according to the german standing commission on immunization, as children, adolescents and adults suffering from chronic diseases of respiratory organs, chronic cardiovascular or liver diseases, as well as nephropathies and diabetes, or other metabolic disorders. in our study, people suffering from heart diseases, pulmonary diseases, diabetes, or other chronic illnesses were included in the chronic illness group. the survey questions have been published previously. the questions covered reasons to get vaccinated this winter, reasons for not getting vaccinated against influenza, and options that would encourage persons to get vaccinated against influenza. for the ⁄ survey, questions on influenza pandemics and avian influenza were added. the survey populations were representative of the adult population from age years (germany, italy, spain); from age (france), or from age (great britain). in spain, persons above age were not covered. sample weights were applied to correct for small deviations from the applicable age and gender quota and the annual datasets were pooled. statistical evaluation used spss Ò version for windows. bivariate associations of categorical variables were assessed using the chi-squared test. a chi-squared test for trend was used to assess time trends. in the case of continuous variables, differences of means were tested using oneway anova. for all statistical tests, two-sided p = ae was used as the level of statistical significance. ninety-five percent confidence intervals (ci) were reported as appropriate. due to the descriptive nature of these data, no correction for multiple testing was made. covariates identified as predictors of influenza vaccination in univariate analysis were considered as candidates for multivariable analysis. logistic regression was used to identify independent correlates of the outcome of interest, i.e. vaccination coverage. the overall sample consisted of persons. in table an overview of the sample is given for the year ⁄ only. in an earlier publication, similar data can be found for the years ⁄ and ⁄ . spain was expected to show a lower number of people over years of age, as the survey covered only persons £ years old. the reason for the great deviation in the number of chronic ill persons in germany compared to other countries remains unclear as there is no difference in the way the question was asked in the five countries. the overall vaccination coverage across countries, based on an average of the country samples, decreased from ae % ( % ci: ae - ae %) in season ⁄ to ae % ( % ci: ae - ae %) in season ⁄ . thereafter, it increased to ae % ( % ci: ae - ae %) in season ⁄ , to ae % ( % ci: ae - ae %) in season ⁄ , and to ae % ( % ci: ae - ae %) in season ⁄ ( figure ). the increase between season ⁄ and season ⁄ was statistically significant (p < ae ). this was mainly due to significant increases in immunization uptake in germany and italy, where the coverage increased to ae % and ae %, respectively, in ⁄ . adjusting the overall vaccination rate in europe (weighting the population sizes) resulted in an average vaccination rate of ae % in season ⁄ . vaccination rates were highly age-dependent. older age was associated with higher vaccination rates. in season ⁄ the immunization uptake across all countries was holm et al. ª the authors higher for all age groups compared to the previous seasons ( figure ). across all five seasons, vaccination rates appeared to be associated with gender in great britain, italy, and spain. in great britain a higher vaccination rate was observed in women, whereas in italy and spain, the majority of the vaccinated were men (details not shown). in the year ⁄ , ae % of the respondents expressed the intention to get vaccinated against influenza in the coming winter of ⁄ . over the years, the proportion of those expressing such an intention was on average %, about % higher than the actual vaccination rate. the gap was highest in germany (between % and % over the years) and almost non-existent in italy in season ⁄ . the overall vaccination coverage rate in persons aged ‡ increased over time ( figure ). the increase between season ⁄ and season ⁄ was statistically significant (p < ae ). coverage in the elderly was highest in great britain ( %) and lowest in germany and italy ( ae %). it was significantly different from the population under years of age. since season ⁄ , data on health status in terms of chronic illness were collected. persons with a chronic illness showed significantly higher vaccination coverage than those not suffering from a chronic disease (figure ) . the highest coverage among the chronically ill persons was found in great britain ( ae %) and the lowest in france ( ae %). working in the medical field did not seem to be a driving factor for vaccination as the vaccination coverage rate in this sub-population was not significantly different from the rest of the sample (figure ) , at the unadjusted level. however, adjustment for age and other covariates revealed the presence of an association ( table ). for persons in the combined target group a significant difference in coverage was found compared to the non-target group population. the vaccination rate in this group increased over the years and the increase in season ⁄ was significantly different from the previous season. the coverage rate in the combined target group was highest in great britain ( %) and lowest in germany ( %). however, this result could be influenced by the observed difference in the proportion of chronically ill respondents in germany (table ) . table shows unadjusted odds ratios for the target groups for the year ⁄ . odds ratios across all seasons did not greatly differ from the ⁄ results. adjusted odds ratios were investigated in logistic regression models. the adjustment took into account gender, age over years, work in medical field, and chronic illness. for years where data on chronic illness were not available, data were only adjusted for the remaining covariates. the odds ratios for the combined target group were only adjusted for age. multivariate adjustment showed significantly higher vaccination rates for healthcare workers in great britain (or: ae , % ci: ae - ae ), france (or: ae , % ci: ae - ae ), italy (or: ae , % ci: ae - ae ), and spain (or: ae , % ci: ae - ae ). the impact of chronic illness on the vaccination rate was significantly lower after multivariate adjustment, mainly due to taking into account the effect of age (germany or: ae , % ci: ae ; ae , italy or: ae , % ci: ae ; ae , france or: ae , % ci: ae ; ae and spain or: ae , % ci: ae ; ae ). all other odds ratios were not substantially changed by multivariate adjustment (details not shown). for those who reported to have been vaccinated in season ⁄ , the most frequently stated reasons were that influenza is a serious illness that people want to avoid and that they have received a recommendation from their family physician or nurse (table ). in france the most commonly stated reason for vaccination was that the vaccine is provided free. over the -year period, the ranking of the cause for getting vaccinated did not change substantially. the proportion of respondents whose decision to get vaccinated was influenced by the recent attention given to avian influenza or a possible influenza pandemic varied from % in germany to ae % in spain. it was ae % in great britain, ae % in italy, and ae % in france. across all countries, the persons who gave the threat of avian influenza as a reason for vaccination were not found to be statistically different from other vaccinated persons (table ) . only the proportion of those vaccinated for first time was statistically higher among the group influenced by the attention given to avian influenza (p < ae ). for those of the total survey population who had never been vaccinated, the reasons for not being vaccinated varied across countries over the years of observation. overall, the most frequently stated reasons were no expectation of catching influenza, not having considered vaccination, and absence of a family physician's recommendation ( table ) . the level of knowledge about influenza and the vaccine among the general population was similar across countries. seventy-nine percent of the respondents agreed with the statement that you can catch influenza even if you are vaccinated against it. sixty-eight percent agreed with the statement that if you catch influenza after having had the vaccine, the infection is less severe. fifty-eight percent said that it is important to get the influenza vaccine each year and % agreed that the side effects associated with the vaccine (fever, headache...) are acceptable. most of the participants did not agree with the following statements: the vaccine is not useful if you are in good health and if you have the vaccine, you will not catch influenza. a recommendation by the family physician or nurse, and receiving more information regarding the vaccine being efficacious and well tolerated were regarded as the most important factors that might encourage vaccination (table ) . data on this question were not available for france. the vaccination coverage rate in the total sample is currently ae % (season ⁄ ). a statistically significant increment of ae % was observed between season ⁄ and season ⁄ . this was mainly due to significant increases in immunization uptake in germany and italy. in germany reimbursement of vaccination for all age groups has been implemented in several federal states to encourage vaccination rates. this may explain the high coverage rates in germany. a sub-analysis of the data obtained in great britain showed that wales reached a vaccination rate of ae % in season ⁄ , higher than the german coverage rate ( ae %). the immunization rates in the defined highrisk target groups were also increased in season ⁄ . in particular, higher age and suffering from chronic illness were important predictors of vaccination. in the elderly ‡ years, the lowest coverage was observed in germany and italy and the highest in great britain. in great britain or, odds ratio; ci, confidence interval; p-value, pearson chi-squared. *reference category. holm et al. ª the authors general practitioners are encouraged to recommend vaccination to eligible high-risk patients, which may have contributed to the high vaccination rates in the target groups. in spain, vaccination coverage increased in those aged ‡ after the age threshold of vaccination recommendations was reduced to age in some communities. as healthcare workers are in contact with patients, it is critical for this group to be vaccinated in order to reduce transmission of the disease. additionally, they play an important role in the communication and motivation of the public to get vaccinated. however, the vaccination rate among healthcare workers remained low compared to the other high-risk groups. a recent published literature review identified low coverage rates in this professional group to be especially a problem in europe, with vaccination rates between % and %. our observation of coverage rates increasing from % to % over the years is consistent with earlier findings. considering the entire population, % of the ⁄ respondents expressed the intention to get vaccinated in season ⁄ . the gap between those who intended to get vaccinated and those who actually received vaccination was stable over the years, at % on average. there was, however, substantial variation between countries. the persistence of this gap indicates the potential to increase vaccination coverage rates in europe. however, realizing this potential, activating the correct drivers, and dealing with the barriers to vaccination remains a challenge. only italy seems to have been able to diminish the gap. in season ⁄ the italian vaccination campaign was intensified by the ministry of health due to the increased focus on severe acute respiratory syndrome. a realistic vaccination coverage rate target in europe could be set at the level of vaccination intentions ( %). in the general population, the characteristics of those who gave the attention to avian influenza -a possible influenza pandemic as a reason for vaccination -were not found to be statistically different from the rest of the vacci-nated group. nonsignificant trends hinted at a larger proportion of women and a slightly lower mean age of this relatively small subgroup. the majority of persons influenced by the attention given to avian influenza were those who were vaccinated for the first time. in the general population, a recommendation from the family physician is the most important encouragement for vaccination. this confirms findings from several previous studies. , , it was also stated that more information on the vaccines regarding tolerability and efficacy would motivate persons to get vaccinated. we did not cover the vaccination rates of schoolchildren in our article. however, high vaccination coverage in children and subsequent positive external effects will be difficult to achieve at least in some countries. this reason makes high vaccination rates in the risk populations even more important. telephone surveys are an appropriate method to investigate influenza vaccination uptake at the population level. telephone interviews have been used on several occasions to study vaccination rates in europe. , , the main advantage of telephone interviews is a potentially high response rate obtained in an affordable and fast manner. the selection process based on random dialing of telephone numbers has been shown to be of high quality. in france, the questionnaire was a self-administered mail survey. in mailed questionnaires, there is a high risk of respondents omitting questions and of a low return rate. on the other hand, mailed questionnaires are an even more affordable option for large-scale surveys. the limitations of the present data collection are described in greater detail in an earlier publication. an increasing problem is the use of wireless telephones. in the usa people with landlines had a higher odds ( ae ) of being vaccinated than those with only access to wireless telephones. if this is believed to be similar in europe, we might have slightly overestimated the vaccination rate. the different methodological approach used in france may have affected the reliability of the comparison across countries. this is supported by the fact that the french gave different reasons for and against vaccination compared to the other countries. the who considers the current influenza pandemic risk to be at its highest level since the last pandemic. hence, efforts should be made at all national and international levels to increase vaccination coverage according to the who objectives (i.e. % vaccination coverage to be reached in the elderly in and % in ). among elderly ‡ years, a vaccination rate of % or higher was reached in all the countries studied. so far, only great britain has reached the target of % with an immunization rate of % in season ⁄ . the existence of national targets may provide a partial explanation for this success. vaccines for preventing influenza in the elderly individual and community impact of influenza control of influenza. public health policies influenza vaccination in europe: an inventory of strategies to reach target populations and optimise vaccination uptake influenza vaccination coverage rates in five european countries-a population-based cross-sectional analysis of two consecutive influenza seasons rki-ratgeber infektionskrankheiten -merkblä tter fü r Ä rztezielgruppen der impfung the influenza immunisation programme [www document protocole de mise en place de la chimio-prophylaxie dans une collectivité de personnes à risque lors d'une é pidè mie de grippe, en pé eriode de circulation du virus grippal influenza coverages in spain and vaccination-related factors in the subgroup aged - years zahlt meine kasse fü r die grippeschutzimpfung? influenza vaccination of healthcare workers: a literature review of attitudes and beliefs seasons determinants of adult influenza and pneumonia immunization rates cross-sectional study on influenza vaccination influenza vaccination coverage in elderly people influenza vaccination coverage and reasons to refrain among high-risk persons in four european countries health measurement scales. a practical guide to their development and use telephone coverage and health survey estimates: evaluating the need for concern about wireless substitution prevention and control of influenza pandemics and annual epidemics, th wha, th plenary meeting department of health. summary of flu immunisation policykey points about flu immunisation policy in england this study was made possible by an unrestricted research grant from aventis-pasteur msd, lyon, france. we thank the geig for making the french data available for analysis. furthermore, we would like to thank bertrand verwee, christine pilet from sanofi pasteur, and matthias schwenkglenks from the european center of pharmaceutical medicine, basel, switzerland, for their comments on the study and on the data analyses. key: cord- -p ysi authors: davis-wurzler, gina m. title: update on current vaccination strategies in puppies and kittens date: - - journal: vet clin north am small anim pract doi: . /j.cvsm. . . sha: doc_id: cord_uid: p ysi vaccines remain one of the practitioner’s greatest tools in preventing disease and maintaining individual and population health. this article is an update to “current vaccination strategies in puppies and kittens” published in veterinary clinics of north america, small animal practitioner, in may . there are now comprehensive guidelines readily available for small animal practitioners regarding canine and feline pediatric (and adult) vaccination recommendations. perhaps more importantly, there is an increased dialogue regarding all aspects of preventive medicine, of which vaccination is only a small, yet significant portion; and an increased drive to provide scientific evidence for developing vaccination recommendations. recommendations, and adverse events; as such, a comprehensive discussion is not possible here. as veterinarians we should look forward to the ongoing growth of this area of interest within clinical practice and within the research community, to eventually provide practitioners with answers currently sought by pet owners and veterinarians alike. it is far better to prevent than experience disease. this tenet should be the philosophy and goal of every veterinarian and every pet owner. for decades the veterinary profession has diligently educated pet owners about the benefits of preventing infectious disease, so well that there has been a significant decline in many of these diseases, in large part attributable to the development and use of effective vaccines. veterinary practice staff members have done remarkable jobs sending reminder cards to ensure that canine and feline patients are current on their vaccinations. in fact, vaccines have become such a priority that many pet owners are inclined to forfeit other, indicated medical care in lieu of vaccines lest their beloved pets fall behind on their vaccine schedule. veterinarians should commend themselves on a job well done, and commend pet owners for such conscientious stewardship of their pets. now, however, the veterinary community must reflect on what has been accomplished, and make decisions for current and future patient care based on scientific, rational merit. with the advent of knowledge on demand (ie, the internet), pet owners have access to information regarding all issues of animal care. however, such information may not be accurate. it is our duty to educate pet owners; in fact, it should be seen as an opportunity. who better to disseminate knowledge about veterinary medicine to the general public than veterinarians? no other group of individuals is as equipped with knowledge, skills, and insight as the veterinary community. to adequately discuss and understand how to make appropriate choices regarding pediatric vaccinations, a brief review and discussion of terms relative to basic immunology are warranted. passive transfer of immunity occurs when maternal antibody is transferred by the dam or queen to the fetus via the placenta, which occurs minimally in dogs and cats. it also occurs during initial suckling through the ingestion of colostrum, which has more significant effects in these species. this maternal immunity does provide initial protection against many pathogens, but of course depends on the health and immune status of the mother and the health of the fetus and neonate. although this may result in temporary protection for the neonate, in the long term it may be deleterious to that individual's health by essentially keeping the animal naïve to different antigens (eg, maternal antibody interference with vaccination of the neonate). maternal or passive immunization is effective in protecting neonates for the first several weeks of life, but begins to decline and lose the ability to protect against diseases rapidly as the maternal antibodies are degraded through natural catabolic processes. between the ages of and weeks, depending on multiple factors (including species, amount of maternal antibody produced, transferred, and absorbed, and the individual health status of the neonate), most puppies and kittens have maternal antibody levels below protective levels. however, if present at high enough levels, maternal antibodies can interfere with the neonate's ability to respond to vaccination, as the circulating maternal antibody within the puppy or kitten may effectively respond to and neutralize the vaccine antigen, or render it ineffective by preventing recognition of the antigen by the immune system. this is one reason why multiple, sequential vaccines are recommended in kittens and puppies until davis-wurzler they are at least to weeks of age. , of importance is that maternal antibodies can interfere with immunization, although the level of maternal antibody present may not be protective against pathogens. a functioning immune system is composed of multiple parts. innate immunity is the oldest (evolutionarily), least specific, and most immediate (in terms of response to potential invaders/pathogens) form of immunity. macrophages, neutrophils, dendritic cells, and natural killer (nk) cells combined with numerous products produced by these cells comprise the innate immune system. examples of some of the chemical components produced and released by these cells in response to microbial invasion include lysozyme, complement, various cytokines such as tumor necrosis factor a and interleukins, and various vasoactive molecules such as histamine. active immunization is the process of the individual responding to an antigenic stimulus appropriately, by either natural infection or vaccination. active immunization is processed through the acquired immune system. the main types of acquired immunity are cell-mediated immunity and antibody, or humoral, immunity. cell-mediated immunity is predominantly directed against pathogens that typically are obligate, intracellular organisms. examples include viruses, some obligate intracellular bacteria, some fungi, and protozoa. t lymphocytes are the predominant effector cells, and depend on foreign protein (antigen) being presented to them before they can take effect against the pathogens; thus, multiple cell types are involved in forming cellmediated immunity. antibody or humoral immunity is predominantly directed against pathogens that can survive outside the host, or at least survive extracellularly. examples include most bacteria, fungi, protozoa, and helminths. multiple cells act in concert to confer humoral immunity as well, but the primary effector cell is the b lymphocyte. having stated this, in actuality humoral immunity is extremely important in protection against viral infections, and is intricately and definitively dependent on competent cellmediated immunity. kittens and puppies will have varying degrees of ability to respond to antigens, whether resulting from natural or vaccine exposure, based on antigen load, route of exposure, antigenic virulence, genetics of the individual animal, and levels of persistent maternal immunity. in naïve animals whose maternal immunity has declined sufficiently so as not to interfere with an immune response; the first vaccine should stimulate a primary immune response (priming of the immune system). this initial exposure and recognition process and the ability to produce antibody to respond to the antigen typically takes to days; however, the maximum response takes up to weeks. this primary response must not be confused with the animal having been immunized. a subsequent dose of vaccine (exposure) will lead to immunologic memory. subsequent exposures to the same antigen elicit a stronger response: a greater amount of antibody is produced and the subsequent response is more rapid. this process is known as the secondary or anamnestic immune response, which results in immunity. although multiple cell lines are involved in this response, subsets of t and b lymphocytes known as memory cells preserve the host's ability to recognize and respond to antigens to which the animal had previously been exposed. to design, recommend, and actuate an effective plan for each patient, a practitioner must have familiarity with multiple variables. those variables include duration of protection conferred on the neonate by the mother; the typical length of time maternal antibody may persist and pose interference with the young animal's ability to respond fully to a vaccine; and the length of time needed for an appropriate response. in vaccination strategies in puppies and kittens addition, knowledge of the various diseases that pose risks to pediatric patients and knowledge of available safe, efficacious vaccines is critical. in essence, each patient must be assessed as an individual within the population to provide optimal wellness over the lifetime of each individual, as well as the population. this rationale has led to the concepts of core and noncore vaccines, terms commonly used when discussing vaccination within the veterinary field. criteria for assigning vaccines into these categories, and a third category, "generally not recommended," are based on: ( ) morbidity and mortality associated with the specific disease (does the organism cause serious illness or does it cause a mild, transient disease that may pose only minimal risk to the individual or population?); ( ) the prevalence and/or incidence rate of the disease (although a specific disease may not commonly be seen, the organism is ubiquitous in the environment and therefore poses risk to the individual or population); ( ) the risk of the individual for exposure to the disease (indoor-only animal vs free-roaming individual, regional variations of occurrence); ( ) the efficacy of the vaccine (does the vaccine prevent infection or simply ameliorate some signs or length of disease?); ( ) the risks associated with administering the vaccine (are the risks associated with that vaccine greater than the risk of the disease?); ( ) the potential for zoonotic disease; ( ) the route of infection or transmissibility. , , - when these criteria are assessed, general guidelines may be generated for the individual practitioner and the veterinary community at large. again, guidelines are not to be thought of as absolutes, nor are they to be used to establish standard of care. simply stated, they are tools for each of us to use to promote optimal wellness for our patients when considering all factors affecting the individual's health (environmental, organismal [both pathogen and host], owner concerns, and current vaccine technologies). , , - multiple vaccines are available for canine and feline patients, although most fall within basic categories. assignment of vaccine products (which are considered biological agents, not drugs, and are therefore assessed and approved under the united states department of agriculture [usda] animal and plant health inspection service rather than the food and drug administration) into these categories is based on how the product is created. simply stated, modified live virus (mlv) vaccines are vaccines created by altering (attenuating) the pathogen in some way so that it is no longer able to cause serious or clinical disease in the targeted species. killed vaccines are vaccines produced by inactivating the pathogen completely, rendering it incapable of reproducing and thereby unable to cause disease. the third category of vaccines consists of recombinant vaccines, of which there are multiple types, and this category itself has subcategories. these vaccines use genetic technologies to either introduce genetic material directly into the host (no vector, eg, purified subunit vaccines or type i recombinant, is used), alter the genetic material to change its virulence (gene deletion, type ii recombinant), or incorporate genetic material from the desired pathogen into an attenuated vector organism (eg, feline rrabies [r recombinant], type iii recombinant). , within the near future, multiple new technologies are likely to provide even more choices, potentially providing patients with better protection against disease with minimal vaccine-associated risks. a more recent discussion for categorizing vaccines has evolved, and assigns vaccines to of groups: infectious or noninfectious. simply stated, infectious vaccines include those biologics that have the ability to enter host cells and undergo replication within the host (ml, rcanary poxvectored vaccines). noninfectious vaccines do not have the ability to undergo replication within the host. for a comparison between vaccine types, the reader is referred to table . vaccines are available in single-dose and multiple-dose (tank) vials. the use of singledose vial vaccines is highly recommended in these species. conversely, the use of multiple-dose vials is discouraged because of the increased risk of contamination and the inability to assure consistent levels of antigen and adjuvant in individual doses from a single vial. , multivalent vaccines are not recommended in cats other than the core feline vaccine designed to protect against feline panleukopenia, feline herpesvirus i, and feline calicivirus. owing to increased inflammation at the site of multivalent vaccines, all other vaccines should be given as a separate vaccine, at the indicated site (see later discussion on feline core and noncore vaccines). , allowing vaccines to acclimatize to room temperature before administration, particularly in cats, is recommended, as the administration of cold vaccines was found to have an increased association for tumorigenesis in cats. use of sterile, single-use syringes is also recommended, as vaccines may become inactivated and/or ineffective with exposure to various products used to clean and sterilize syringes. mixing of more than vaccine within a syringe should not be performed because of the potential for inactivation of vaccine material, in addition to increasing the amount of antigen deposited within a single site. moreover, administration of reconstituted vaccines (mlv r) should be done within hour of reconstitution or otherwise discarded, owing to the potential inactivation of product and loss of efficacy. the practitioner is advised to always follow the manufacturer's directions for dose and route of administration. using a topical product parenterally or splitting doses should never be done. a full dose is required to stimulate the immune system; there is no medical basis for giving a smaller dose to a toy breed dog, and this practice could lead to vaccine failure in that animal. if done with a rabies vaccine the practitioner is not following federal requirements, which carries potential legal implications. , the interval between various vaccines, whether using the same product serially in the initial series or whether using different products in an adult animal, should never less than to weeks. interference between the first product administered and a second vaccine product may lead to failure to optimally respond to the second vaccine. the exact mechanism of this interference is unknown, but may be associated with interferon produced by cells processing an mlv agent, or by transient immunosuppression by an mlv agent. multiple vaccines administered at the same time do not appear to elicit this interference and is therefore an acceptable practice. , the reader is referred to tables and for comparison between pediatric canine and feline core, noncore, and generally not recommended vaccines. the diseases that fall within this category carry high rates of morbidity and/or mortality, are of public health concern, or are readily transmissible or may be ubiquitous in the environment. in addition, safe, efficacious vaccines are available and either provide sterile immunity (prevent infection) or confer a high degree of protection (do not prevent infection, but may confer protection such that the animal will not develop clinical signs of disease). , essentially, the vaccines that fall within this category are recommended for each individual within the population regardless of the animal's lifestyle or locale. canine distemper virus (cdv), an enveloped morbillivirus, has been well controlled because of the widespread vaccination programs over the last several decades. however, the disease still persists and, in addition to high virulence, it is readily vaccination strategies in puppies and kittens transmissible. infection with the virus causes respiratory, gastrointestinal, and neurologic signs, and is often fatal. the distemper vaccine is commonly administered as part of a multivalent product. the general recommendation is to use a modified live or recombinant, multivalent product (cdv, canine adenovirus type ii [cav-ii], canine parvovirus [cpv]) beginning at to weeks, and to give serial vaccines every to weeks until the puppy has reached to weeks of age. , , many studies support the improved ability of recombinant vaccines to overcome maternal antibody interference in comparison with modified live virus vaccines. , most puppies will receive or distemper vaccinations, depending on the age at which they are first presented to the veterinarian. however, it is the interval between or the timing of the vaccinations, rather than the number, that is important. serial vaccinations help to increase the likelihood of a complete response of the patient and thereby decrease the risk of vaccine failure that may occur when only vaccine is administered. in addition, by eliciting a secondary immune response, they may help to increase the level of circulating antibody and decrease the lag time between exposure to an antigen and achievement of maximal antibody level. potential causes for vaccine failure include: a modified live vaccine that was improperly stored and therefore has lost its efficacy; the vaccine was improperly administered (wrong route or accidental loss of vaccine onto the skin of the patient); the patient's immune system did not respond (the immune system may have been responding to another antigenic challenge or the vaccine may have been given too soon after a previous vaccine); or maternal interference. in theory, if a puppy were kept sequestered from exposure to this virus, modified live distemper vaccine administered after weeks of age would confer protection for at least year. , however, in reality most pet owners are not inclined to isolate their puppies for the first months of life, nor should they. early socialization is an important part of families bonding with their puppies. exposure to various people, other dogs, and new places helps decrease behavioral problems in the young adult and mature dog. as long as the last distemper vaccine is administered after weeks of age, the puppy should be able to mount a strong active response and fully overcome any residual maternal antibody. the current recommendation is to have the puppy return year later (when approximately months old) for another distemper vaccine. after the first annual vaccination, triennial immunization is recommended, regardless of vaccine type used. , , canine adenovirus there are types of adenovirus that cause disease in canine patients. canine adenovirus type i (cav-i), a nonenveloped virus in the family adenoviridae, causes the potentially fatal disease infectious canine hepatitis. clinical signs include fever, depression, vomiting and diarrhea, and potential petechiation and ecchymotic hemorrhage secondary to hepatic dysfunction. in addition, uveitis and renal disease are associated with infection with this virus. cav-ii causes respiratory tract disease. cav-i is associated with severe, potentially fatal disease, and protection against this disease is recommended. transmission is via the oronasal route and exposure to infected secretions. cav-ii infection typically results in mild self-limiting disease and is therefore considered to be a noncore disease; however, the modified live vaccine designed for prevention of cav-i has been associated with adverse effects such as uveitis and corneal edema (an arthus reaction, similar to effects caused by natural infection). , the current recommendation is to use the cav-ii modified live virus product, as it stimulates the immune system to protect against both cav-i and cav-ii, without the associated adverse reaction caused by the type i vaccine. , , the modified live adeno-type ii virus is typically included in a multivalent injection (as mentioned earlier) and is therefore usually administered at intervals of to weeks, beginning between and weeks of age and ending between and weeks old. a vaccination year later is recommended before instituting triennial vaccinations. cpv is a nonenveloped type parvovirus. the predominant form currently causing infection in the united states is type b, but other subtypes exist and cause disease elsewhere. because the virus is nonenveloped, it may exist (outside of a host) under certain environmental conditions, and is somewhat resistant to many disinfectants. transmission is via the fecal-oral route, and clinical signs include lethargy, anorexia, pyrexia, vomiting, and diarrhea (typically hemorrhagic). young animals appear to be at highest risk for developing severe, life-threatening disease. the current recommendation for vaccination is to use a multivalent mlv vaccine beginning at to weeks and to repeat the vaccine at intervals as already stated (every - weeks, until the puppy is - weeks old). in the past there was concern that certain breeds may have been at increased risk for contracting and developing severe parvoviral disease (doberman pinschers, rottweilers), but it is generally agreed that these breeds will mount an appropriate response to a quality product if the last vaccine is given between and weeks of age. , , there is, however, a small population of dogs that is genetically unable to respond to vaccination against cpv , regardless of the number of vaccinations (nonresponders). one benefit of having a well-vaccinated population is that even those nonresponders are at decreased risk of exposure and subsequent infection by parvovirus, based on strong herd immunity. studies using mlv cpv b strains showed a higher antibody response to cpv and cpv b, and were better able to overcome maternal antibody interference than the cpv -strain vaccines used , ; however, all cpv vaccines currently available should produce strong immunity in immunocompetent dogs. immunization year after completing the initial puppy series is recommended, with subsequent triennial vaccinations. , , there is also emerging evidence that weimaraner puppies are at increased risk of developing a severe form of hypertrophic osteodystrophy (hod) in association with vaccination with mlv distemper, adenoviral, and parvoviral products. the exact vaccination strategies in puppies and kittens mechanism is unknown, but the current recommendation is to use killed products in this breed for their pediatric vaccinations, and consider starting vaccinations when they are slightly older. rabies virus, an enveloped virus in the rhabdoviridae family, is capable of infecting all mammals. because it is an enveloped virus, it is not stable in the environment and is readily inactivated by most common disinfectants. the virus is transmitted through infected saliva, most commonly from a bite by an infected animal. clinical signs range from anxiety or other vague behavioral changes to pica, dysphagia, photophobia, and paralysis. because of the zoonotic potential and implications regarding public health, canine vaccination programs are strongly regulated and enforced. the current recommendation is to vaccinate puppies using a killed-virus vaccine at a minimum of or weeks of age. state regulations vary as to the minimum age for canine rabies vaccination: in california the legal minimum age of canine vaccination against rabies is weeks. a second rabies vaccine (killed product) is administered year later and then annually or triennially thereafter, depending on local regulations. , it is the practitioner's professional responsibility for knowledge of and adherence to regional laws regarding rabies vaccination frequency. vaccines in the noncore category may have limited efficacy, or the organism causing disease is not readily transmissible or may have limited geographic distribution or prevalence. in addition, the diseases these vaccines are designed to prevent may be so mild or self-limiting that the risks associated with administering the vaccines may be greater than the actual disease. lastly, some vaccines may interfere with common screening methods for disease detection, and are therefore not recommended unless absolutely warranted for a specific individual. it is the burden of the practitioner, along with the pet owner, to make decisions regarding which, if any, of the noncore vaccines should be administered to a puppy. , [ ] [ ] [ ] leptospirosis a bacterial pathogen that causes acute hepatic and renal disease, leptospirosis is typically transmitted through urine of infected animals (reservoir hosts include dogs, rats, wildlife, and livestock), and in contaminated water. there are at least different species (leptospira interrogans and leptospira kirschneri) that can infect dogs, with multiple serovars (variants of the same species) of l interrogans causing disease in dogs. although these organisms have the potential to cause serious disease, dogs are not likely to be at risk in a mostly urban, controlled environment (housed in a fenced yard with no exposure to wildlife or livestock). however, a dog that frequents rural environments or has exposure to waterways or livestock is definitely at risk of infection and should therefore be protected against the disease. again, the initial puppy appointments should involve a through history and include the owner's plans for the dog's future use. if an owner brings a labrador retriever puppy to the veterinarian for "whatever vaccines he needs," it is up to the practitioner to ask "will he be a hunting dog, will he be used in field trials, will he be exposed to wildlife and waterways?" the border collie who lives on a working sheep ranch surely should be vaccinated appropriately against leptospirosis. conversely, a long-haired miniature dachshund who will spend her days on her owner's lap in an urban setting will be at minimal risk of exposure and, therefore, vaccination is most likely not warranted. in essence, regional distribution, seasonality (increased prevalence during and immediately following the rainy season), and lifestyle of the puppy will be factored into the decision as to whether the puppy should be vaccinated. if the decision is made to vaccinate against leptospirosis, the general recommendation is to wait until the puppy is at least weeks old, at which time a killed or purified subunit vaccine is administered. infection is serovar specific, and no cross-protection is seen between different serovars; therefore, vaccination with as many serovars known to cause disease in a given region is recommended. an initial series of vaccinations should be administered to weeks apart and repeated at least annually thereafter, as long as the risk of exposure to the agent exists. the recommendation to wait until the puppy is at least weeks old before administering the leptospirosis vaccine is based on the increased potential for adverse events associated with killed vaccines, and to increase the likelihood of a complete immune response. , bordetella bordetella bronchiseptica is a bacterial agent that causes infectious tracheobronchitis. infection with this agent may occur in concert with other agents infecting the respiratory tract (canine parainfluenza virus [cpiv], cav-ii). transmission occurs via direct contact or through aerosolized microdroplets from infected dogs, and is most likely to occur under crowded conditions such as boarding and grooming facilities and dog-show venues. the current recommendation is to vaccinate puppies at risk a minimum of week before potential exposure with a combination vaccine containing both an avirulent live bacterin for b bronchiseptica and a modified live cpiv. the vaccine can be administered to puppies as young as to weeks of age, but is generally not indicated unless the puppy is in a kennel environment. many organized puppy socialization and obedience classes commonly require proof of vaccination against bordetella at the time of enrollment or before beginning the course. the general consensus is that intranasal vaccines are superior to parenteral vaccines, as they stimulate rapid local immunity (which is not affected by persistent maternally derived antibody). , intranasal vaccines should never be given subcutaneously, owing to the potential for severe (in some cases fatal) reactions (fig. ) . if the puppy will be intermittently exposed throughout the year (traveling to shows, boarding or grooming facilities) the vaccine should be repeated every months to annually. as already stated, cpiv may occur in concert with other respiratory tract agents. the vaccine recommendations are as stated for b bronchiseptica if indicated. there are vaccination strategies in puppies and kittens multiple products available, but the product currently recommended is the combination of intranasal vaccine containing a modified live parainfluenza virus with an attenuated b bronchiseptica bacterin. intranasal vaccines can be used in puppies aged to weeks for individuals at high risk of exposure (depending on vaccine manufacturer label restrictions). for optimal protection, the vaccine should be administered every months to annually if indicated. alternatively many multivalent, parental products containing modified live cdv, cav-ii, cpv, and parainfluenza are available and appropriate for use. , borreliosis borrelia burgdorferi is a vector-borne, spirochete bacterium responsible for lyme disease (borreliosis). transmission occurs when an infected tick (various species within the ixodes genera, also referred to as hard ticks) bites and remains attached to a host, in this case a puppy. direct, horizontal transmission is not likely to occur, so the risk to humans and other pets is thought to be minimal. if a puppy has a significant burden with infected ticks, it of course increases the exposure to others in the household but, as ticks typically do not reattach once they have taken a complete meal, the risk is considered to be fairly small unless appropriate tick control is not instituted. vaccination to protect against lyme disease is controversial, as the duration of immunity and degree of protection provided by vaccination is unknown, and vaccination with some vaccines interferes with standard screening diagnostics. therefore, vaccination against lyme disease is warranted only if a puppy will be expected to be at high risk for tick exposure, and only if it lives in a borrelia-endemic area. there are killed and recombinant (ospa subunit) vaccines available for use against b burgdorferi, and if vaccination is deemed warranted, the current recommendation is to use one of the subunit vaccines before exposure to ticks. the vaccine can be given as early as weeks and should be repeated to weeks later. the best prophylaxis is likely achieved by using appropriate tick prevention, such as fipronil with methoprene spray or spot-on products (eg, frontline top spot; merial ltd, iselin, nj), amitraz collars (eg, preventic collar; virbac animal health, fort worth, tx), or an imidacloprid/permethrin topical product (eg, canine advantix; bayer animal health, shawnee mission, ks). , these products should be chosen and recommended carefully by the veterinarian based on household situations, owner concerns, and the age of the puppy. this virus, also a morbillivirus, can stimulate an immune response that is crossprotective against cdv. the indication for using this vaccine is for puppies that may have maternal antibody to distemper virus sufficient to cause interference with distemper vaccination but inadequate to protect against infection. if indicated (see later discussion on special circumstances), a single vaccination with a modified live vaccine should be given intramuscularly as early as weeks of age. subsequent immunizations with mlv cdv vaccines should be given serially as recommended (see cdv section). , , canine measles vaccines should never be administered to female puppies older than weeks, as they may develop an acquired immune response to the virus, which could be problematic if a female puppy vaccinated against measles at weeks of age later became pregnant. if she developed antibodies to the measles virus and maintained immunologic memory, she would confer measles antibody to her puppies via passive transfer, thus rendering measles vaccination in those puppies ineffective. a more appropriate alternative to administering a measles vaccine to a young puppy thought to be at risk for infection but too young to receive an mlv cdv vaccine would davis-wurzler be to use a recombinant cdv vaccine, thereby decreasing the likelihood of maternal antibody interference. , canine influenza virus canine influenza virus has been seen in various countries, most notably in enzootic outbreaks. this virus is typically seen in puppies and dogs in shelter, boarding, and day-care facilities, and often occurs as a coinfection in canine infectious respiratory disease (cird) with bacterial pathogens. there is a commercially available inactivated vaccine available for use in puppies as young as weeks. vaccination with this product should be used only in puppies with a high risk of exposure, such as to shelters and areas known to be dealing with current/recent outbreaks (typically not in client-owned puppies). in addition, some countries now require an initial vaccination series ( doses, given - weeks apart) before importation. , rattlesnake vaccine a vaccine designed to protect against envenomation by crotalus atrox, the western diamondback rattlesnake, was released onto the market several years ago. the original provisional licensure was granted to provide possible protection against this single species of snake, and was granted for use only in california. the company was later granted extended licensure for multiple states, and has extended its claim for potential protection against multiple species of members of the crotalidae (pit vipers). to date, no challenge studies have been performed in the canine species to validate efficacy claims. all claims are based on antibody titer to the venom component included in the vaccine, to murid challenge studies, and to field reports of protection of naturally occurring envenomation. no controlled, independent studies exist concerning the impact of prior vaccination on therapeutics after envenomation. the manufacturer does not claim that vaccination with this product will completely protect against effects of envenomation; rather, they claim it may slow the onset of clinical signs and decrease the severity of signs. immediate veterinary care is still the gold standard for any snake bite. because of the great potential for variability in envenomation (site of bite on animal, size and age of snake, amount of venom injected into animal, and species of snake), field observations and anecdotal reports of protection are difficult to substantiate. challenge studies conducted under controlled conditions will likely be necessary to validate the efficacy of this product. at present, owing to the preceding statements, this vaccine is not recommended for general use. aversion training and keeping dogs out of areas known to favor rattlesnake habitation, and immediate veterinary evaluation and care are still the standard recommendations for preventing and treating disease associated with rattlesnake envenomation. if an owner is extremely concerned about the potential for exposure and envenomation by a western diamondback rattlesnake, the decision to vaccinate should be made after a discussion between the veterinarian and owner, with full disclosure of vaccine efficacy and a risk/benefit analysis, understanding the potential for adverse events from vaccination. this vaccine has been shown to be safe for use in puppies as young as months. an enveloped virus belonging to the family coronaviridae, this virus is transmitted via the fecal-oral route. vaccination against this disease is generally not recommended because the vaccines provide questionable protection, and the actual prevalence vaccination strategies in puppies and kittens and severity of the disease are unknown. those most likely to be infected and develop clinical disease are neonates younger than weeks. clinical signs may include diarrhea, possibly hemorrhagic, but typically self-limiting. the general recommendation is to vaccinate puppies against cpv (as recommended in the section on cpv), as this practice appears to confer protection against coronavirus in addition to preventing infection with cpv . , canine adenovirus type i as stated in the canine core vaccine section, cav-i causes serious disease in dogs; however use of the cav-i is associated with a high incidence of adverse events. vaccination with cav-ii induces an immune response that is protective against both cav-i and cav-ii without the adverse effects. the recommendation is to use cav-ii as part of the canine core vaccination program; cav-i should not be used. feline panleukopenia, a nonenveloped parvovirus closely related to canine parvovirus, causes serious, often fatal disease in kittens. transmission typically occurs from direct contact with infected animals, although in utero infection and fomite transmission also occurs. clinical signs typically include pyrexia, anorexia, lethargy, vomiting, and diarrhea. kittens may be immunosuppressed subsequent to pancytopenia associated with this viral infection. kittens infected in utero may exhibit cerebellar disease. prevention is achieved by using modified live virus vaccines beginning between and weeks of age. the standard recommendation is to use a parenteral product (as opposed to intranasal products, which have higher incidences of postvaccinal viral shedding and potential for clinical disease induced by the more virulent viruses in these vaccines). , , as is the case for canine distemper, adenovirus, and parvovirus, the core feline diseases, with the exception of rabies, are typically administered in a multivalent product in series. there are numerous vaccine products containing feline panleukopenia virus, herpesvirus i, and calicivirus (see later discussion). the current recommendation is to choose an mlv or killed product from a reputable manufacturer. vaccines are administered subcutaneously in the distal aspect of the right thoracic limb (elbow or distally) and given every to weeks until the kitten is at least to weeks old. repeat administration is recommended year later before instituting a triennial schedule. , feline herpesvirus i feline herpesvirus i (fhv-i), also known as feline viral rhinotracheitis virus, is an enveloped virus causing respiratory tract disease in cats. clinical signs include sneezing, nasal congestion and discharge, conjunctivitis, and ocular discharge. in addition, kittens may exhibit pyrexia, anorexia, and lethargy along with oral/lingual ulcerations and associated hypersalivation. in some cases ulcerative, crusting dermatitis occurs, which may mimic other dermatologic disease. the virus typically causes upper respiratory disease but the lower respiratory tract may become involved, especially in neonates or debilitated animals. infection with this virus is lifelong, although many cats will "recover" and not show clinical signs. however, cats infected with fhv-i may have recurrent outbreaks, especially under times of stress or if their immunity is otherwise compromised. cats may persistently shed the virus and act as a source of infection in shelters, catteries, and multiple-cat households. therefore, prevention before exposure is key to controlling this disease. , vaccination with a modified live virus (or killed product) beginning as early as to weeks is recommended, this being commonly administered as part of a multivalent product, given subcutaneously, in the right thoracic limb. the current recommendation is for kittens to receive a second vaccination weeks later. the last vaccine in the series should be given when kittens are to weeks of age. a vaccine should be given year later before beginning the triennial schedule. feline calicivirus causes respiratory tract disease in kittens and cats. because it is a nonenveloped virus, it is more resistant to disinfectants and may therefore persist in the environment. signs are similar to those associated with fhv-i, but lameness and stomatitis are also commonly seen. transmission of both fhv-i and calicivirus is through direct contact, exposure to contaminated secretions, aerosolization, and fomites. , another, highly virulent, strain of feline calicivirus was identified several years ago and carries a higher incidence of mortality. transmission is through either direct contact or via fomites. prior vaccination against feline calicivirus does not appear to be protective against this strain, and adult cats appear to be more severely affected than kittens. , the current recommendation is as for panleukopenia and fhv-i: administering a modified live virus inactivated-virus parenteral vaccine beginning at or weeks with a subsequent vaccine weeks later (the last vaccination should be when the kitten is at least to weeks old). a booster vaccine should be administered year later, and then every years. as stated earlier, rabies virus affects all mammals and in the united states, with most documented cases of rabies in pet animals occurring in cats. because of the significant risk to pets, wildlife, and humans, vaccination against rabies virus is highly recommended for all kittens and cats, even those kept inside. , local requirements vary, but the general recommendation is that all kittens should be vaccinated beginning at weeks of age with either the recombinant rabies vaccine (preferable) or a killed rabies virus vaccine. , , the recombinant product uses gene-splicing technology: reverse transcriptase is applied to rabies viral rna to create complementary dna. the segment of rabies virus dna that codes (a codon) for the immunogenic protein associated with the virus (glycoprotein g) is then spliced from the rabies dna and inserted into a canarypox virus. the canarypox virus, which is attenuated, is nonpathogenic to mammalian cells and therefore carries no potential to cause disease in this species. because the vaccine is essentially a modified live product, the canarypox virus can enter cells, delivering the codon for rabies virus glycoprotein g to its targeted site. once inside the cell the canarypox virus is unable to replicate, but the rabies glycoprotein g codon is preserved, leading the host cell to express the glycoprotein on its surface; this stimulates both cell-mediated and humoral immune responses. besides the benefit of stimulating both types of immunity, because this product is adjuvant-free there may be a decreased risk of local inflammation associated with vaccination, thereby potentially decreasing the risk of subsequent vaccine reactions and tumorigenesis. the current recommendation is to use either the rrabies virus vaccine (preferred when possible) or a killed-virus vaccine in a case where increased duration of immunity is required (not pertinent to kittens because all pediatric/initial rabies vaccinations provide only months of protection, regardless of label claims). , rabies vaccines should be administered subcutaneously in the right pelvic limb, as distally as is reasonably possible: the level of the stifle is acceptable and areas distal to the tarsus are difficult to inject, and therefore not really feasible or appropriate. administering vaccines (or any injections for that matter) in the tail should be avoided. giving injections in the tail is difficult because of the scant amounts of loose skin and subcutaneous tissue, which is vaccination strategies in puppies and kittens likely to cause more discomfort in patients during vaccination. more importantly, if a tumor does arise proximally on the tail, the potential for complete resection and cure are decreased because of the potential for tumor infiltration into the vertebral column. at present there is only one recombinant rabies vaccine approved for use in cats (pure-vax feline rabies vaccine'; merial ltd, duluth, ga). the current usda approval/label states that this product should be administered annually. there are multiple killed-virus rabies vaccines approved for use in cats, with initial vaccination occurring at weeks of age with a subsequent vaccination year later. because regulations vary depending on state or region, the veterinary practitioner must be familiar with local laws regarding rabies vaccination in this species. feline leukemia virus (felv) is a retrovirus primarily affecting cats of any age, but kittens and juvenile cats appear to be most susceptible to infection. clinical signs are numerous and nonspecific, and include pyrexia, failure to thrive, chronic or recurrent respiratory tract, and gastrointestinal disease. infection in kittens occurs via vertical transmission from the queen to the fetus, but may also spread horizontally from queen to kitten during lactation and grooming. transmission also occurs through direct and usually prolonged contact with other infected cats from behaviors such as grooming and sharing food, and water bowls, and litter boxes. viral screening using an enzymelinked immunosorbent assay (elisa) test designed to detect antigenemia should be performed on all kittens, even if their owners plan to house them strictly indoors. because the elisa test detects antigen, maternal antibody and vaccination do not interfere with test results. therefore kittens of any age may be tested, and the current recommendation is to test every kitten (and adult cats with an unknown viral status) prior to felv vaccination. if a kitten is antigen negative, the current recommendation is to administer either a killed or a recombinant vaccine on the first or second kitten visit. a second vaccine should be administered weeks later followed by vaccination year after the last felv kitten vaccine. , the recommended site for administration of any felv vaccine is the left pelvic limb, as distally as is reasonably possible. at present there is only one recombinant felv vaccine available (purevax recombinant leukemia vaccine; merial ltd, duluth, ga). although felv is considered a noncore vaccine in adult cats because kittens are most vulnerable to infection and may be exposed if outdoors, and immunity increases with age, it is rational to vaccinate all kittens against this disease with a repeat vaccination year later. if the cat is subsequently housed strictly indoors and does not live with an infected (felv) cat, additional vaccinations are not indicated. chlamydophila felis, formerly known as chlamydia psittaci, is a bacterium that causes upper respiratory tract disease in kittens and cats. the most common sign is conjunctivitis, but sneezing and nasal discharge may also be present. transmission is typically through direct contact with infected cats. kittens are most commonly affected, but usually recover fully with appropriate antibiotic therapy: either topical oxytetracycline (terramycin ophthalmic ointment) or systemic tetracycline (panmycin aquadrops) or doxycycline (vibramycin). vaccination against this agent typically does not prevent infection but may prevent clinical signs of disease. because the vaccine does not fully prevent infection and carries an association with adverse events that may be greater than the actual disease, routine vaccination of household pets with this product is davis-wurzler generally not recommended. however, it may be of use in some environments where the risk of infection is high, such as shelters or catteries with recent outbreaks. , if vaccination is deemed appropriate by the practitioner, an attenuated parenteral vaccine can be given to kittens beginning at weeks, with a second dose given to weeks later. bordetella this bacterial agent causes respiratory tract disease in cats, and cats affected by stress, poor nutrition, or overcrowding seem more susceptible. many kittens infected show mild, self-limiting disease with signs including pyrexia, sneezing, and nasal and ocular discharge, although bronchopneumonia has been documented. there is a topical, modified live bacterin vaccine designed for use in this species, but it is generally not recommended for routine use. if the practitioner feels protection against b bronchiseptica is warranted based on the kitten's risk of exposure, such as attendance at cat shows or visiting a boarding facility, or is in a shelter with potential contact with dogs (with a recent b bronchiseptica outbreak), administration of the vaccine designed for use in cats may be considered. a single dose of the modified live intranasal vaccine can be given to kittens as young as weeks of age. the product designed for use in canines should not be used in cats. there are multiple vaccines in addition to those described and recommended here; however, many of these diseases pose a minimal risk to most of the feline population or the vaccines are minimally efficacious at preventing infection or disease, and therefore are generally not recommended. additional reasons not to use some of these products are vaccine interference with screening tests and adverse events associated with some vaccines. a retrovirus, feline immunodeficiency virus (fiv) primarily affects cats by compromising their immune system, leaving them vulnerable to opportunistic infections. in addition to immunosuppression, with most of the effect targeted against the cellmediated (t-cell) immune response, infection with fiv also carries an increased risk for development of certain types of neoplasia, b-cell lymphoma being the most common. transmission occurs most commonly from breeding and fighting. the virus is not spread through casual contact between housemates not engaging in the behaviors stated, nor is it spread through casual encounters between nonbreeding, nonfighting cats outside. naturally occurring infection of kittens from queens is rare; however, kittens can become fiv-antibody positive via passive transfer from ingestion of colostrum of fiv-positive queens or queens previously vaccinated against fiv. , fiv-antibody levels acquired from maternal transfer in kittens who are actually fivvirus negative decline over the first several months of life. the standard screening test for fiv is an elisa test designed to detect fiv antibody. the elisa was designed to detect antibody rather than antigen, because infected cats produce high levels of circulating antibody in contrast to low levels of circulating virus. because kittens may have circulating fiv antibody although actually may be fiv-antigen negative, it is generally not recommended to test kittens younger than months. if a kitten is tested and a positive result is obtained, the test result should be repeated with a different methodology (western blot or polymerase chain reaction [pcr] ) and should be repeated once the kitten is more than months old. if a kitten is truly not infected, the maternal antibody will wane by months of age, leading to seroconversion. if, however, a kitten or cat remains seropositive, the recommendation is made to keep the cat indoors only from that point, both to prevent infection of other cats and to decrease exposure to potential environmental pathogens. fiv-infected cats can live for years and, unless otherwise indicated by concurrent disease, euthanasia is generally not indicated for most owned pets. there is a killed fiv vaccine available, but the efficacy of this product is still unknown. there are known subtypes of fiv virus, and the vaccine has been formulated to protect against subtypes a and d; however, the predominant subtype infecting cats in north america and europe appears to be subtype b. it is unknown whether cross-protection exists between the different subtypes. because the vaccine elicits a strong antibody response, vaccinated kittens and cats will become seropositive on both elisa and western blot tests, as both tests detect antibody. a pcr test is available but is currently only performed at certain laboratories, and results and reliability vary with testing centers. because of the increased technological needs and increased costs of this test, it is not considered the standard screening test. if done under specific conditions it can detect virus, and therefore may be of benefit in differentiating between cats with viremia (truly infected cats) and kittens or cats with circulating antibody, attributable either to maternal transfer or vaccination. because of the nature of transmission of the virus and interference with the standard screening methods for infection, the vaccination against fiv is not currently recommended. keeping cats indoors if possible, neutering all cats going outside, and preventing exposure to stray or feral cats that may be more likely to engage in fighting behaviors remain the gold standards for preventing this disease. , feline infectious peritonitis the disease feline infectious peritonitis (fip) is caused by a member of the coronaviridae. feline enteric coronavirus (fecv) and fip virus are phenotypes of the same virus. fecv transmission occurs through the fecal-oral route where it typically infects intestinal epithelium, but the organism can be transmitted via fomites and persists for long periods of time in the environment. most cats infected with fecv either do not show clinical signs of disease or may have transient diarrhea, and some will persistently shed the virus in their feces. fecv can, however, undergo random mutations within a host, creating fip virus, although in most cats the virus does not mutate into this form and most cats will not develop fip. the fip virus enters and replicates within macrophages where it can then be disseminated throughout the body. clinical signs are numerous, but commonly include weight loss, failure to thrive, diarrhea, pyrexia, and chronic respiratory tract disease. two main types of the disease exist, the dry (noneffusive) and the wet (effusive) forms. both are ultimately fatal diseases. although there is a vaccine available, its efficacy and indication for use is believed to be minimal, if at all. the current recommendation is not to use this vaccine, based on efficacy concerns and the minimal risk of infection in most kittens and cats. infection with fecv and mutation with subsequent development of disease occurs most commonly in multiple-cat households ( ), catteries, and shelters. the standard screening test for fip is a serologic, indirect immunofluorescent antibody (ifa) test designed to detect antibody. this test may be of some value, but results need to be interpreted with caution, and concomitantly with signalment, clinical signs, and other laboratory data. prior vaccination against fip will yield positive ifa results, further posing potential complications in routing screening of this disease. in general, kittens are most vulnerable to this disease, with greater than % of cats with fip being younger than years. prevention is directed toward decreasing stress in kittens and cats in multiple-cat households, preventing exposure of naïve kittens and cats in environments known to have high endemic levels of feline enteric corona virus, and at depopulating catteries known to have high prevalence rates of fecv and fip. , because of the complexity of this disease and the limited space and objectives of this discussion, readers are encouraged to review infectious diseases of the dog and cat, rd edition, by greene, and textbook of veterinary internal medicine, th edition, by ettinger and feldman, for a more comprehensive review of this disease. vaccines are potent biological agents designed to prevent disease. any foreign product administered to an animal has the potential to be associated with an unexpected response by that animal. while vaccines must meet usda requirements for safety, efficacy, potency, and purity, there still exists the potential for adverse events with products that have met these standards. veterinarians should always report adverse events associated with vaccination to the vaccine manufacturer. some adverse events are more likely to occur with certain agents, whereas others appear to have an increased rate of occurrence in certain breeds. still others may be idiosyncratic and are not predictable. the following is offered as a brief overview of some types of adverse events associated with vaccination, with suggestions as to how a practitioner might best respond to and prevent such events from recurring. the reactions seen most commonly are local inflammation at the site of the injection or general malaise, pyrexia, and anorexia for to days after vaccination. most of these reactions are self-limiting and require nothing more than monitoring by the animal owner. it is appropriate for the practitioner to note any reaction along with a description of signs documented in the medical record, and offer supportive care if indicated. in some instances administration of an mlv vaccine will cause transient mild clinical disease. supportive care and isolation from unvaccinated animals is recommended, as the vaccinated animal showing clinical disease will shed the vaccinal organism and is potentially infectious to other animals. contact information for vaccine manufacturers, support agencies, and disease-reporting organizations is included in table . feline injection-site sarcomas (fiss), formerly known as feline vaccine-associated sarcomas or fibrosarcomas, develop secondarily to local inflammation at injection sites. originally it was thought that there was an increased risk for development of these tumors associated with specific adjuvants and vaccines; however, it is now accepted that all vaccines and repositol agents such as long-acting penicillin and corticosteroid injections, in addition to other injections, can be associated with the formation of fiss. measures to prevent these tumors are aimed at decreasing the local inflammatory response by avoiding the use of adjuvants in this species and administering only those vaccines indicated for the individual animal. , multiple vaccines should not be administered in one site, as this may increase the amount of inflammation in that site. following the recommended sites for injection is strongly recommended (see individual vaccine sections for specific sites) , and avoiding adjuvanted products when there is a reasonable alternative (mlv or recombinant) product available is ideal, as a recent study confirmed an increased association of tumor formation with adjuvanted vaccines compared with recombinant vaccines, although no vaccine was risk free. , there are specific guidelines as to how a practitioner should proceed if a cat develops a swelling at the site of a vaccine or injection. the practitioner is advised to monitor the patient closely, documenting -dimensional measurements and temporal association if a mass or swelling develops at the site of a vaccine. the - - rule developed by the table feline vaccine-associated sarcoma task force should be closely applied. "three" refers to persistence of the mass for months or greater; " " refers to a size of cm or greater; and " " applies if the mass increases in size after month. if any of these criteria are met, the mass should be biopsied with wedge technique or needle biopsy allowing for complete resection of the biopsy margins in the future, and subsequent referral to an oncologist or surgical oncologist if fibrosarcoma is confirmed. fine-needle aspiration is not recommended for evaluation of potential injection-site sarcomas. , most vaccine manufacturers have programs established to help defray the medical and surgical costs associated with these tumors, and the practitioner is advised to always notify the vaccine manufacturer any time an adverse event is seen. type i hypersensitivity, also known as immediate hypersensitivity and, in some cases, anaphylaxis, is mediated by immunoglobulin e antibody. the host's immune system may react to anything contained within the vaccine product, including cellular products used for culture, adjuvant, preservative, and the antigen itself, and reaction typically occurs within to hours after the administration of a vaccine. in the dog, signs range from urticaria, angioedema, and pruritus ( fig. ) to respiratory distress and fulminant vascular collapse (anaphylaxis). in the cat, acute onset of vomiting and diarrhea with associated hypovolemia and respiratory and vascular shock may be seen. if an animal develops any of these signs within the first several hours after vaccination, it should be presented to the veterinarian immediately for emergency medical care and support. it is not the goal of this review to offer therapies for shock, so the reader is referred to emergency veterinary literature for recommended therapies. the point here is to advise the practitioner to proceed with caution when using vaccines that may have a higher incidence of these reactions, or in breeds that may be at increased risk for immediate hypersensitivity. the increased association between killed bacterin vaccines and type i reactions is well documented, and there are reports that toy breeds may be at increased risk for type i reactions associated with these vaccines. if an animal does have a type i reaction to a vaccine, the signs shown by the patient, interval between vaccine and onset of signs, and therapeutics administered should be well documented in the medical record, as well as plans for future vaccination of the patient in question. once an animal has this type of reaction to a vaccine, ideally the product should not be used again in that patient. all subsequent vaccines should be administered after a complete physical examination, and the vaccine should be given early in the day to allow monitoring of the patient in the hospital for several hours. however, if this is not possible the patient should remain in the veterinary hospital for monitoring for at least minutes followed by subsequent monitoring by the owner at home for several hours. pretreatment with diphenhydramine (benadryl) is an option, given parenterally (subcutaneous or intramuscular routes) at the dose of . mg/kg to minutes before vaccination if hypersensitivity is a concern. however, administration of corticosteroids concurrently with vaccination to prevent a hypersensitivity reaction is neither appropriate nor recommended because of potential immunosuppression and vaccine interference. the patient's medical record should be identified, outside and inside, to prevent future accidental readministration of the product. advising the owner that the patient should never receive that product again is important. type ii hypersensitivity reactions (autoimmune reactions) are suspected to occur in dogs secondarily to vaccine administration. although this theory is yet unproved, there are reports of dogs developing immune-mediated thrombocytopenia and immunemediated hemolytic anemia temporally associated with recent vaccination. if a dog develops either of these conditions within to months after vaccine administration, the practitioner is advised to strongly consider the risk/benefit ratio of subsequent use of that product in the patient. , type iii hypersensitivity type iii hypersensitivity reactions are immune complex reactions. examples include the anterior uveitis associated with use of the cav-i vaccine and the complement-mediated rabies vaccine induced vasculitis-dermatitis seen in dogs. other examples include glomerulonephritis and polyarthritis. antihistamine administered at the time of vaccine will do nothing to prevent the reaction, nor is it recommended to administer corticosteroids concurrently with vaccination. once an animal has had this type of reaction, subsequent use of the product should be avoided in that patient. , type iv hypersensitivity type iv hypersensitivity reactions are cell-mediated responses occurring locally or systemically. examples include sterile granulomas at the sites of vaccine administration or polyradiculoneuritis. many sterile granulomas resolve without any intervention, but for more severe reactions the practitioner is referred to various medicine texts for recommendations. , the foregoing discussion applies mainly to puppies and kittens owned by individuals. puppies and kittens housed in shelters face unique challenges, as do orphaned animals. these animals may not have received colostrum, and it is more likely that their mothers were not adequately vaccinated. the implications are that these animals are less likely to have received maternal antibodies, leaving them more vulnerable in the earliest stages of life. in addition, they frequently are malnourished, have an increased parasite burden, and are placed in crowded environments possibly with high numbers of endemic pathogens. the american animal hospital association canine vaccination task force and american association of feline practitioners have developed recommendations specifically designed for puppies and kittens in these environments. in general, neonates who may not have vaccination strategies in puppies and kittens received colostrum or who are housed under the aforesaid conditions may be vaccinated at an earlier age, and ideally should be vaccinated before or at the time of entry into the shelter. use of recombinant products may be of benefit in these animals, as well as additional vaccines (noncore vaccines). husbandry is extremely important in these animals: providing proper nutrition, anthelmintics, and clean, dry housing is paramount. in general, these animals are special subsets of the general population facing challenges most young animals do not experience. fiscal considerations and overall population health applies in these cases much more so than to individual, client-owned pets. vaccines are perhaps one of the practitioner's greatest tools in preventing disease and maintaining individual and population health. vaccination is to be used with forethought based on the risk of disease to the population and the individual, balanced with assessment of the risks associated with individual vaccines. it is the practitioner's role to educate pet owners regarding actual risks associated with both undervaccination and overvaccination. the goal is to reach the highest level of overall animal health with the minimum number of adverse events, based on scientific and epidemiologic merit. immunity in the fetus and newborn aafp feline vaccination advisory panel report american animal hospital association canine vaccination task force the defense of the body cells and their response to antigen avma council on biologic and therapeutic agents' report on cat and dog vaccines vaccines & vaccinations: guidelines vs. reality vaccines and vaccinations: the strategic issues infectious diseases of the dog and cat vaccines and their production multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats the use of vaccines canine viral diseases canine vaccination vaccination of puppies born to immune dams with a canine adenovirus-based vaccine protects against a canine distemper virus challenge vaccination against canine distemper virus infection in infant ferrets with and without maternal antibody protection using recombinant attenuated poxvirus vaccines quedgeley (gloucester): british small animal veterinary association infectious canine hepatitis and canine acidophil cell hepatitis infectious diseases of the dog and cat seroconversion of puppies to canine parvovirus and canine distemper virus: a comparison of two combination vaccines canine parvovirus (cpv) vaccination: comparison of neutralizing antibody responses in pups after inoculation with cpv or cpv b modified live virus vaccine evaluation of the efficacy and duration of immunity of a canine combination vaccine against virulent parvovirus, infectious canine hepatitis virus, and distemper virus experimental challenges duration of serologic response to five viral antigens in dogs national association of state public health veterinarians. compendium of animal rabies prevention and control prevalence of and risk factors for leptospirosis among dogs in the united states and canada: cases ( - ) leptospirosis: a re-emerging zoonotic disease st louis (mo): elsevier saunders infectious diseases of the dog and cat canine borreliosis saunders infectious diseases of the dog and cat protection of dogs against canine distemper by vaccination with a canarypox virus recombinant expressing canine distemper virus fusion and hemagglutinin glycoproteins efficacy of the canine influenza virus h n vaccine to decrease severity of clinical disease after cochallenge with canine influenza virus and streptococcus equi subsp rattlesnake vaccine to prevent envenomation toxicity in dogs. presented at the dr ross o. mosier th annual western veterinary conference use of serologic tests to predict resistance to feline herpesvirus , feline calicivirus, and feline parvovirus infection in cats other feline viral diseases infectious diseases of the dog and cat update on feline calicivirus: new trends an outbreak of virulent systemic feline calicivirus disease rabies surveillance in the united states during epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats feline leukemia virus american association of feline practitioners' feline retrovirus management guidelines infectious diseases of the dog and cat feline immunodeficiency virus infection feline immunodeficiency virus infection infectious diseases of the dog and cat feline infectious peritonitis and feline coronavirus infection vaccine-associated feline sarcoma task force. vaccine-associated feline sarcomas vaccine-associated feline sarcoma task force. the current understanding and management of vaccine-associated sarcomas in cats resistance to tumors comparative vaccine-specific and other injectable-specific risks of injection-site sarcomas in cats vaccine-associated adverse events immune complexes and type iii hypersensitivity key: cord- -leu hygk authors: gallagher, j.; watson, c.; ledwidge, m. title: association of bacille calmette-guerin (bcg), adult pneumococcal and adult seasonal influenza vaccines with covid- adjusted mortality rates in level european countries date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: leu hygk introduction non-specific effects of vaccines have gained increasing interest during the covid- pandemic. in particular, population use of bcg vaccine has been associated with improved outcomes. this study sought to determine the association of population use of bcg, adult pneumococcal and adult seasonal influenza vaccination with covid- mortality when adjusted for a number of confounding variables. methods: using publicly available data, mortality adjusted for the timeframe of crisis, population size and population characteristics was calculated. the primary analysis was the relationship between each of the day and day standardised mortality rates and bcg, adult pneumococcal and influenza vaccination scores using unadjusted measures and with adjustment for population structure and case fatality rates. secondary analyses were measures of case increases and mortality increases from day to day for each of the relative vaccination scores. finally, we also analysed the peak z score reflecting increases in total mortality from historical averages reported by euromomo (euromomo.eu), results: following adjustment for the effects of population size, median age, population density, the proportion of population living in an urban setting, life-expectancy, the elderly dependency ratio (or proportion over years), net migration, days from day to lockdown and case-fatality rate, only bcg vaccination score remained significantly associated with covid- mortality at day . in the best fit model, bcg vaccination score was associated with a % reduction in log( ) mortality per million population (or . reduction [ % ci . to . ]), following adjustment for population size, median age, density, urbanization, elderly dependency ratio, days to lockdown, yearly migration and case fatality rate. conclusion bcg vaccine was associated with reduced mortality rates in level countries while adult pneumococcal and adult seasonal influenza vaccines were not when adjusted for a number of confounding variables. a number of trials are ongoing to determine if bcg is protective against severe covid- infection. using publicly available mortality data from the john's hopkins coronavirus research centre and demographic information presented on worldometers.info, we constructed curves of cumulative mortality adjusted for timeframe of crisis and population size, as previously described in a rapid response to an editorial on sars-cov- testing and comparative international mortality rates [ a] . in order to standardise the timeframe, we designated the baseline (day ) as the day that mortality rates exceeded per million population. we calculated the day and day mortality rate per million population for each of the following level european countries austria, belgium, czechia, denmark, estonia, finland, france, germany, greece, hungary, iceland, ireland, italy, lithuania, luxembourg, netherlands, norway, poland, portugal, slovakia, slovenia, spain, sweden, switzerland, united kingdom. we also obtained recent data on population structure including population size, the median age (years), population density (persons/km ), the proportion of population living in an urban setting, life-expectancy (years), the elderly dependency ratio (proportion of people over years divided by the proportion aged - ) and net migration (expressed per million population). in multivariable modelling we also included the case fatality rate on day to account for differences in testing rates, testing strategy and case definition as well as the relative number of days between baseline (day ) and lockdown. in order to standardise the estimation of the proportion of the population covered with bcg vaccination, we generated a bcg vaccination score by dividing the median life expectancy by the total number of years that bcg vaccination was available and recommended for all children. we adjusted this calculation by multiplying with a measure of vaccination programme efficacy, using the most recent vaccination coverage rate for either bcg or universal childhood vaccination rates as appropriate. in the case of two countries that do not routinely recommend bcg vaccination and where few details were available (iceland, luxembourg) we used referenced estimates of the total population covered by bcg vaccination. similarly, for pneumococcal vaccination, we generated a pneumococcal vaccination score by estimating the proportion of older people covered by pneumococcal vaccination over the past decade using a variety of referenced sources in circumstances where uptake is considered relatively low in most european countries, despite recommendations for their use in over s and vulnerable populations. finally, we created an influenza vaccination score as the proportion of older adults with seasonal influenza vaccination from most recent sources provided by the european centre for disease control and other referenced reports. the primary analysis of our report was the relationship between each of the day and day standardised mortality rates and bcg, pneumococcal and influenza vaccination scores using unadjusted measures and with adjustment for population structure and case fatality rates. secondary analyses were measures of case increases and mortality increases from day to day for each of the relative vaccination scores. finally, we also analysed the peak z score reflecting increases in total mortality from historical averages reported by euromomo (euromomo.eu), a european mortality monitoring activity, aiming to detect and measure excess deaths related to seasonal influenza, pandemics and other public health threats, supported by the european centre for disease prevention and control (ecdc) and the world health organization (who). primary and secondary outcomes were analysed using generalized linear modeling with a poisson outcome distribution for adjusted mortality rates. analyses were performed both with and without adjustment for the effects of population size, the median age, population density, the proportion of population living in an urban setting, life-expectancy, the elderly dependency ratio (or proportion over years), net migration, days from day to lockdown and case-fatality rate. variables such as day and day mortality rates, case fatality rates, population size, population density and life expectancy, were not normally distributed across the countries and were log-transformed before inclusion in the generalized linear model. nominal statistical significance was set at p< . with bonferroni correction for the pairwise correlations involved in the primary analyses (three vaccination scores linked to day mortality rates), meaning a p value of . / = . was considered statistically significant. descriptive data are presented as either mean ± sd or median ( th: th percentile) for normally and non-normally distributed continuous variables, respectively. frequencies and percentages (in parentheses) summarize categorical variables. graphs were presented using graphpad prism v and statistical analysis was performed using the r statistical software package (version . . , - - , copyright the r foundation). the population structure of the countries are presented in table . the date of exceeding sars-cov- death per million population, date of lockdown and cases, deaths and case fatality rates (cfr) on days and are presented in table . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . the unadjusted linear regression between log of deaths per million on day versus bcg, pneumococcal and influenza vaccination scores are presented in figure a -c. following adjustment for the effects of population size, median age, population density, the proportion of population living in an urban setting, life-expectancy, the elderly dependency ratio (or proportion over years), net migration, days from day to lockdown and case-fatality rate, bcg vaccination score remained significantly associated with covid mortality at day . in the best fit model, bcg vaccination score was associated with a % reduction in log ( ) similarly, as shown in figure a . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . studies suggesting that countries providing universal bcg vaccine coverage have decreased mortality with covid ( - ) have been the source of wide media interest. however, there have been significant concerns about confounding factors and the lack of randomised controlled data to determine if there is a true causation between bcg vaccination and reduced mortality with covid ( ). while this ecological study may be the first to evaluate bcg vaccination in models with standardisation of mortality rates for timeframe of the outbreak as well as population size, as well as incorporating extensive covariate adjustment related to population structure, the major limitation is that it demonstrates correlation but cannot definitively assign causation. there may be many other confounding variables, which could account for the relationship between bcg vaccination and mortality. furthermore, it is well accepted that differences in recording mortality between countries have been reported which may affect numbers. finally, the bcg vaccination score is an estimate of the population coverage with bcg and may not accurately reflect the true population vaccination. conversely, the extensive covariate adjustment as well as differential relationship between bcg and influenza/pneumococcal vaccination scores, may support the hypothesis that bcg vaccination is associated with protection from the severest consequences of covid . there is a persistent relationship between bcg vaccination and a variety of mortality and morbidity measures, including peak standardised z-scores reported for the pandemic. the present study builds on a growing body of evidence that bcg vaccination may be associated with decreased illness severity unrelated to mycobacterium infection. many have been epidemiological studies looking at overall mortality rates . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint but others have looked at specific unrelated causes such as parasites ( ) , fungi ( ) and bacteria ( ) in humans and animals. a recent systematic review concluded that there is evidence with low to moderate risk of bias that bcg vaccination prevents respiratory infections (pneumonia and influenza) in children and the elderly( ) a number of trials are ongoing at present to elucidate the role of bcg in preventing severe covid with three reported in clinicaltrials.gov ( ) ( ) ( ) . to date, the nature of non-specific effects with bcg has not been fully elucidated, yet there are a number of possible mechanisms of causation to explain the correlations described in our study. vaccines with non-specific effects would induce reprogramming of the innate immune responses, a mechanism that clearly differs from the adaptive immunity induced by the antigen-specific responses to the vaccine. also, since bcg is generally administered to children, any putative innate immune cell "priming" following bcg would, necessarily, be retained many years following vaccination, suggesting an epigenetic link. interestingly, bcg vaccination has been shown to cause epigenetic changes in innate immune cells via histone- -lysine- (h k ) methylation [ ] , which can can augment human ifn and isg responses to non-mycobacterium and even fungal infections. therefore, the bcg "primed" innate immune system could counter the sars-like coronavirus early ifn and isg suppression, providing a more robust initial innate immune response to limit replication of sars-cov- virus. [ ] interestingly the search for a vaccine to manage the sars-cov- pandemic is a global healthcare priority because of high transmissibility and covid mortality rates. however, following a small, non-human primate . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . study of the oxford rna vaccine, the world's largest producer of vaccines is in negotiation to dedicate its production capacity to this developmental vaccine for sars-cov- . [ , ] however, this could limit normal childhood vaccination programmes despite risks of using novel technology platforms to treat the novel sars-cov- virus. while we await the results of prospective, randomised, controlled clinical studies on novel vaccines specific for sars-cov- , recent clinical progress with known drugs such as remdesivir highlight the potential of repurposing known therapies to combat covid- ( ) . the present study suggests that ongoing, prospective clinical studies to determine if bcg vaccination reduces the severity of covid- in vulnerable patients could provide important information on the potential for innate immune priming with bcg as an adjunct to other clinical strategies for protection against the worst consequences of sars-cov . the association of bcg and reduced mortality from covid- was seen even after standardising mortality between level european countries and adjusting for confounding variables relating to population structure. a similar association was not seen with adult influenza and pneumococcal vaccination. the results of prospective clinical studies on bcg vaccination as an adjunct to usual care in the setting of covid- are awaited. abbreviations: bcg bacille calmette-guérin vaccination coverate rate pneumococcal vaccination; influenza, influenza; uk united kingdom using dpt / as proxy for national childhood vcr; no data available, replaced with average of reported data for countries vaccine coverage of pre-school age children in france in bcg vaccination reported mandatory from to referencing "tuberkulosevaksinasjon -veileder for helsepersonell european centre for disease prevention and control. seasonal influenza vaccination and antiviral use in eu/eea member states -overview of vaccine recommendations for - and vaccination coverage rates for - and - influenza seasons the effect of oral polio vaccine at birth on infant mortality: a randomized trial non-specific effects of standard measles vaccine at . and months of age on childhood mortality: randomised controlled trial heterologous) protection of neonatal bcg vaccination against hospitalization due to respiratory infection and sepsis non-specific effect of vaccines: immediate protection against respiratory syncytial virus infection by a live attenuated influenza vaccine the vaccine trialist group. a role for streptococcus pneumoniae in virusassociated pneumonia correlation between universal bcg vaccination policy and reduced morbidity and mortality for covid- : an epidemiological study connecting bcg vaccination and covid- : additional data association of bcg vaccination policy with prevalence and mortality of covid- differential covid- -attributable mortality and bcg vaccine use in countries bacille calmette-guérin (bcg) vaccination and covid- scientific brief bcg vaccination is associated with reduced malaria prevalence in children under the age of years in sub-saharan africa the role of bcg/ppd-activated macrophages in resistance against systemic candidiasis in mice bacille calmette-guerin induces nod -dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes does bcg vaccination protect against acute respiratory infections and covid ? a rapid review of current evidence does bcg vaccination protect against acute respiratory infections and covid- ? a rapid review of current evidence reducing health care workers absenteeism in covid- pandemic through bcg vaccine (bcg-corona) bcg vaccination to protect healthcare workers against covid- (brace) bcg vaccine for health care workers as defense against covid (badas) remdesivir for the treatment of covid- -preliminary report no funding was received for this study key: cord- -j sfiyz authors: ward, kirsten; seale, holly; zwar, nicholas; leask, julie; macintyre, c. raina title: annual influenza vaccination: coverage and attitudes of primary care staff in australia date: - - journal: influenza other respir viruses doi: . /j. - . . .x sha: doc_id: cord_uid: j sfiyz please cite this paper as: ward et al. ( ) annual influenza vaccination: coverage and attitudes of primary care staff in australia. influenza and other respiratory viruses ( ), – . background annual influenza vaccination is recommended for all australian health care workers (hcws) including those working in primary health care. there is limited published data on coverage, workplace provision, attitudes and personal barriers to influenza vaccination amongst primary health care staff. the aim of this study was to contribute to the limited literature base in this important area by investigating these issues in the primary health care setting in new south wales (nsw), australia. methods a postal survey was sent to general practitioners (gps) and practice nurses (pns) from inner city, semi‐urban and rural areas of nsw, australia. there were responses in total (response rate %) from gps (response rate %) and pns (response rate %). results reported influenza vaccination coverage in both and was greater than %, with gps reporting higher coverage than pns in both years. the main barriers identified were lack of awareness of vaccination recommendations for general practice staff and concern about adverse effects from the vaccine. conclusions rates of influenza vaccination coverage reported in this study were higher than in previous studies of hospital and institutional hcws, though it is possible that the study design may have contributed to these higher results. nevertheless, these findings highlight that more needs to be done to understand barriers to vaccination in this group, to inform the development of appropriate strategies to increase vaccination coverage in primary health care staff, with a special focus on pns. influenza is a serious respiratory virus which costs the australian healthcare system $ million annually. primary health care workers (hcws) like general practitioners (gps) and practice nurses (pns) have found to be at higher risk for influenza than the general population. this may be because of: (i) exposure to influenza infection in both the general community and the workplace; and (ii) close proximity to visitors and patients. , vaccines remain the cornerstone of influenza prevention in many countries worldwide and are considered to be - % effective in healthy persons aged - years. annual influenza vaccination of australian hcws is recommended by the national health & medical research council (nhmrc), the australian committee on safety and quality in healthcare and various jurisdictional health departments, including new south wales (nsw). the royal australian college of general practitioners recommend that general practice staff members are offered immunisation appropriate to their duties. whilst there have been numerous australian studies on influenza vaccine uptake amongst hospital and institutional hcws , [ ] [ ] [ ] [ ] [ ] and some studies on attitudes of primary care clinicians to influenza vaccination for their patients , , there has been limited published studies to date on influenza vaccination coverage, barriers and enablers amongst primary health care staff in australia. influenza vaccination coverage amongst gps in australia was % in . in neighbouring new zealand, coverage amongst gps was % and % in pns in . other countries have reported lower coverage estimates, with only % of canadian family physicians from québec and % of gps from the netherlands vaccinated in and , respectively. a study across all primary health care professions in israel reported an average of % coverage across physicians, nurses, pharmacists and administration staff. factors associated with influenza vaccination status have been examined in primary health care clinicians in other countries. [ ] [ ] [ ] [ ] [ ] amongst this group of hcw's, significant predictors for vaccine acceptance include the following: agreement that hcw's have professional responsibility to be vaccinated, on-site access to free vaccine, workplace recommendation for staff influenza vaccination, desire for self-protection and belief that the benefits of vaccination outweigh the risk of vaccine side effects. , furthermore, previous influenza vaccination has been significantly associated with current vaccine acceptance in both hospital hcws and primary care physicians. factors significantly associated with lack of vaccine acceptance include the following: no medical indication for vaccination, belief that regular medical exposure will protect against the disease, low risk of contracting influenza, fear of vaccine side effects and lack of time or priority. , , some of these factors are similar to those cited by hospital hcws whilst others differ. in a review of attitudes and predictors to influenza vaccination of hospital hcw's, lack of convenient access to vaccine and poor knowledge about influenza infection were prominent reasons for lack of vaccination with the desire for self-protection and belief in the vaccine's effectiveness the most prominent reasons for vaccine acceptance in this group. to the best of our knowledge, there have been limited studies which specifically examine: influenza vaccination coverage, workplace provision of vaccination, knowledge, attitudes and personal barriers to influenza vaccination amongst gps and pns in australia. the aim of this study therefore was to contribute to the limited literature base in this important area by investigating this in the primary health care setting in nsw, australia. a paper-based survey was developed based on pilot work undertaken by the authors and commonly identified barriers to vaccination from the literature. , , it elicited demographic data about the respondents, their influenza vaccination status from to and identified barriers to being immunised. it also posed questions intended to determine the respondent's attitude towards vaccination, based on seven statements about efficacy, safety, adverse events and recommended target groups for influenza vaccine and was part of a wider survey that incorporated questions on pandemic influenza. the survey was piloted with four gps and pns from outside the study area. feedback from this process contributed to enhanced content, altered survey structure and modified wording. our sample was drawn from divisions of general practice (dgp) in nsw. dgps are government-funded organisations that provide support to a defined geographical catchment of general practices in australia. they are classified by population and locality into five categories based on rural, remote metropolitan areas (rrma). , nsw has the highest number of dgps, with . purposive sampling by the authors was used to select four dgps in nsw to represent a diverse sample from metropolitan, semiurban and rural areas. the final sample size for each participating division was weighted according to how many gps and pns were practicing in the area. the study was undertaken from the st february to st april , prior to the pandemic (h n ) influenza which was identified in late april . authors were blinded to participant selection, as they were randomly selected from de-identified dgp databases of gps and pns. surveys were posted by dgps and were accompanied by personalised explanatory letter and a reply-paid envelope. non-responders were sent a second letter and survey by the dgps within weeks. quantitative data was entered into microsoft access and was analysed using microsoft excel. responses to the geographical location question were categorised into inner city, semi-urban and rural areas. questions about influenza vaccine-related barriers, attitudes and beliefs were categorised into either agree, disagree or uncertain. the categories were compared with demographic characteristics and selfreported vaccination status of respondents using categorical data analysis. ethical approval was granted by the university of new south wales ethics committee. of the staff that was sent a survey, completed and returned it, giving an overall response rate of %. fifteen surveys were returned uncompleted as the staff member was no longer at the practice. response rates were higher amongst pns ( %) than gps ( %). the demographic and occupational characteristics of the respondents are summarised in table . there was some variation in geographical location of respondents, with ae % ( ⁄ ) located in semi-urban areas, % ( ⁄ ) in the inner city and the remaining ae % ( ⁄ ) in rural locations. of the respondents, % ( ⁄ ) were working in practices with £ gps. our sample parallels the findings of the - bettering the evaluation and care of health (beach) survey in terms of the spread in gp age, years worked in general practice and geographical location. the beach program is a continuous national study of general practice activity in australia. it provides a reliable, ongoing, representative description of general practice activity nationwide. just over % of respondents were vaccinated against influenza in ( ae %, ⁄ , % ci: ae - ae ) and in ( ae %, ⁄ , % ci: ae - ae ). differences in vaccination coverage between gps and pns for both (p = ae ) & (p = ae ) (see table participants indicated that free influenza vaccine was most commonly provided at the practice for gps ( ae %, ⁄ , % ci: ae - ae ), administration staff ( ae %, ⁄ , % ci: ae - ae ) and pns ( ae %, ⁄ , % ci: ae - ae ). of the gps working at a practice which provided free influenza vaccine for gps, ae % ( ⁄ ) were vaccinated in in contrast to ae % ( ⁄ ) coverage in gps from practices that did not provide the vaccine free of charge for them. for pns, ae % ( ⁄ ) vaccinated in worked at a practice where the vaccine was provided free and % ( ⁄ ) were vaccinated despite the vaccine not being provided free for pns at their practice. respondents' knowledge, attitudes and perceptions of influenza vaccination are summarised in table . over % of the participants believe that the influenza vaccine is attitudes towards vaccination barriers amongst the respondents are presented in table . while there was a low level of agreement with all of the statements provided (< %), the most commonly identified barriers were lack of awareness of any recommendation for general practice staff to receive influenza vaccination ( ae %, ⁄ , % ci: ae - ae ) and unacceptable nature of vaccination side effects ( ae %, ⁄ , % ci: ae - ae ). having to pay for the vaccine was identified as a barrier to getting vaccinated by ae % ( ⁄ ) of respondents. five of the twelve gps, who worked in a practice that did not provide free vaccine, felt that paying for a vaccine was a barrier. our study of primary health care staff found much higher influenza vaccination coverage than hospital hcws in australia. overall reported coverage of gps and pns was markedly higher than those for australian institutional and hospital hcws which have been found to range from % to %. , [ ] [ ] [ ] [ ] self-reported vaccination coverage for gps in our study (for ) was higher than the percentage reported for australian hospital-based doctors from the northern territory ( ae % versus %) and western australia ( ae % versus ae %). pns in our study had higher coverage when compared to nurses in residential aged care facilities (racf) ( ae % versus %) , and hospital-based nurses ( ae % versus ae %) yet had lower coverage than pns from the australian capital territory (act) ( ae % versus %). the australian national influenza & pneumococcal survey provides the earliest available influenza vaccination coverage estimates for gps in australia. results of this survey found coverage for nsw gps was the lowest of any jurisdiction, with % vaccinated in , and just over % for the preceding years. comparing these rates to those observed in our study, influenza vaccination coverage amongst gps in nsw appears to have risen substantially from to . more recently, a national survey from the australian general practice network (agpn) assessed influenza vaccination coverage in gps and pns in the same years as our study ( ⁄ ) with similar response rates ( % versus %). comparing vaccine uptake between the studies for both gps and pns in nsw only, the agpn study reported slightly lower coverage ( %) across both years in both groups. as data was collected at a practice level in the agpn study, individual vaccination status may have been incorrectly reported and may be underestimating the actual coverage rate. however, our results may overestimate actual coverage because of a number of reasons including the low response rate and use of self-reported vaccination status. studies into gp influenza vaccination coverage have been performed in other countries. [ ] [ ] [ ] [ ] [ ] cowen et al. in the united states (us) had a similar response rate to our study ( % versus %), but reported a much higher vaccination coverage rate for us family physicians ( %). semaille et al. and brunton et al. reported influenza vaccination coverage as % amongst french gps and % amongst new zealand gps, respectively. in contrast, studies from the netherlands and israel found lower coverage rates for gps with % and %, respectively. even though the majority of our respondents worked in a practice that provided free vaccine for their staff, many felt that paying for the vaccine was a barrier to getting vaccinated. the wording of the question may have impacted on the result, as respondents could have taken it to mean for gps in general and not for them personally. however, it is interesting to note, of the gps who said their practice does not provide free vaccine, % stated that paying for the vaccine was a barrier to receiving it. further qualitative research would assist in addressing these gaps in understanding. the gps and pns in our study largely disagreed with the common vaccination myths presented in the survey (see table ). in contrast, the most frequently reported reason amongst dutch gps for not being vaccinated was having no medical indication for influenza vaccination and in israel; physicians were much less frequently influenced by the fear that vaccination would cause influenza when compared to other practice staff. there was almost no consistency of agreement with both these misconceptions in our sample or that of litt et al., who found that the main reasons indicated by australian gps for being vaccinated against influenza were concern about getting influenza or its complications and to prevent having time off work because of influenza. live viruses in the influenza vaccine was the most common myth supported by respondents ( ae %, ⁄ ) yet a decade ago, less than % of australian gps gave this as a reason for not getting influenza vaccine. the reasons behind this shift in belief is unknown; however, technology could play a part, with increased access to a variety of information sources. in the light of this, gp education should continue to focus on dispelling this myth through use of evidence-based information. other barriers to influenza vaccination identified in our study were lack of awareness of any recommendations for general practice staff to receive the influenza vaccine ( %) and unacceptable side effects of vaccination ( %). these are similar to those commonly cited by hcws in other countries. [ ] [ ] [ ] for hospital doctors, being too busy has been identified as a major barrier to getting vaccinated against influenza. , , in contrast, only a small number of participants, all of whom were gps, identified lack of time as a barrier as did approximately % of gp respondents the australian influenza and pneumococcal vaccination survey ( ) in the elderly. a previous investigation of general practice staff across dgps in australia found a significant association between workplace influenza vaccination policy and staff vaccination. we found that interrelationship between staff beliefs and practice policies may be an important determinant of hcw immunization behaviours in these practices. office policies demanding immunisation and operating within an effective hierarchy can lead staff members to re-evaluate their beliefs about influenza immunization in the light of their own experience. continued efforts at the practice level to make formal commitments to staff health by developing policies for influenza vaccination of staff may assist in increasing coverage in this group. provision of the influenza vaccine to patients along with consistent, direct, exposure to influenza like illness by this population may further impact on their decision to be vaccinated. pandemic (h n ) influenza is also likely to increase awareness of influenza vaccination and instigate new policies and practices surrounding vaccination of primary health care staff as has been seen in other countries during heightened awareness of an impending influenza pandemic threat. there are a number of limitations to this study including sample size, generalisability and use of self-report for vaccination status. although the sample size was small, compared to other general practice-based surveys, it would be considered reasonable in the light of the challenges with surveying this population. , there is potential for selection bias in this study towards those who are particularly concerned about influenza and ⁄ or vaccination or those who accept vaccination. furthermore, using self-reported vaccination status in adults has been shown to overestimate coverage. , there may also be limitations with generalisability because our study was conducted only in one state of australia. this study did not collect any data on nonrespondents or outcomes for those who intended to be vaccinated in . in addition, the barriers in our survey may not have covered all possible options, thus may have influenced participants response. qualitative research is needed to further explore these findings. despite these limitations, influenza vaccination coverage was found to be relatively high amongst the gps and pns in our study; however, there is still room for improvement. understanding barriers to vaccination is the first step to developing effective strategies to overcome them. for institution-based hcws, there is now an extensive literature base around knowledge, attitudes and practices towards influenza vaccination, whereas, there are only a few studies exploring these topics in the primary health care setting in australia. to enhance development and targeting of strategies to increase coverage, a more complete and current understanding of coverage in this group is needed to build on the estimates presented here. we believe this study to be a basis for future investigations and interventions to increase influenza vaccination rates in primary health care staff in australia. influenza-related disease: the cost to the australian healthcare system the role of influenza vaccine in health care workers in the era of severe acute respiratory syndrome national health and medical research council (nhmrc). the australian immunisation handbook, th edn. canberra: australian government world health organization. influenza vaccines vaccines for preventing influenza in healthy adults discussion paper: influenza vaccination amongst health care workers policy directive: occupational assessment, screening & vaccination against specified infectious diseases royal australian college of general practitioners. infection control standards for office based practices co-ordinated approach to healthcare worker influenza vaccination in an area health service influenza vaccine coverage among health care workers in victorian public hospitals influenza vaccination of staff in aged care facilities in the act: how can we improve the uptake of influenza vaccine? influenza immunisation of doctors at an australian tertiary hospital: immunisation rate and factors contributing to uptake attitudes amongst australian hospital healthcare workers towards seasonal influenza and vaccination barriers and facilitators to influenza vaccination among high-risk groups aged less than years -views from general practitioners and practice nurses differences in attitudes, beliefs and knowledge of hospital health care workers and community doctors to vaccination of older people australian national influenza and pneumococcal survey in the elderly knowledge and attitudes about influenza vaccination amongst general practitioners, practice nurses, and people aged and over vaccination practices of quebec family physicians. influenza vaccination status and professional practices for influenza vaccination influenza immunization of dutch general practitioners: vaccination rate and attitudes towards vaccination influenza vaccination among primary healthcare workers influenza vaccination status and influenza-related perspectives and practices among us physicians influenza vaccination of health care workers in hospitals -a review of studies on attitudes and predictors general practice network influenza survey report national foundation of infectious diseases. improving influenza vaccination rates in health care workers. strategies to increase protection for workers and patients. atlanta: centre for disease control and prevention australian institute of health & welfare (aihw). rural, regional and remote health: a guide to remoteness classifications fast facts: rural remote metropolitan area (rrma) classification initial human transmission dynamics of the pandemic (h n ) virus in north america general practice series no. . (cat. no.gep ). canberra: australian government influenza vaccination in act nurse immunisers evaluation of the vaccine coverage of the general practitioners in the french community organizational culture influences health care workers' influenza immunization behaviour annual report of the national influenza surveillance scheme high coverage of influenza vaccination among health care workers can be achieved during heightened awareness of impending threat response rates of victorian general practitioners to a mailed survey on miscarriage: randomised trial of a prize and two forms of introduction to the research the effect of cash and other financial inducements on the response rate of general practitioners in a national postal study sensitivity and specificity of patient self-report of influenza and pneumococcal polysaccharide vaccinations among elderly outpatients in diverse patient care strata validity of self-reported influenza and pneumococcal vaccination status among a cohort of hospitalized elderly inpatients influenza vaccine coverage and attitudes in australian primary care staff ª thanks to the following for their support in this study; central sydney general practice network, albury wodonga regional gp network shire gps (sutherland division of general practice) and went west ltd. j leask is an investigator on a grant which is part funded by sanofi pasteur. c. r. macintyre receives funding from influenza vaccine manufacturers gsk and csl biotherapies for investigator-driven research. k ward has received funding from wyeth to attend an immunisation conference. all other authors of this manuscript have no conflicts of interest to declare. national centre for immunisation research and surveillance is supported by the australian government department of health and ageing, the nsw department of health and the children's hospital at westmead. key: cord- -c gmu authors: davis-wurzler, gina m. title: current vaccination strategies in puppies and kittens date: - - journal: vet clin north am small anim pract doi: . /j.cvsm. . . sha: doc_id: cord_uid: c gmu motivation in writing this article stems from many things: a lack of time spent in the veterinary curriculum discussing vaccines, a growing concern(by the general public and the veterinary community) regarding adverse reactions associated with vaccines, and a desire to prevent a recurrence of preventable infectious diseases resulting from a fear-driven cessation of vaccine administration. the objectives of this article are to present a basic review of immunology as related to vaccines, to discuss general guidelines for pediatric vaccines in canine and feline patients,and to offer suggestions as to how we can most positively influence our patients' health from the first visit. has a minimal effect in these species. it also occurs during initial suckling through the ingestion of colostrum and lactation, which have more significant effects in these species [ ] . this maternal immunity does provide initial protection against many pathogens but, of course, is dependent on the health and immune status of the mother as well as the health of the fetus and neonate. although this may result in temporary protection for the infant, in the long term, it may be deleterious to that individual's health by essentially keeping that animal naive to different antigens (eg, maternal antibody interference with vaccination of the neonate). maternal or passive immunization is effective in protecting neonates for the first several weeks of life but begins to decline and lose the ability to protect against diseases rapidly as the maternal antibodies are degraded through natural catabolic processes. between the ages of and weeks, depending on multiple factors (including the species; amount of maternal antibody produced, transferred, and absorbed; and individual health status of the neonate), most puppies and kittens have maternal antibody levels below protective levels. if present at high enough levels, however, maternal antibodies can interfere with the neonate's ability to respond to vaccination, because the circulating maternal antibody within the puppy or kitten may effectively respond to and neutralize the vaccine antigen or render it ineffective by preventing recognition of the antigen by the immune system [ ] . this is one reason for multiple sequential vaccines in kittens less than weeks of age and puppies less than weeks of age. maternal antibodies can interfere with immunization, although the level of maternal antibody present may not be protective against pathogens. a functioning immune system is composed of multiple parts. innate immunity is the oldest (evolutionarily), least specific, and most immediate (in terms of response to potential invaders and/or pathogens) form of immunity. macrophages, neutrophils, dendritic cells, and natural killer (nk) cells, combined with numerous products produced by these cells, comprise the innate immune system. examples of some of the chemical components produced and released by these cells in response to microbial invasion include lysozyme, complement, and various cytokines, such as tumor necrosis factor-a and interleukins, as well as various vasoactive molecules, such as histamine [ ] . active immunization is the process of the individual responding to an antigenic stimulus appropriately by natural infection or vaccination. active immunization is processed through the acquired immune system. the two main types of acquired immunity are cell-mediated immunity and antibody, or humoral, immunity. cell-mediated immunity is predominantly directed against pathogens that typically are obligate intracellular organisms. examples include viruses, some obligate intracellular bacteria, some fungi, and protozoa. t lymphocytes are the predominant effector cells and are dependent on foreign protein (antigen) being presented to them before they can take effect against the pathogens; thus, multiple cell types are involved in forming cell-mediated immunity. antibody or humoral immunity is predominantly directed against pathogens that can survive outside the host or at least survive extracellularly. examples include most bacteria, fungi, protozoa, and helminths. multiple cells act in concert to confer humoral immunity as well, but the primary effector cell is the b lymphocyte [ ] . kittens and puppies have varying degrees of ability to respond to antigens, whether attributable to natural or vaccine exposure, based on antigen load, route of exposure, antigenic virulence, genetics of the individual animal, and levels of persistent maternal immunity. in naive animals whose maternal immunity has declined sufficiently so as not to interfere with an immune response, the first vaccine should stimulate a primary immune response. this initial exposure and recognition process and the ability to produce antibody to respond to the antigen typically take to days. subsequent exposures to the same antigen elicit a stronger response; a greater amount of antibody is produced, and the subsequent response is faster. this is known as the secondary, or anamnestic, immune response. although multiple cell lines are involved in this response, subsets of t and b lymphocytes known as memory cells preserve the host's ability to recognize and respond to antigens to which the animal has previously been exposed [ ] . to design, recommend, and actuate an effective plan for each patient, a practitioner must have familiarity with multiple variables. those variables include the duration of protection conferred on the neonate by the mother, the typical length of time maternal antibody may persist and pose interference with the young animal's ability to respond fully to a vaccine, and the length of time needed for an appropriate response. in addition, knowledge of the various diseases that pose risks to pediatric patients and of safe efficacious vaccines available is critical. in essence, we must assess each patient as an individual within the population to provide optimal wellness over the lifetime of each individual as well as the population. this rationale has led to the concept of core and noncore vaccines, two terms commonly used when discussing vaccination within the veterinary field. criteria for assigning vaccines into these categories as well as a third category, ''generally not recommended,'' are based on the following factors [ ] [ ] [ ] [ ] [ ] : . morbidity and mortality associated with the specific disease (does the organism cause serious illness, or does it cause a mild transient disease that may pose only minimal risk to the individual or population?) . prevalence or incidence rate of the disease (although a specific disease may not commonly be seen, the organism is ubiquitous in the environment and therefore poses a risk to the individual or population) . risk of the individual for exposure to the disease (eg, indoor-only animal versus free-roaming individual, regional variations of occurrence) . efficacy of the vaccine (does the vaccine prevent infection or simply ameliorate some signs or length of the disease?) . risks associated with administering the vaccine (are the risks associated with that vaccine greater than the risk of the disease?) . potential for zoonotic disease . route of infection or transmissibility when these criteria are assessed, general guidelines may be generated for the individual practitioner as well as for the veterinary community at large. again, guidelines are not to be thought of as absolutes, nor are they to be used to establish standard of care. they are, simply stated, tools for each of us to use to promote optimal wellness for our patients when considering all factors affecting the individual's health (environmental, organismal [pathogen and host], owner concerns, and current vaccine technologies) [ ] [ ] [ ] [ ] [ ] . there are multiple vaccines available for our canine and feline patients; yet, most vaccines fall within three basic categories. assignment of vaccine products (which are considered biologic agents rather than drugs and are therefore assessed and approved by the us department of agriculture [usda] rather than the us food and drug administration [fda]) into these categories is based on how the product is created. simply stated, modified-live vaccines (ml) are vaccines created by altering (attenuating) the pathogen in some way so that it is no longer able to cause serious or clinical disease in the targeted species. modified-live virus vaccines (mlv) are therefore vaccines containing live but avirulent virus. killed vaccines are vaccines produced by inactivating the pathogen completely, rendering it incapable of reproducing and thereby unable to cause disease. the third category of vaccines consists of recombinant vaccines. there are multiple types of recombinant vaccines, and this category itself has three subcategories. these vaccines use genetic technologies to introduce genetic material directly into the host (no vector is used [eg, purified subunit vaccines, type i recombinant]), alter the genetic material to change its virulence (gene deletion, type ii recombinant), or incorporate genetic material from the desired pathogen into an attenuated vector organism (eg, feline recombinant rabies, type iii recombinant) [ , ] . within the near future, multiple new technologies are likely to provide us with even more choices, hopefully providing our patients with better protection against disease with minimal vaccine-associated risks. for a comparison between vaccine types, the reader is referred to table . vaccines are available in single-dose and multiple-dose (tank) vials. the use of single-dose vial vaccines is highly recommended in these species. conversely, the use of multiple-dose vials is discouraged because of the increased risk of contamination and the inability to ensure consistent levels of antigen and adjuvant in individual doses from a single vial [ , ] . multivalent vaccines are not recommended in cats other than the core feline vaccine designed to protect against feline panleukopenia, feline herpesvirus i (fhv-i), and feline calicivirus (fcv). because of increased inflammation at the site of multivalent vaccines, all other vaccines should be given as a separate vaccine at the indicated site (see discussion on feline core and noncore vaccines) [ , ] . allowing vaccines to acclimate to room temperature before administration, particularly in cats, is recommended, because the administration of cold vaccines was found to have an increased association with tumorigenesis in cats [ ] . the practitioner is advised always to follow manufacturer's directions for dose and route of administration. using a topical product parenterally or splitting doses should never be done. administration of a modified-live bacterin vaccine designed for topical administration yet administered parenterally may have serious and potentially fatal consequences (fig. ) . a full dose is required to stimulate the immune system; there is no medical basis for giving a smaller dose to a toy-breed dog, and this practice could lead to vaccine failure in that animal. if done with a rabies vaccine, the practitioner is not following federal requirements, which carries potential legal implications [ , ] . the interval between various vaccines, whether using the same product serially in the initial series or using different products in an adult animal, should never be less than to weeks. interference between the first product administered and a second vaccine product may lead to failure to respond to that second vaccine optimally. the exact mechanism of this interference is unknown but may be associated with interferon produced by cells processing an ml agent or by transient immunosuppression by an ml agent. multiple vaccines administered at the same time do not seem to elicit this interference and is therefore an acceptable practice [ , ] . the reader is referred to tables and for a comparison between pediatric canine and feline core, noncore, and generally not recommended vaccines. the diseases that fall within this category carry high rates of morbidity or mortality; they are of public health concern, are readily transmissible, or may be ubiquitous in the environment. in addition, safe efficacious vaccines are available and provide sterile immunity (prevent infection) or confer a high degree of protection (do not prevent infection but may confer protection, such that the animal does not develop clinical signs of disease) [ , ] . essentially, the vaccines that fall within this category are recommended for each individual within the population regardless of that animal's lifestyle or locale. canine distemper virus (cdv), an enveloped morbillivirus, has been well controlled because of widespread vaccination programs over the past several decades. the disease still persists, however, and in addition to high virulence, it is readily transmissible. infection with the virus causes respiratory, gastrointestinal, and neurologic signs and is often fatal [ ] . the distemper vaccine is commonly administered as part of a multivalent product. the general recommendation is to use a modified-live or recombinant, multivalent product beginning at to weeks of age and to give serial vaccines every to weeks until the puppy has reached to weeks of age [ , , ] . currently, there is one product that contains modified-live distemper virus, canine adenovirus type ii (cav-ii), and canine parvovirus (cpv) (continuum; intervet, millsboro, delaware), but there are numerous vaccines with high safety and efficacy records that also include canine parainfluenza virus. there is also a vaccine that combines a recombinant canarypox-vectored cdv with modified-live adenovirus ii, parainfluenza, and parvovirus (recombitek; merial ltd, duluth, georgia), and this vaccine seems to be less affected by maternal antibody interference than mlv vaccines [ ] . other studies support the improved ability of recombinant vaccines to overcome maternal antibody interference as compared with mlv vaccines [ , ] . most puppies receive two or three distemper vaccinations, depending on the age when they are first presented to the veterinarian. it is, however, the interval between or the ''timing'' of the vaccinations rather than the ''number'' that is important. serial vaccinations help to increase the likelihood of a complete response of the patient and thereby decrease the risk of vaccine failure that may occur when only one vaccine is administered. in addition, by eliciting a secondary immune response, they may help to increase the level of circulating antibody and decrease the lag time between exposure to an antigen and achievement of maximal antibody level [ ] . potential causes for vaccine failure include an mlv vaccine that was improperly stored and therefore lost its efficacy, the vaccine was improperly administered (wrong route or accidental loss of vaccine onto the skin of the patient), the patient's immune system did not respond (the immune system may have been responding to another antigenic challenge, or the vaccine may have been given too soon after a previous vaccine), and maternal interference [ ] . in theory, if a puppy were kept ''sequestered'' from exposure to this virus, one mlv distemper vaccine administered after weeks of age would confer protection for at least year [ , ] . in reality, however, most pet owners are not inclined to isolate their puppies for the first months of life, nor should they. early socialization is an important part of families bonding with their puppies. exposure to various people, other dogs, and new places helps to decrease behavior problems in young adult and mature dogs [ ] . as long as the last distemper vaccine is administered after weeks of age, the puppy should be able to mount a strong active response and fully overcome any residual maternal antibody. the current recommendation is to have the puppy return year later (when approximately months old) for administration of another dose of distemper vaccine. after the first ''annual'' vaccination, triennial immunization is recommended for mlv vaccines [ , ] . annual revaccination is currently recommended if the recombinant product is used [ , ] . there are two types of adenovirus that cause disease in our canine patients. canine adenovirus type i (cav-i), a nonenveloped virus in the family adenoviridae, causes the potentially fatal disease infectious canine hepatitis. clinical signs include fever, depression, vomiting and diarrhea, and potential abbreviations: ab, antibody; felv, feline leukemia virus; fvr, feline viral rhinotracheitis; mlv, modified-live virus; pma, persistent maternal antibodies. a because of increased susceptibility for infection in kittens, vaccination against felv is strongly recommended for all kittens. in single-cat households, households with known negative viral status of all cats, and households with indoor only cats, the practitioner may elect to consider this a noncore vaccine. petechiation and ecchymotic hemorrhage secondary to hepatic dysfunction. in addition, uveitis and renal disease are associated with infection with this virus. cav-ii causes respiratory tract disease. cav-i is associated with severe potentially fatal disease, and protection against this disease is recommended. transmission is via the oronasal route and exposure to infected secretions. cav-ii infection typically results in mild self-limiting disease and is therefore considered to be a noncore disease; however, the mlv product designed for prevention of cav-i has been associated with adverse effects, such as uveitis and corneal edema (an arthus reaction, similar to effects caused by natural infection) [ , ] . the current recommendation is to use the cav-ii mlv because it stimulates the immune system to protect against cav-i and cav-ii without the associated adverse reaction caused by the type i vaccine [ , , ] . a modified-live adeno-type ii virus is typically included in a multivalent injection (as mentioned previously) and is therefore usually administered at intervals of to weeks, beginning between and weeks of age and ending between and weeks of age. a vaccination year later is recommended before instituting triennial vaccinations. canine parvovirus cpv is a nonenveloped type parvovirus. the predominant form currently causing infection in the united states is type b, but other subtypes exist and cause disease elsewhere [ ] . because the virus is nonenveloped, it may exist (outside a host) under certain environmental conditions and is somewhat resistant to many disinfectants. transmission is via the fecal-oral route, and clinical signs include lethargy, anorexia, pyrexia, vomiting, and diarrhea (typically hemorrhagic). young animals seem to be at highest risk for developing severe life-threatening disease. the current recommendation for vaccination is to use a multivalent mlv beginning at to weeks of age and to repeat the vaccine at intervals as stated previously (every to weeks until the puppy is to weeks of age). there has been some concern that certain breeds may be at increased risk for contracting and developing severe parvoviral disease (eg, doberman pinschers, rottweilers), but it is generally agreed that these breeds mount an appropriate response to a quality product if the last vaccine is given between and weeks of age [ , ] . recent studies using mlv cpv b strains showed a higher antibody response to cpv and cpv b and that the cpv b strain vaccines were better able to overcome maternal antibody interference than the cpv strain vaccines used [ , ] . an alternative would be to use serial vaccinations of killed virus if the practitioner were concerned about the potential for vaccine-induced clinical disease in one of the breeds believed to be more susceptible to this virus; however, these vaccines are less immunogenic [ ] . immunization year after completing the initial puppy series is recommended, with subsequent triennial vaccinations [ , , ] . rabies virus, an enveloped virus in the rhabdoviridae family, is capable of infecting all mammals [ ] . because it is an enveloped virus, it is not stable in the environment and is readily inactivated by most common disinfectants. the virus is transmitted through infected saliva, most commonly from a bite by an infected animal. clinical signs range from anxiety or other vague behavior changes to pica, dysphagia, photophobia, and paralysis. because of the zoonotic potential and implications regarding public health, canine vaccination programs are strongly regulated and enforced. the current recommendation is to vaccinate puppies using a killed virus vaccine at a minimum of or weeks of age. state regulations vary as to the minimum age for canine rabies vaccination; in california, the legal minimum age of canine vaccination against rabies is weeks. a second rabies vaccine (killed product) is administered year later and then annually or triennially thereafter depending on local regulations [ , ] . it is the practitioner's professional responsibility to acquire knowledge of and maintain adherence to regional laws regarding rabies vaccination frequency [ ] . vaccines in the noncore category have limited efficacy, or the organism causing disease is not readily transmissible or may have limited geographic distribution or prevalence. additionally, the diseases these vaccines are designed to prevent may be so mild or self-limiting that the risk associated with administering the vaccines may be greater than that of the actual disease. finally, some vaccines may interfere with common screening methods for disease detection and are therefore not recommended unless absolutely warranted for a specific individual. it is the burden of the practitioner, along with the pet owner, to make decisions regarding which, if any, of the noncore vaccines should be administered to a puppy [ ] [ ] [ ] [ ] . a bacterial pathogen that causes acute hepatic and renal disease, leptospirosis is typically transmitted through urine of infected animals (reservoir hosts include dogs, rats, wildlife, and livestock) and in contaminated water. there are at least two different species (leptospira interrogans and leptospira kirschneri) that can infect dogs, with multiple serovars (variants of the same species) of l interrogans causing disease in dogs [ ] . although these organisms have the potential to cause serious disease, dogs are not likely to be at risk in a mostly urban and controlled environment (eg, housed in a fenced yard with no exposure to wildlife or livestock). a dog that frequents rural environments or has exposure to waterways or livestock is definitely at risk of infection, however, and should therefore be protected against the disease. again, the initial puppy appointments should involve a thorough history and include the owner's plans for that dog's future use. if an owner brings a labrador retriever puppy to the veterinarian for ''whatever vaccines it needs,'' it is up to the practitioner to ask: ''will it be a hunting dog, will it be used in field trials, or will it be exposed to wildlife and waterways?'' the border collie that lives on a working sheep ranch surely should be vaccinated as well. conversely, a long-haired miniature dachshund that spends its days on its owner's lap is at minimal risk of exposure; therefore, vaccination is most likely not warranted. in essence, the regional distribution, seasonality (increased prevalence during and immediately after the rainy season), and lifestyle of the puppy should factor into the decision as to whether the puppy should be vaccinated. if the decision is made to vaccinate against leptospirosis, the general recommendation is to wait until the puppy is at least weeks of age; at that time, a killed or purified subunit vaccine is administered. infection is serovar specific, and no cross-protection is seen between different serovars; therefore, vaccination with those serovars known to cause disease in a given region is recommended. currently, there is one killed purified subunit vaccine (leptovax; fort dodge animal health, overland park, kansas) that contains four serovars (icterohaemorrhagiae, canicola, pomona, and grippotyphosa); however, the duration of immunity against grippotyphosa and pomona is unknown, and there are no vaccines available for autumnalis or bratislava. an initial series of two to three vaccinations should be administered monthly and repeated at least annually thereafter as long as exposure to the agent exists [ ] . the recommendation to wait until the puppy is at least weeks old before administering the leptospirosis vaccine is based on the increased potential for adverse events associated with this vaccine and to increase the likelihood of a complete immune response minimizing ineffective vaccinations [ , ] . bordetella bronchiseptica is a bacterial agent that causes infectious tracheobronchitis. infection with this agent may occur in concert with other agents infecting the respiratory tract (eg, canine parainfluenza virus, cav-ii). transmission occurs via direct contact or through aerosolized microdroplets from infected dogs and is most likely to occur under crowded conditions, such as boarding and grooming facilities and dog show venues. the current recommendation is to vaccinate puppies at risk a minimum of week before potential exposure with a combination vaccine containing an avirulent live bacterin for b bronchiseptica and a modified-live canine parainfluenza virus. although the vaccine can be administered to puppies as young as to weeks of age, it is generally not indicated unless the puppy is in a kennel environment [ ] . many organized obedience classes commonly require proof of vaccination against bordetella at the time of enrollment or before beginning the course. the general consensus is that intranasal vaccines are superior to parenteral vaccines because they stimulate rapid local immunity [ , ] . if the puppy is intermittently exposed throughout the year (eg, traveling to shows or boarding or grooming facilities), the vaccine should be administered every months. as stated previously, parainfluenza may occur in concert with other respiratory tract agents. the vaccine recommendations are as stated for b bronchiseptica if indicated. there are multiple products available, but the product currently recommended is the combination intranasal vaccine containing a modified-live parainfluenza virus with an attenuated b bronchiseptica bacterin. for optimal protection, the vaccine should be administered every months to annually if indicated. alternatively, many multivalent products containing modified-live cdv, cav ii, cpv, and parainfluenza are available and appropriate for use [ ] . borrelia burgdorferi is a vector-borne spirochete bacterium responsible for lyme disease (borreliosis). transmission occurs when an infected tick (various species within the ixodes genera, also referred to as ''hard ticks'') bites and remains attached to a host, in this case, a puppy. direct horizontal transmission is not likely to occur; therefore, the risk to human beings and other pets is thought to be minimal. if a puppy has a significant burden with infected ticks, this, of course, increases the exposure to others in the household; however, because ticks typically do not reattach once they have taken a complete meal, the risk is thought to be quite small unless appropriate tick control is not instituted [ ] . vaccination to protect against lyme disease is controversial, because the duration of immunity and degree of protection provided by vaccination are unknown and vaccination with some vaccines interferes with standard screening diagnostics [ ] . therefore, vaccination against lyme disease is warranted only if a puppy is at high risk for tick exposure and only if it lives in a borrelia endemic area. there are killed and recombinant (outer surface protein a [ospa] subunit) vaccines available for use against b burgdorferi, and if vaccination is deemed warranted, the current recommendation is to use one of the subunit vaccines before exposure to ticks. the vaccine can be given as early as weeks of age and should be repeated to weeks later [ ] . the best prophylaxis is likely achieved by using appropriate tick prevention, such as fipronil with methoprene spray or spot-on products (frontline top spot; merial ltd, iselin, new jersey), amitraz collars (preventic collar; virbac, fort worth, texas), or an imidacloprid/permethrin topical product (canine advantix; bayer animal health, shawnee mission, kansas) [ , ] . these products should be chosen and recommended carefully by the veterinarian based on household situations, owner concerns, and age of the puppy. this virus, also a morbillivirus, can stimulate an immune response that is crossprotective against cdv. the indication for using this vaccine is for puppies that may have maternal antibody to distemper virus sufficient to cause interference with distemper vaccination but not adequate to protect against infection. if indicated (see discussion of special circumstances), a single vaccination with an mlv vaccine should be given intramuscularly as early as weeks of age. subsequent immunizations with mlv cdv vaccines should be given serially as recommended previously (see section on cdv) [ , , ] . canine measles vaccines should never be administered to female puppies older than weeks of age because they may develop an acquired immune response to the virus. this could be problematic if a female puppy vaccinated against measles at weeks of age, for example, later became pregnant. if the dog developed antibodies to the measles virus and maintained immunologic memory, it would confer measles antibody to puppies via passive transfer, thus rendering measles vaccination in those puppies ineffective. a more appropriate alternative to administering a measles vaccine to a young puppy thought to be at risk for infection but too young to receive an mlv cdv vaccine would be to use a recombinant cdv vaccine, thereby decreasing the likelihood of maternal interference [ ] an enveloped virus belonging to the family coronaviridae, this virus is transmitted via the fecal-oral route. vaccination against this disease is generally not recommended, because the vaccines provide questionable protection and the actual prevalence of the disease is unknown. those most likely to be infected and develop clinical disease are neonates less than weeks of age. clinical signs may include diarrhea, possibly hemorrhagic but typically self-limiting. the general recommendation is to vaccinate puppies against cpv (as recommended previously), because this practice seems to confer protection against coronavirus in addition to preventing infection with cpv- [ , ] . this protozoal parasite causes diarrhea in canine and feline patients as well as in many other mammalian species, including human beings. transmission is via the fecal-oral route, with animals contracting the agent from contaminated feces or water. there is a killed vaccine available; however, vaccination against this agent is typically not recommended, because most animals are not at risk to contract the parasite, the vaccine does not prevent infection (it may ameliorate clinical signs and decrease cyst shedding), and the disease is readily amenable to therapy (fenbendazole, albendazole, and metronidazole are off-label uses but commonly accepted as standard of care). because puppies should be prophylactically dewormed at regular intervals, it is unwarranted to use this vaccine even if the disease is suspected, because a standard anthelmintic dose of fenbendazole given for several days should resolve the infection [ , , , ] . a vaccine designed to protect against envenomation by crotalus atrox, the western diamondback rattlesnake, was released onto the market recently. the original provisional licensure was granted to provide possible protection against that single species of snake and was granted for use only in california. recently, the company was granted extended provisional licensure for multiple states and has extended their claim for potential protection against multiple species of members of the crotalidae (pit vipers). at this time, no challenge studies have been performed in the canine species to validate efficacy claims; all claims are based on antibody titer to the venom component included in the vaccine, to murid challenge studies, and to anecdotal reports of protection of naturally occurring envenomation [ ] . the manufacturer does not claim that vaccination with this product completely protects against the effects of envenomation; rather, the manufacturer claims that it may slow the onset of clinical signs and decrease the severity of signs. immediate veterinary care is still the ''gold standard'' for any snakebite. because of the great potential for variability in envenomation (site of bite on an animal, size of the snake, amount of venom injected into an animal, and species of snake), field observations and anecdotal reports of protection are difficult to substantiate. challenge studies done under controlled conditions are likely necessary to validate the efficacy of this product. at present, because of the preceding statements, this vaccine is not recommended for general use. aversion training and keeping dogs out of areas known to favor rattlesnake habitation as well as immediate veterinary evaluation and care are still the standard recommendations for preventing and treating disease associated with rattlesnake envenomation. canine adenovirus type i as stated in the canine core vaccine section, cav-i causes serious disease in dogs; however, the use of the cav-i vaccine is associated with a high incidence of adverse events. vaccination with the cav-ii vaccine induces an immune response that is protective against cav-i and cav-ii without the adverse effects. the recommendation is to use the cav-ii vaccine as part of the canine core vaccination program; the cav-i vaccine should not be used [ ] . feline panleukopenia, a nonenveloped parvovirus closely related to cpv, causes serious and often fatal disease in kittens. transmission typically occurs from direct contact with infected animals, although in utero infection and fomite transmission also occur. clinical signs typically include pyrexia, anorexia, lethargy, and vomiting and diarrhea. kittens may be immunosuppressed subsequent to pancytopenia associated with this viral infection. kittens infected in utero may exhibit cerebellar disease. prevention is achieved using mlv vaccines beginning between and weeks of age. the standard recommendation is to use a parenteral product (as opposed to intranasal products, which have a higher incidence of postvaccinal viral shedding and potential for clinical disease induced by the more virulent viruses in these vaccines) [ , , , ] . as is the case for canine cdv, cav, and cpv, the core feline diseases, with the exception of rabies, are typically administered in a multivalent product in a series. there are numerous vaccine products containing feline panleukopenia virus, herpesvirus i, and calicivirus (see additional discussion). the current recommendation is to choose an mlv nonadjuvanted product from a reputable manufacturer. vaccines are administered subcutaneously in the right thoracic limb and given every to weeks until the kitten is to weeks of age. repeat administration is recommended year later before instituting a triennial schedule [ , , ] . feline herpesvirus i fhv-i, also known as feline viral rhinotracheitis virus, is an enveloped virus causing respiratory tract disease in cats. clinical signs include sneezing, nasal congestion and discharge, conjunctivitis, and ocular discharge. in addition, kittens may exhibit pyrexia, anorexia, and lethargy along with oral and/or lingual ulcerations and associated hypersalivation. in some cases, ulcerative crusting dermatitis that may mimic other dermatologic disease occurs [ ] . the virus typically causes upper respiratory disease, but the lower respiratory tract may become involved, especially in neonates or debilitated animals. infection with this virus is lifelong, although many cats ''recover'' and do not show clinical signs. cats infected with fhv-i may have recurrent ''outbreaks,'' especially in times of stress or if their immunity is otherwise compromised. cats may persistently shed the virus and act as a source of infection in shelters, catteries, and multiple-cat households. therefore, prevention before exposure is key in controlling this disease [ , ] . vaccination with an mlv or recombinant vaccine beginning as early as to weeks of age is recommended. this is commonly administered as part of a multivalent product and is given subcutaneously in the right thoracic limb. the current recommendation is for kittens to receive a second vaccination weeks later. the last vaccine in the series should be given when kittens are at least weeks old. the vaccine should be given year later before beginning the triennial schedule [ , ] . feline calicivirus fcv causes respiratory tract disease in kittens and cats. because it is a nonenveloped virus, it is more resistant to disinfectants and may therefore persist in the environment. signs are similar to those associated with fhv-i, but lameness and stomatitis are also commonly seen. transmission of fhv-i and fcv is through direct contact, exposure to contaminated secretions, aerosolization, and fomites [ , ] . a newer highly virulent strain of fcv was recently identified and carries a high incidence of mortality. transmission is through direct contact or via fomites. prior vaccination against fcv does not seem to be protective against this strain, and adult cats seem to be more severely affected than kittens [ , ] . the current recommendation is as previously discussed for panleukopenia and fhv-i: administering an mlv or recombinant virus parenteral vaccine beginning at or weeks of age, with a subsequent dose of vaccine weeks later (last vaccination should be when the kitten is at least weeks old). a booster vaccination should be administered year later and then every years [ , ] . as stated previously, rabies virus affects all mammals; in this country, most documented rabies cases in pet animals occur in cats [ ] . because of the significant risk to pets, wildlife, and human beings, vaccination against rabies virus is highly recommended for all kittens and cats, even those kept inside [ , ] . local requirements vary, but the general recommendation is that all kittens should be vaccinated beginning at weeks of age with the recombinant rabies vaccine designed for use in cats [ ] . this product uses gene-splicing technology: reverse transcriptase is applied to rabies viral rna to create complementary dna. the segment of rabies virus dna that codes (a codon) for the immunogenic protein associated with the virus (glycoprotein g) is then spliced from the rabies dna and inserted into a canarypox virus. the canarypox virus is attenuated and nonpathogenic to mammalian cells and therefore carries no potential to cause disease in this species. because the vaccine is essentially a modified-live product, the canarypox virus can enter cells, delivering the codon for rabies virus glycoprotein g to its targeted site. once inside the cell, the canarypox virus is unable to replicate, but the rabies glycoprotein g codon is preserved, leading the host cell to express the glycoprotein on its surface. this stimulates cell-mediated and humoral immune responses. in addition to the benefit of stimulating both types of immunity, the fact that no adjuvant is needed is beneficial [ ] . rabies vaccines should be administered subcutaneously in the right pelvic limb as distally as is reasonably possible; the level of the stifle is acceptable, and areas distal to the tarsus are not appropriate. currently, there is only a recombinant rabies vaccine approved for use in cats (purevax feline rabies vaccine; merial ltd, duluth, georgia). the current usda approval and label state that this product should be administered annually. there are multiple killed virus rabies vaccines approved for use in cats, with initial vaccination occurring at weeks of age and a subsequent vaccination year later. these products are highly efficacious but may carry an increased association with the development of fibrosarcoma formation because they contain adjuvants [ , , , , ] . because regulations vary depending on the state or region, the veterinary practitioner must be familiar with local laws regarding rabies vaccination in this species [ ] . feline leukemia virus (felv) is a retrovirus affecting cats of any age, but kittens and juvenile cats seem to be most susceptible to infection [ ] . clinical signs are numerous and nonspecific, and they include pyrexia, failure to thrive, and chronic or recurrent respiratory tract and gastrointestinal disease. infection in kittens occurs via vertical transmission from the queen to the fetus but may also spread horizontally from the queen to the kitten during lactation and grooming. transmission also occurs through direct and usually prolonged contact with other infected cats from behaviors like grooming and sharing food and water bowls as well as litter boxes. viral screening using an elisa test designed to detect antigenemia should be performed on all kittens, even if their owners plan to house them strictly indoors. because the elisa test detects antigen, maternal antibody and vaccination do not interfere with test results. therefore, kittens of any age may be tested [ ] . if a kitten is antigen-negative, the current recommendation is to administer a recombinant vaccine on the second visit. a second dose of vaccine should be administered weeks later, followed by vaccination year after administration of the last felv vaccine in the kitten [ , ] . the recommended site for administration of any felv vaccine is the left pelvic limb as distally as is reasonably possible [ ] . currently, there is only one recombinant felv vaccine available (purevax recombinant leukemia vaccine; merial ltd, duluth, georgia). this vaccine is administered with a needle-free high-pressure device that deposits the vaccine in skin, subcutaneous, and muscle tissues (vetjet delivery system, merial ltd, duluth, georgia, which is manufactured by bioject, tualatin, oregon) [ ] . there are killed virus vaccines that are efficacious; however, because they contain killed virus, they require an adjuvant to maximize the host's immune response. because of documented associations between adjuvants and the formation of fibrosarcomas, the use of adjuvants in cats should be avoided when adjuvantfree products with comparable efficacy are available. the most recent findings linking injections of any type with fibrosarcoma formation in this species further support the use of a needle-free system as a viable means of vaccine delivery [ , , ] . under the current vaccine guidelines released in in the american veterinary medical association council on biologic and therapeutic agents' report on cat and dog vaccines, vaccination against felv is only indicated if a kitten or cat is allowed to go outside or if the kitten or cat lives with an felv-positive cat. because kittens are most vulnerable to infection and may have exposure if outdoors and because immunity increases with age, it is rational to vaccinate all kittens against this disease with a repeat vaccination year later. subsequent to that, if the cat is housed strictly indoors and does not live with an infected (felv-positive) cat, additional vaccinations are not indicated [ ] . chlamydophila felis, formerly known as chlamydia psittaci, is a bacterium that causes upper respiratory tract disease in kittens and cats. the most common sign is conjunctivitis, but sneezing and nasal discharge may also be present. transmission is typically through direct contact with infected cats. kittens are most commonly affected but usually recover fully with appropriate antibiotic therapy-topical oxytetracycline (ophthalmic ointment) or systemic tetracycline or doxycycline. vaccination against this agent typically does not prevent infection but may prevent clinical signs of disease. because the vaccine does not fully prevent infection and carries an association with adverse events that may be greater than the actual disease, routine vaccination of household pets with this product is generally not recommended. it may be of use in some environments in which the risk of infection is high, however, such as shelters or catteries [ , ] . if vaccination is deemed appropriate by the practitioner, an attenuated parenteral vaccine can be given to kittens beginning at weeks of age, with a second dose given to weeks later [ ] . this bacterial agent causes respiratory tract disease in cats, and cats affected by stress, poor nutrition, or overcrowding seem to be more susceptible. although many infected kittens show mild self-limiting disease with signs that include pyrexia, sneezing, and nasal and ocular discharge, bronchopneumonia has been documented. there is a topical modified-live bacterin vaccine designed for use in this species, but it is generally not recommended for routine use. if the practitioner thinks protection against b bronchiseptica is warranted based on the kitten's risk of exposure (eg, attends cat shows, goes to a boarding facility), administration of the vaccine designed for use in cats may be considered [ ] . a single dose of the ml intranasal vaccine can be given to kittens as young as weeks of age [ ] . the product designed for use in dogs should not be used in cats. there are multiple vaccines in addition to those described and recommended previously; however, many of these diseases pose a minimal risk to most of the feline population or the vaccines are minimally efficacious at preventing infection or disease and therefore are generally not recommended. additional reasons not to use some of these products are vaccine interference with screening tests and adverse events associated with some vaccines. a retrovirus, feline immunodeficiency virus (fiv) primarily affects cats by compromising their immune system, leaving them vulnerable to opportunistic infections. in addition to immunosuppression, with most of the effect targeted against the cell-mediated (t-cell) immune response, infection with fiv carries an increased risk for development of certain types of neoplasia, with b-cell lymphoma being the most common. transmission occurs most commonly from breeding and fighting. the virus is not spread through casual contact between housemates not engaging in the behaviors stated previously, nor is it spread through casual encounters between nonbreeding and nonfighting cats outside. naturally occurring infection of kittens from queens is rare; however, kittens can become fiv antibody-positive via passive transfer from ingestion of colostrum of fiv-positive queens or queens previously vaccinated against fiv [ ] . fiv antibody levels acquired from maternal transfer in kittens that are actually negative for fiv virus decline over the first several months of life. the standard screening test for fiv is an elisa test designed to detect fiv antibody. the elisa was designed to detect antibody rather than antigen, because infected cats produce high levels of circulating antibody in contrast to low levels of circulating virus [ ] . because kittens may have circulating fiv antibody, although actually being negative for fiv antigen, it is generally not recommended to test kittens less than months of age. if a kitten is tested and a positive result is obtained, the test result should be repeated with a different methodology (western blot or polymerase chain reaction [pcr] ) and should be repeated once the kitten is older than months of age [ ] . if a kitten is truly not infected, the maternal antibody wanes by months of age, leading to seroconversion. if, however, a kitten or cat remains seropositive, the recommendation is made to keep the cat indoors only from that point on so as to prevent infection of other cats and to decrease exposure to potential environmental pathogens. fiv-infected cats can live for years; unless otherwise indicated by concurrent disease, euthanasia is generally not indicated for most owned pets. there is a killed fiv vaccine available, but the efficacy of this product is still unknown. there are five known subtypes of fiv virus, and the vaccine has been formulated to protect against subtypes a and d; however, the predominant subtype infecting cats in north america and europe seems to be subtype b. it is unknown if cross-protection exists between the different subtypes [ ] . because the vaccine elicits a strong antibody response, vaccinated kittens and cats become seropositive on elisa and western blot tests, because both tests detect antibody. a pcr test is available but is currently only performed at certain laboratories. because of the increased technologic needs and increased costs of this test, it is not considered the standard screening test. if done under specific conditions, it can detect virus and therefore may be of benefit in differentiating between cats with viremia (truly infected cats) and kittens or cats with circulating antibody attributable to maternal transfer or vaccination. because of the nature of transmission of the virus and interference with the standard screening methods for infection, vaccination against fiv is not currently recommended. keeping cats indoors if possible, neutering all cats going outside, and preventing exposure to stray or feral cats that may be more likely to engage in fighting behaviors remain the gold standards for preventing this disease [ , ] . the disease feline infectious peritonitis (fip) is caused by a member of the coronaviridae. feline enteric coronavirus (fecv) and fip virus are two phenotypes of the same virus. fecv transmission occurs through the fecal-oral route, where it typically infects the intestinal epithelium, but the organism can be transmitted via fomites and persists for long periods in the environment. most cats infected with fecv do not show clinical signs of disease or may have transient diarrhea; some persistently shed the virus in their feces [ ] . fecv can, however, undergo random mutations within a host, creating fip virus, although the virus does not mutate to this form in most cats and most cats do not develop fip. the fip virus enters and replicates within macrophages, where it can then be disseminated throughout the body. clinical signs are numerous but commonly include weight loss, failure to thrive, diarrhea, pyrexia, and chronic respiratory tract disease. two main types of the disease exist, the dry (noneffusive) and the wet (effusive) forms. both are ultimately fatal diseases [ ] . although there is a vaccine available, efficacy and indication for use are believed to be minimal, if at all [ ] . the current recommendation is not to use this vaccine based on efficacy concerns and the minimal risk of infection in most kittens and cats. infection with fecv and mutation with subsequent development of disease occur most commonly in multiple-cat households (five or more), catteries, and shelters. the standard screening test for fip is a serologic indirect immunofluorescent antibody (ifa) test designed to detect antibody. this test may be of some value, but results need to be interpreted with caution and concomitantly with signalment, clinical signs, and other laboratory data. prior vaccination against fip yields positive ifa results, further posing potential complications in routine screening of this disease. in general, kittens are most vulnerable to this disease, with greater than % of cats with fip being less than years of age [ ] . prevention is directed toward decreasing stress in kittens and cats in multiple-cat households and preventing exposure of naive kittens and cats in environments known to have high endemic levels of fecv and at depopulating catteries known to have high prevalence rates of fecv and fip [ , ] . because of the complexity of this disease and the limited space and objectives of this discussion, readers are encouraged to review the texts by greene [ ] and ettinger and feldman [ ] for a more comprehensive review of this disease. as discussed in the canine section, vaccination with this product does not prevent infection but may decrease fecal shedding of infective cysts. because vaccination does not prevent infection and the organism is readily treated with fenbendazole or metronidazole, routine use of this product in cats is generally not recommended [ ] . vaccines are potent biologic agents designed to prevent disease. any foreign product administered to an animal has the potential to be associated with an unexpected response by that animal. although vaccines must meet usda requirements for safety, efficacy, potency, and purity, there still exists the potential for adverse events with products that have met those standards. veterinarians should always report adverse events related to vaccination to the vaccine manufacturer. some adverse events are more likely to occur with certain agents, whereas others seem to have an increased rate of occurrence in certain breeds. still others may be idiosyncratic and are not predictable. the following is offered as a brief overview of some types of adverse events associated with vaccination and to offer suggestions as to how a practitioner might best respond to and prevent those events from recurring. the reactions seen most commonly are local inflammation at the site of the injection or general malaise, pyrexia, and anorexia for to days after vaccination [ ] . most of these reactions are self-limiting and require nothing more than monitoring by the animal owner. it is appropriate for the practitioner to note any reaction, along with a description of signs exhibited, in the medical record and to offer supportive care if indicated. in some instances, administration of an ml causes transient mild clinical disease. supportive care and isolation from unvaccinated animals are recommended, because the vaccinated animal showing clinical disease sheds the vaccinal organism and is potentially infectious to other animals [ ] . contact information for vaccine manufacturers, support agencies, and disease-reporting organizations is included in table . feline injection site sarcomas, also known as feline vaccine-associated sarcomas or fibrosarcomas, develop secondary to local inflammation of injection sites. there is an increased risk for development of these tumors associated with adjuvants and certain repositol agents, such as long-acting penicillin and corticosteroid injections [ ] . measures to prevent these tumors are aimed at decreasing the local inflammatory response by avoiding the use of adjuvants in this species and administering only those vaccines indicated for the individual animal. multiple vaccines should not be administered in one site because this may increase the amount of inflammation in that site. following the recommended sites for injection is strongly recommended (see individual vaccine sections for specific sites) [ , ] . there are specific guidelines as to how a practitioner should proceed if a cat develops a swelling at the site of a vaccination or injection. the practitioner is advised to monitor the patient closely, documenting three-dimensional measurements and temporal association if a mass or swelling develops at the site of a vaccination. the ''three-two-one rule'' developed by the feline vaccine-associated sarcoma task force should be closely applied. ''three'' refers to persistence of the mass for months or longer, ''two'' refers to a size of cm or greater, and ''one'' applies if the mass increases in size after month. if any of these criteria are met, the mass should be biopsied using wedge technique or needle biopsy, allowing for complete resection of the biopsy margins in the future and subsequent referral to an oncologist or surgical oncologist if fibrosarcoma is confirmed. fine needle aspiration is not recommended for evaluation of potential injection site sarcomas [ , ] . most vaccine manufacturers have programs established to help defray the medical and surgical costs associated with these tumors, and the practitioner is advised always to notify the vaccine manufacturer whenever an adverse event is seen. type i hypersensitivity type i hypersensitivity, also known as immediate hypersensitivity and, in some cases, anaphylaxis, is mediated by ige antibody. the host's immune system may react to anything contained within the vaccine product, including cellular products used for culture, adjuvant, preservative, and the antigen itself, and such a reaction typically occurs within to hours after the administration of a vaccine. in the dog, the most common signs are angioedema (fig. ) , urticaria, and pruritus, but symptoms may progress to respiratory distress and fulminant vascular collapse (anaphylaxis). in the cat, the acute onset of vomiting and diarrhea with associated hypovolemia and respiratory and vascular shock may be seen [ ] . if an animal develops any of these signs within the first several hours after vaccination, it should be presented to the veterinarian immediately for emergency medical care and support. it is not the goal of this review to offer therapies for shock; thus, the reader is referred to emergency veterinary literature for recommended therapies. the point here is to advise the practitioner to proceed with caution when using vaccines that may have a higher incidence of these reactions or in breeds that may be at increased risk for immediate hypersensitivity. the increased association between leptospirosis vaccines and type i reactions is well documented, and there are reports that toy breeds, particularly miniature dachshunds, may be at increased risk for type i reactions associated with leptospirosis vaccination [ ] . if an animal does have a type i reaction to a vaccine, the signs exhibited by the patient, interval between vaccine administration and onset of signs, and therapeutics administered should be well documented in the medical record as well as plans for future vaccination of that patient. ideally, once an animal has this type of reaction to a vaccine, that product should not be used again in that patient. all subsequent vaccines should be administered after a complete physical examination, and the vaccine should be given early in the day to allow monitoring of the patient in the hospital for several hours; however, if this is not possible, the patient should remain in the veterinary hospital for monitoring for at least minutes, followed by subsequent monitoring by the owner at home for several hours. pretreatment with diphenhydramine is an option; it is given parenterally (subcutaneous or intramuscular route) at a dose of . - . mg/kg to minutes before vaccination if hypersensitivity is a concern. administration of corticosteroids concurrently with vaccination to prevent a hypersensitivity reaction is neither appropriate nor recommended because of potential immunosuppression and vaccine interference, however [ , ] . the patient's medical record should be identified, outside and inside, to prevent future accidental readministration of that product. advising the owner that the patient should never receive that product again is important. type ii hypersensitivity reactions (autoimmune reactions) are suspected to occur in dogs secondary to vaccine administration. although this theory is yet unproven, there are reports of dogs developing immune-mediated thrombocytopenia and immune-mediated hemolytic anemia temporally associated with recent vaccination. if a dog develops either of these conditions within to months after vaccine administration, the practitioner would be advised to consider the risk/ benefit ratio of subsequent use of that product in that patient [ , ] . type iii hypersensitivity reactions are immune complex reactions. examples include the anterior uveitis associated with the use of the cav-i vaccine and table the complement-mediated rabies vaccine-induced vasculitis-dermatitis seen in dogs. other examples include glomerulonephritis and polyarthritis. antihistamine administered at the time of vaccine does nothing to prevent the reaction, nor is it recommended to administer corticosteroids concurrently with vaccination. once an animal has had this type of reaction, subsequent use of that product should be avoided in that patient [ , ] . type iv hypersensitivity reactions are cell-mediated responses occurring locally or systemically. examples include sterile granulomas at the sites of vaccine administration or polyradiculoneuritis. many sterile granulomas resolve without any intervention; however, for more severe reactions, the practitioner is referred to various medical texts for recommendations [ , ] . the previous discussion applies mainly to puppies and kittens owned by individuals. puppies and kittens housed in shelters face unique challenges, as do orphaned animals. these animals may not have received colostrum, and it is more likely that their mothers were not adequately vaccinated. the implications are that these animals are less likely to have received maternal antibodies, leaving them more vulnerable in the earliest stages of life. in addition, they frequently are malnourished, have an increased parasite burden, and are placed in crowded environments, possibly with high numbers of endemic pathogens. the american animal hospital association task force is currently developing recommendations specifically designed for puppies in these environments. in general, neonates that may not have received colostrum or are housed under these conditions may be vaccinated at an earlier age and ideally should be vaccinated before or at the time of entry into the shelter. the recombinant distemper vaccine could be given in this circumstance and should be administered . vaccination against additional diseases (canine and feline upper respiratory diseases) is indicated as well (see previous vaccine sections). husbandry is extremely important in these animals: providing proper nutrition, anthelmintics, and clean and dry housing is paramount. in general, these animals are special subsets of the general population facing challenges that most young animals do not experience. fiscal considerations and overall population health applies in these cases much more so than to individual client-owned pets. vaccines are perhaps one of the practitioner's greatest tools in preventing disease and maintaining individual and population health. they are to be used with forethought based on the risk of disease to the population and the individual balanced with assessment of the risks associated with individual vaccines. it is the practitioner's role to educate pet owners regarding actual risks associated with undervaccination and overvaccination. the goal is to reach the highest level of overall animal health with the minimum number of adverse events based on scientific and epidemiologic merit. immunity in the fetus and newborn the defense of the body b cells and their response to antigen report of the american animal hospital association (aaha) canine vaccine task force: executive summary and canine vaccine guidelines and recommendations avma council on biologic and therapeutic agents' report on cat and dog vaccines vaccines and vaccinations: guidelines vs. reality vaccines and vaccinations: the strategic issues report of the american association of feline practitioners and academy of feline medicine advisory panel on feline vaccines infectious diseases of the dog and cat in: veterinary immunology an introduction. th edition. philadelphia: saunders elsevier multicenter case-control study of risk factors associated with development of vaccine-associated sarcomas in cats philadelphia: saunders elsevier canine viral disease canine vaccination protection of dogs against canine distemper by vaccination with a canarypox virus recombinant expressing canine distemper virus fusion and hemagglutinin glycoproteins vaccination of puppies born to immune dams with a canine adenovirus-based vaccine protects against a canine distemper virus challenge vaccination against canine distemper virus infection in infant ferrets with and without maternal antibody protection using recombinant attenuated poxvirus vaccines bsava manual of canine and feline behavioural medicine. quedgeley, gloucester (united kingdom): british small animal veterinary association evaluation of the efficacy and duration of immunity of a canine combination vaccine against virulent parvovirus, infectious canine hepatitis virus, and distemper virus experimental challenges infectious canine hepatitis and canine acidophil cell hepatitis infectious diseases of the dog and cat seroconversion of puppies to canine parvovirus and canine distemper virus: a comparison of two combination vaccines canine parvovirus (cpv) vaccination: comparison of neutralizing antibody responses in pups after inoculation with cpv or cpv b modified live virus vaccine duration of serologic response to five viral antigens in dogs national association of state public health veterinarians. compendium of animal rabies prevention and control prevalence of and risk factors for leptospirosis among dogs in the united states and canada: cases ( - ) leptospirosis: a re-emerging zoonotic disease canine vaccination infectious diseases of the dog and cat canine borreliosis diseases caused by systemic bacterial infections infectious diseases of the dog and cat impact of giardia vaccination on asymptomatic giardia infections in dogs at a research facility enteric protozoal infections, giardiasis presented at the dr. ross o. mosier th annual western veterinary conference use of serologic tests to predict resistance to feline herpesvirus , feline calicivirus, and feline parvovirus infection in cats other feline viral diseases infectious diseases of the dog and cat update on feline calicivirus: new trends an outbreak of virulent systemic feline calicivirus disease rabies surveillance in the united states during epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats feline leukemia virus report of the american association of feline practitioners and academy of feline medicine advisory panel on feline retrovirus testing and management comparison of the safety and efficacy of a recombinant feline leukemia virus (felv) vaccine delivered transdermally and an inactivated felv vaccine delivered subcutaneously chlamydial infections textbook of veterinary internal medicine feline immunodeficiency virus infection feline immunodeficiency virus infection and related diseases infectious diseases of the dog and cat feline infectious peritonitis and feline enteric coronavirus infectious diseases of the dog and cat textbook of veterinary internal medicine vaccine-associated feline sarcoma task force. vaccine-associated feline sarcomas vaccine-associated feline sarcoma task force. the current understanding and management of vaccine-associated sarcomas in cats plumb's veterinary drug handbook vaccine-associated adverse events immune complexes and type iii hypersensitivity key: cord- -rrsgl authors: beutels, philippe; scuffham, paul a; macintyre, c raina title: funding of drugs: do vaccines warrant a different approach? date: - - journal: the lancet infectious diseases doi: . /s - ( ) - sha: doc_id: cord_uid: rrsgl summary vaccines have features that require special consideration when assessing their cost-effectiveness. these features are related to herd immunity, quality-of-life losses in young children, parental care and work loss, time preference, uncertainty, eradication, macroeconomics, and tiered pricing. advisory committees on public funding for vaccines, or for pharmaceuticals in general, should be knowledgable about these special features. we discuss key issues and difficulties in decision making for vaccines against rotavirus, human papillomavirus, varicella-zoster virus, influenza virus, and streptococcus pneumoniae. we argue that guidelines for economic evaluation should be reconsidered generally to recommend ( ) modelling options for the assessment of interventions against infectious diseases; ( ) a wider perspective to account for impacts on third parties, if relevant; ( ) a wider scope of costs than health-care system costs alone, if appropriate; and ( ) alternative discounting techniques to explore social time preference over long periods. in many high-income countries, public funding of preventive vaccines is assessed based on the same criteria as the funding of curative pharmaceutical drugs. such routine drug assessment processes consider evidence on quality, safety, effi cacy, and cost-eff ectiveness. because of the increase in the number of diff erent vaccines available and advances in the science behind decision making, we have drawn on existing literature and practices to develop the arguments around potential disparities with other pharmaceuticals when assessing vaccines for public funding. these arguments revolve around vaccine-specifi c features of herd immunity and eradication, which are not evident in pharmaceuticals, and features for which the eff ects of quality-of-life losses in very young children, parental care and work loss, time preference, macroeconomics, and uncertainty substantially infl uence cost-eff ectiveness estimates. vaccines may increasingly be judged as unacceptable if these features are not acknowledged. we also illustrate these points for fi ve specifi c vaccines that are currently under consideration for widespread use in high-income countries. we use the term "cost-eff ectiveness" in a broad sense throughout this article, encompassing cost-utility and cost-benefi t analysis, although there are technical diff erences. in , australia was the fi rst country to make evidence on cost-eff ectiveness a mandatory part of funding decisions of drugs. the australian pharmaceutical benefi ts advisory committee is a rigorous and well-run system for evaluating drugs for acute care, chronic disease, palliation, and more recently vaccines. many other countries have adopted a similar philosophy towards cost-eff ectiveness considerations for funding pharmaceuticals (eg, belgium, finland, norway, canada [ontario] , portugal, sweden, netherlands, uk, and usa [some organisations]), but they deal with preventive public-health measures, such as mass vaccination, in diff erent ways. some countries have specifi c advisory groups to make funding recommendations on vaccinations (eg, uk joint committee on vaccination and immunisation, us advisory committee on immunization practices). often, cost-eff ectiveness evidence for vaccines is assessed in the same manner as for any drug. nevertheless, as we discuss below, vaccination has special features that make it particularly challenging to assess. furthermore, vaccination constitutes one of the largest preventive health programmes around the world, and increasing pressures on health-care budgets are as much a challenge for the use of vaccines as for other drugs. vaccines provide primary prevention of future morbidity and mortality. thus, unlike secondary prevention interventions, such as statins for cholesterol lowering, vaccines are targeted before, or in the initial stages of, the recipient's potential risk exposure. additionally, the recipient may or may not benefi t on an individual basis. vaccination may even harm some recipients through vaccine-associated adverse events (panel); for example, - % of varicella-zoster virus (vzv) vaccine recipients report a localised rash. the individual perception of risks of disease and risks of adverse events drives the demand panel: why many vaccines require a diff erent approach • primary prevention in healthy people, but with possibility of adverse events • unvaccinated or poorly vaccinated people may experience benefi cial or, more rarely, detrimental impact from herd immunity • many vaccines prevent short-lived illness in very young children, causing extra family care and work loss, for which evaluation methods lack credibility and acceptability • the cost-eff ectiveness of many vaccines is highly sensitive to the choice of discount method • some infections are eradicable • some emerging infections (eg, sars, pandemic infl uenza) would have a major macroeconomic impact that goes beyond lost productivity of sick people sars=severe acute respiratory syndrome. for vaccines, and may dominate the infl uence of other factors, such as price. the need to show protective effi cacy beyond the typical duration of clinical trials generally aff ects the assessment of vaccines more than therapeutic pharmaceuticals, primarily because the endpoints may not be immediate. in fact, the clinical endpoints might not show clinical effi cacy at the time of trial reporting because the numbers required can be extremely large. clinical endpoints of mortality or hospital admissions might require follow-up of thousands to millions of participants over as long as several decades. as such, some vaccines have been funded on the basis of immunogenicity data or intermediate endpoints alone (eg, meningococcal c conjugate vaccine and human papillomavirus [hpv] vaccine in several countries). , vaccination not only protects vaccine recipients, but reduces exposure of unvaccinated people to infection through herd immunity. herd immunity, in addition to lowering the incidence of infection in the unvaccinated, is well known to lead to an increased average age at infection. vaccination is therefore not always entirely benefi cial to public health because some childhood infections are more severe if contracted in adolescence or adulthood. furthermore, vaccination itself may modify vaccine eff ectiveness over time because of factors such as strain replacement and cross reactivity. some of these indirect eff ects improve the cost-eff ectiveness (eg, non-exposure of most of the unvaccinated, cross reactivity), whereas others may reduce the costeff ectiveness (eg, shift in the average age of infection, serotype replacement). for most vaccination programmes, the sum of these eff ects substantially improves cost-eff ectiveness, but sometimes the reverse may be true. , convincing evidence for the extent of herd immunity, and the duration of immunity, may only come from widespread use in another country, not from clinical trials. for example, the population impact of vaccinations against vzv and streptococcus pneumoniae in the usa are of major interest to other countries. appropriately parameterised dynamic transmission models could also provide credible estimates of herd-immunity eff ects. lieu and colleagues were the fi rst to estimate the costeff ectiveness of a vaccine based on dynamic model simulations. such models, which take into account the above indirect eff ects, are gradually becoming more widespread, but are not yet part of the traditional toolbox of epidemiologists or health economists. all these features add to the uncertainty under which vaccine funding decisions are made, as opposed to those of other drugs. for whatever the reason some people decline vaccination for their child, they may trade the uncertain value of direct protection for the certainty of avoiding the risk of vaccine-associated adverse events and the cost of vaccination, while potentially counting on a "free ride" from herd immunity induced by others being vaccinated. the risk perceptions driving this trade-off are distorted as a result of imperfect information. reductions in vaccine-preventable disease make people believe that their child's risk of disease has decreased. however, their risk is highly dependent on historical and future rates of exposure and vaccination in the rest of the population and can quickly rebound when uptake declines. , therefore, government intervention in the form of subsidies or public funding is required to ensure that vaccine uptake remains high enough to guarantee benefi cial herd immunity. the uk's recent struggle with the measles, mumps, and rubella vaccine uptake illustrates this point. for other pharmaceuticals, this kind of trade-off is not even conceivable. potential global eradication is another feature that sets some vaccines apart. for example, polio has been eliminated in high-income and middle-income countries. the risk of acquiring paralytic polio from the live oral polio vaccine is thus particularly sensitive to public scrutiny. however, replacing the oral vaccine with the risk-free inactivated polio vaccine is far more expensive, and would be judged unacceptable if cost-eff ectiveness were the only criterion under consideration. nevertheless, until polio is eradicated globally, vaccination must continue or polio will again become endemic, as shown by occasional outbreaks in unvaccinated communities. although not usually quantifi ed in cost-eff ectiveness analysis, , the prospect of eradication and concerns over the public's perception about the entire vaccination programme has led to the replacement of oral vaccine by inactivated vaccine in nearly all highincome countries. some infections have the capacity to aff ect not only patients and their direct contacts (ie, their family, health-care provider, employer) in terms of economic costs and medical eff ects, but they may also aff ect health-care use, and expectations and behaviour of consumers and investors. for instance, pandemic infl uenza is likely to lead to capacity problems within the health-care system, aff ecting the timely treatment of patients with infl uenza in addition to those with unrelated illnesses. additionally, it would have a macroeconomic impact that goes beyond lost productivity to employers of sick patients, because virtually everyone-employers, con sumers, and investors-would adapt their intentions under its perceived threat. , the latter was also shown in countries aff ected by the outbreak of severe acute respiratory syndrome. finally, affl uent countries pay much higher prices than poorer countries. this system of tiered pricing is not unique to vaccines, but might be most relevant for new vaccines (eg, rotavirus, pneumococcal, and hpv) and medications (eg, highly active antiretroviral therapy) with great lifesaving potential in poor countries. some economists argue that market prices set for high-income countries need to be much higher to suffi ciently stimulate personal view innovation through market mechanisms, rather than rely on publicly funded research. conversely, if a vaccine is added to a low-income country's national programme, it is likely to become cheaper for high-income countries through price discrimination mechanisms. clearly, decision making becomes more complex if such moral or opportunistic considerations are thought to be important. there are some methodological aspects to which the cost-eff ectiveness of vaccines is particularly sensitive. first, the defi nition of the analytical viewpoint is crucial. guidelines for economic evaluation, as used by most advisory committees, generally focus on direct health-care costs and do not consider indirect costs to society (eg, the value of lost productive and leisure time from illness or caregiving). these indirect costs can be very large for infectious diseases that aff ect virtually the entire population, even for generally benign illness. for example, the cost-eff ectiveness of childhood vzv vaccination is unlikely to be thought acceptable from the health-care budget perspective, but is possibly cost-saving from a societal perspective. , , second, the use of quality-adjusted life-years is widely advocated as the best measure currently available for valuing health states. however, standardised quality-oflife estimates for short-term diseases in young children are virtually non-existent, and the appropriate methods to measure them are subject to debate. [ ] [ ] [ ] additionally, the impact of a child's illness on the quality of life of caregivers can be substantial, just as it is for lifethreatening and severe chronic diseases in adults (eg, cancer). however, such indirect quality-of-life losses are typically not accounted for. these impacts have the potential to change decisions, for instance on rotavirus vaccine. finally, the peace of mind off ered through the reassurance of vaccine protection is a quality-of-life improvement of prevention programmes that is routinely ignored in economic evaluation. a third issue is the impact that discounting has in accounting for time preference. discounting is a technique that aims to put costs and benefi ts occurring at diff erent timepoints on the same basis of comparison. discounting scales down future events, such that, the further into the future they occur or the higher the discount rate, the less important they are to a decision maker in the present. in health economics, there is continued debate about whether the discount rate for health outcomes should be lower than or equal to that for costs. , for curative therapies, most benefi ts accrue immediately or shortly after the intervention is initiated, and the cost-eff ectiveness of these interventions is therefore largely independent of these methodological disagreements on discounting. conversely, the costeff ectiveness of most prevention programmes is highly sensitive to discounting because of the long time spans over which benefi ts accrue. a slight decrease in discount rate-eg, from % to %-could change the costeff ectiveness of vaccination from unacceptable to attractive. country-specifi c recommend ations on discount rates vary to the extent that a vaccine could be deemed cost eff ective in one country and cost-ineff ective in another for this reason alone (table ). in the standard discount procedure, as recommended in all guidelines known to us, the discount rate is constant, implying that preferences between outcomes are held constant through time and depend only on the length of the time interval between them. one can argue that discounting at a constant rate exaggerates the importance we give for the present over the future. [ ] [ ] [ ] this assertion is backed by psychological empirical evidence, which suggests that the diff erence between equidistant outcomes is thought less important the further into the future the outcomes occur. so-called "slow" discounting procedures could be used for cases in which the discount rate decreases and falls close to zero for the more distant future (eg, · % for years - , · % for years - , % thereafter), thus yielding a higher present value of benefi ts. , additionally, time preference may exist only to the time until risk exposure, and not the time until health consequences from risk exposure arise (eg, cervical cancer is the health consequence of a much earlier exposure to hpv). adjustment of the discount procedure to account for these aspects is not current practice, but would substantially improve the estimated cost-eff ectiveness of prevention versus cure. , currently, policy makers are presented with very wide cost-eff ectiveness ranges for preventive public-health actions when sensitivity to discounting is illustrated to them. in , baumol noted the "sorry spectacle" that economists provided through their diverging understandings on this subject, and his assertion that "little help is provided to the decision maker who is confronted with such an enormous range of finally, the equity impact of vaccination is far less predictable than for most drugs. generally, the less healthy or less wealthy are those least likely to be vaccinated, and thus more likely to experience the eff ect of herd immunity from other people receiving vaccination. as shown for measles in bangladesh, this eff ect is often equitable, but the reverse may also occur for poorly executed vaccination programmes. the redistribution eff ects on health and wealth are thus less straightforward in the prediction of decisions on vaccination compared with those used for therapeutic medicines. the fi rst generation of vaccines, such as measles, pertussis, and polio vaccines, were against serious childhood diseases that were common worldwide. little analysis was done before their introduction because their benefi ts were obvious and their costs were low in an era when there was less pressure on the health-care budget. new vaccines are much more expensive and often aimed at less common or less serious diseases, particularly in wealthy countries. thus, whether these vaccines are worth introducing is less clear. we will explain key aspects of the cost-eff ectiveness of current vaccines, while focusing on high-income countries. rotavirus is the commonest cause of dehydrating gastroenteritis in the world and accounts for most gastroenteritis hospital admissions in children under years of age. deaths are infrequent because of good medical care in high-income countries (eg, about three deaths per year in the uk). a challenge to the evaluation of both current oral rotavirus vaccines is the estimation of the part of the gastroenteritis disease burden specifi cally attributable to rotavirus, as well as assessing the extent to which these vaccines would invoke herd immunity. in high-income countries, the main benefi t of rotavirus vaccines is the prevention of parental care and productivity losses in virtually all households with infants or toddlers. however, as we have outlined, gains in quality-adjusted life-years in such young children and their parents, as well as parental care and work loss, are not standard features in cost-eff ectiveness analyses. given the current price setting (€ - per fully vaccinated child) and the recommended schedule for these vaccines (two doses rotarix [glaxosmithkline]; three doses rotateq [merck]), they are unlikely to be judged as cost eff ective unless these so-called "soft" benefi ts are also included. , [ ] [ ] [ ] but if they are, why should they not also be considered for all other health-care interventions, thus potentially reshuffl ing the comparison between all health-care programmes (including the other vaccines discussed here)? table describes potential consequences of including soft costs and benefi ts at various levels of government decision making. hpv vaccines are eff ective against the two hpv serotypes associated with most cervical cancers, and one of these vaccines also protects against two of the serotypes that cause genital warts. eff ectiveness against cervical cancer would have to be modelled based on the premise that hpv infection is a necessary condition for cervical cancer to develop, although often only decades later. the cost- programmes that prevent disease, with a proportionately larger aggregated impact on the quality of life and productivity of patients and/or their families, become more cost eff ective compared with other vaccination programmes ·· hpv=human papillomavirus. *costs and benefi ts arising to parties generally not considered relevant in guidelines for economic evaluation of pharmaceuticals for which public funding is sought. these third parties can consist of people not receiving the intervention, parents of patients, employers of patients, and employers in general. †cost-benefi t analyses do not routinely inform other sector decisions in many countries (eg, education, transport infrastructure, military, etc.). politics may dominate rational decision rules in other sectors more than in health care. ‡produced by glaxosmithkline. §produced by merck. ¶produced by wyeth. personal view eff ectiveness of hpv vaccines depends heavily on the choice of the discounting approach used. , furthermore, mathematical models for hpv vaccination ideally have to build in complexities related to herd-immunity eff ects from vaccinating cohorts of girls only and boys additionally, the optimum frequency of cervical cancer screening, and type-specifi c progressive infection and replacement, all over long time periods, which makes this a very complex programme to assess properly. , however, a more simple approach, based on static models, could give insights on the basic question: should we vaccinate girls before their sexual debut? such models would underestimate the benefi ts of hpv vaccination, and therefore would only be helpful for policy if they resulted in favourable cost-eff ectiveness ratios. the static models that have been published so far have tended to be favourable. , , policy makers could therefore quickly decide about vaccinating a limited number of cohorts before their sexual debut, and have reasonably confi dent cost-eff ectiveness evidence to support this decision. however, they cannot rely on such analyses to decide on more complicated aspects of the programme, such as the breadth of the programme in girls and boys. in view of the high costs of this programme (€ - per fully vaccinated individual), the uncertainty surrounding these more complicated decisions could unnecessarily postpone policy on the more basic issue. vzv childhood vaccination prevents chickenpox in vaccinated children and is likely to protect these vaccinees against shingles later in life. since chickenpox infects virtually all children by age years, the accumulated societal savings, including avoided parental care and productivity losses, are likely to be greater than the costs of vaccination at a price of € - per fully vaccinated person. however, childhood vzv vaccination increases the occurrence of shingles in adults and this may be such that it counteracts these societal savings and leads to adverse health eff ects. a further complication is that with single-dose infant vaccination many teenage breakthrough cases can still be expected, but the addition of a second dose to prevent this would make it a much less cost-eff ective programme. modifi ed vzv vaccine in adults was recently shown to prevent shingles, and was shown by static models to be cost eff ective. , finally, vaccination of susceptible pre-adolescents is an alternative strategy that has consistently been shown to be cost eff ective to the health-care budget, and is thus independent of the wider societal perspective. however, it is not advocated by public-health specialists, because it would only prevent a small part of all chickenpox disease, albeit the most severe proportion. , , clearly, the simultaneous modelling of all these strategies and considerations requires complex models and data from various sources to establish eff ectiveness. empirical studies alone cannot answer all these questions. infant infl uenza vaccination may be a cost-eff ective way of preventing seasonal infl uenza and pneumonia in young children directly and the elderly indirectly through herd immunity. , however, vaccinating a child partially to save a grandparent from experiencing serious illness does not only raise concerns over intergenerational equity, but also the eff ectiveness of such an approach could only be shown if put into practice on a large scale, or by applying an appropriately parameterised model. seasonal variations in incidence, severity of disease, and vaccine effi cacy are complicating factors that contribute to uncertainty. furthermore, preparing for pandemic infl uenza demands very large investments, and this can only be shown to be worthwhile by modelling. a policyrelevant approach to modelling the cost-eff ectiveness of pandemic infl uenza vaccination would entail considering macroeconomic impacts across sectors and across countries. clearly, deciding on the best options to prevent and control infl uenza requires an analytical framework and applied modelling work that substantially digresses from usual drug assessments. the currently available seven-valent pneumococcal conjugate vaccine (pcv ), which costs about € - per vaccinated child, is eff ective against invasive and non-invasive disease caused by seven serotypes of s pneumoniae. because of its high price, in the short term the cost-eff ectiveness of pcv depends in most high-income countries on the inclusion of positive herd-immunity eff ects in adults, which were observed after year of widespread use in the usa. if the long-term eff ect of its widespread use, consisting of a mix of herd immunity, serotype replacement, antibiotic resistance, and cross reactivity, remains benefi cial and if the cheaper three-dose schedule confers near-equivalent protection to the original four-dose schedule, pcv vaccination programmes are judged to be cost eff ective in high-income countries. to budget for this vaccine, european policy makers should accept imputations from herd-immunity eff ects observed in other countries in the short term as well as uncertainties with both positive and negative impacts of the programme in the longer term. advisory processes on drug funding can be generally eff ective at selecting which pharmaceuticals, and which subgroups of patients, should be subsidised to make the most of scarce health-care resources. vaccines are diff erent and more complex than most drugs assessed by such processes for the reasons we have outlined. this implies that such processes should be more fl exible in accepting the best available quantifi ed evidence of the unique features of vaccination programmes, and that decision makers and their advisers should be aware of these features if they cannot be quantifi ed. the best personal view available evidence depends on the type of infection and vaccine, and the time of its consideration. guidelines for economic assessment of pharmaceuticals dictate the approach to use to make such analyses acceptable for a country's decision makers. since economic evaluation is not an exact science, such guidelines are made on the basis of compromises between the people designing them and therefore can be changed (table ) . economic evaluation requires quantifi cation of the eff ects of interventions, as well as valuing these eff ects. in terms of quantifying the eff ects of vaccination, governments should adapt their guidelines to specify modelling options for the assessment of interventions against infectious diseases. this should enable submitters and drug-reimbursement committees to better understand which models are acceptable (or unacceptable) under which circumstances. crucially, drug-reimbursement committees must be represented by the required expertise to properly understand and evaluate complex vaccine models. in terms of valuing the eff ects of vaccination, we do not plead for a special case, but for a level playing fi eld. that is, we argue that not all aspects of ill health and time preference are currently captured by recommended techniques for economic evaluation, and that this may disadvantage the cost-eff ectiveness of interventions against diseases in children relative to interventions against diseases in adults, and prevention relative to cure. therefore, guidelines should also be adapted in general terms to allow for ( ) a wider perspective to account for eff ects on third parties, if these are aff ected substantially by specifi c interventions (eg, parents experiencing a quality-of-life impact through the illness of their child); ( ) a wider scope of costs to be included, if appropriate, than health-care system costs alone (eg, irrecoverable losses caused by modifi ed behaviour when faced with a large public-health threat); and ( ) alternative discounting techniques to deal with social time preference over long time periods. large uncertainties about the value and distribution of particular variables imply that timely vaccine decisions may need to be taken with more uncertainty than decisions on other drugs. this should not deter the widespread use of new safe and effi cacious vaccines, if-all things considered-these are unlikely to be judged cost-ineff ective relative to other interventions. furthermore, other criteria, including the programme's acceptability, feasibility, budget, and equity impact, are also important. a who guide for the standardisation of economic evaluations of immunisation programmes, which will become shortly available for public use, could be used as a starting point for governments to adapt their guidelines with respect to some of the issues mentioned here. economic evaluation of vaccination vaccine adverse events: separating myth from reality economic epidemiology and infectious disease the role of economic evaluation in vaccine decision making: focus on meningococcal group c conjugate vaccine human papillomavirus vaccination-reasons for caution the seroepidemiology of human papillomavirus infection in australia herd immunity: history, theory, practice impact of model, methodological, and parameter uncertainty in the economic analysis of vaccination programs evaluating the cost-eff ectiveness of vaccination programmes: a dynamic perspective eff ectiveness of sevenvalent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study cost-eff ectiveness of a routine varicella vaccination program for us children theoretical epidemiologic and morbidity eff ects of routine varicella immunization of preschool children in the united states impact of anti-vaccine movements on pertussis control: the untold story eradication versus control for poliomyelitis: an economic analysis compulsory vaccination and conscientious or philosophical exemptions: past, present, and future improving uptake of mmr vaccine cost-eff ectiveness analysis of changing from live oral poliovirus vaccine to inactivated poliovirus vaccine in australia poliomyelitis outbreak in an unvaccinated community in the netherlands, - cost-eff ectiveness of incorporating inactivated poliovirus vaccine into the routine childhood immunization schedule world wide experience with inactivated poliovirus vaccine partially wrong? partial equilibrium and the economic analysis of public health emergencies of international concern precautionary behavior in response to perceived threat of pandemic infl uenza the economic impact of sars: how does the reality match the predictions? tiered pricing of vaccines: a win-win-win situation, not a subsidy who benefi ts from new medical technologies? estimates of consumer and producer surpluses for hiv/aids drugs is g putting profi ts before the world's poorest children? economic evaluations of varicella vaccination programmes: review of the literature comments on the prosser et al approach to value disease reduction in children quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health preferences and willingness to pay for health states prevented by pneumococcal conjugate vaccine eff ect of pneumococcal vaccination on quality of life in children with recurrent acute otitis media: a randomized, controlled trial cost-eff ectiveness of rotavirus vaccination: exploring caregiver(s) and "no medical care" disease impact in belgium methodological issues and new developments in the economic evaluation of vaccines need for diff erential discounting of costs and health eff ects in cost eff ectiveness analyses discounting and cost-eff ectiveness in nice-stepping back to sort out a confusion recommendations of the panel on cost-eff ectiveness in health and medicine guidelines for the pharmaceutical industry on preparation of submissions to the pharmaceutical benefi ts advisory committee (pbac): including major submissions involving economic analyses. canberra: commonwealth department of health and ageing guide to the methods of technology appraisal. london: national institute for health and clinical excellence dutch health insurance board. guidelines for pharmacoeconomic research canadian agency for drugs and technologies in health. guidelines for the economic evaluation of health technologies: canada, rd edn. ottawa: canadian agency for drugs and technologies in health prescription for pharmacoeconomic analysis national institute for clinical excellence. guidance for manufacturers and sponsors pharmac responds to richard milne on discounting health benefi ts and costs a prescription for pharmacoeconomic analysis time preference, the discounted utility model and health anomalies in intertemporal choice: evidence and an interpretation the social rate of discount and the optimal rate of investment saving future lives. a comparison of three discounting models proportional discounting of future costs and benefi ts valuing prevention through economic evaluation: some considerations regarding the choice of discount model for health eff ects with focus on infectious diseases social rate of discount measles vaccination improves the equity of health outcomes: evidence from bangladesh epidemiology of rubella and congenital rubella syndrome in greece estimating the number of deaths with rotavirus as a cause in england and wales evaluating rotavirus vaccination in england and wales. part ii. the potential cost-eff ectiveness of vaccination the cost-eff ectiveness of rotavirus vaccination in australia cost-eff ectiveness and potential impact of rotavirus vaccination in the united states cost-eff ectiveness analyses of human papillomavirus vaccination the potential cost-eff ectiveness of prophylactic human papillomavirus vaccines in canada the epidemiological and economic impact of a quadrivalent human papillomavirus vaccine ( / / / ) in the uk modeling human papillomavirus vaccine eff ectiveness: quantifying the impact of parameter uncertainty varicella vaccination in england and wales: cost-utility analysis a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults the epidemiology of herpes zoster and potential cost-eff ectiveness of vaccination in england and wales an economic evaluation of varicella vaccination in italian adolescents infl uenza vaccine eff ectiveness in healthy -to -month-old children during the - season interdisciplinary epidemiologic and economic research needed to support a universal childhood infl uenza vaccination policy school-based infl uenza vaccination program reduces infl uenza-related outcomes among household members optimal allocation of pandemic infl uenza vaccine depends on age, risk and timing convincing or confusing? economic evaluations of childhood pneumococcal conjugate vaccination-a review the global burden of disease assessments-who is responsible? pb acknowledges funding from simulation models for infectious disease processes (simid), a strategic basic research project funded by the institute for the promotion of innovation by science and technology in flanders (project number ). we thank the anonymous referees for their helpful comments. key: cord- - kod oah authors: pravieux, j. j.; poulet, h.; charreyre, c.; juillard, v. title: protection of newborn animals through maternal immunization date: - - journal: journal of comparative pathology doi: . /j.jcpa. . . sha: doc_id: cord_uid: kod oah summary providing protective immunity to neonatal animals in early life is associated with numerous challenges regarding vaccine safety and efficacy. a much simpler approach is maternal vaccination, either before or during pregnancy, to provide the neonate with passively transferred immunity. in humans, the medical, societal and legal risks of immunizing pregnant women are important considerations in undertaking this approach. by contrast, maternal vaccination has been successfully employed in the animal health industry for decades. these veterinary vaccines have proven to be safe and efficient. although only passively transferred antibodies have been extensively studied, other immunological mechanisms may be equally important in providing maternally derived immunity. the period immediately after birth is critical for the health and development of animals. the high susceptibility to infectious disease during this period is related to a variety of factors including immaturity of the immune system and susceptibility to tolerogenic signals (barrios et al., ) . in particular, suboptimal interactions between antigen-presenting cells and tcells, and the inability of these cells to secrete some cytokines, may result in responses that are qualitatively di¡erent from those in adults, with decreased cytotoxic e¡ector cell function and b-cell help (upham et al., ) . an alternative strategy to provide early life protection against infectious disease is maternal vaccination. in humans, the medical, societal and legal risks of immunizing pregnant women pose important barriers to this process (brent, ) . by contrast, active maternal vaccination of various animal species has been practiced for a long time and provides a good level of safety and protection against some pathogens. the placentae of all eutherian (placental) mammals share common structural and functional features, but there are also striking di¡erences between species in the gross and microscopical structure of the placenta. two characteristics form the basis for classi¢cation of placental types: the shape and area of contact between fetal and maternal tissue, and the number of layers of tissue between the maternal and fetal vascular systems. these di¡erences in the structure of the placental interface determine the nature of molecular transport across the placenta. in primates and rodents, there is substantial transfer of immunoglobulin (ig) g from the maternal to the fetal circulation prior to birth. by contrast, there is no transplacental transfer of immunoglobulin in animals like cattle, sheep, horses and pigs. in these species, the neonate is essentially devoid of circulating antibodies until it absorbs them from colostrum. antibodies contained in the colostrum reach the neonatal vascular circulation through the intestine which is permeable to immunoglobulin for a few hours following birth. in dogs, in addition to postnatal transfer of maternal igg through colostrum, some passive immunity is conferred to the fetus during the last third of pregnancy (sto¡el et al., ) . whatever the placental structure and transport mechanisms involved, successful maternal vaccination programmes are employed in various domestic animal species. some examples of maternal vaccines used in cattle, dogs and pigs will be discussed in this overview. diarrhoea is common in newborn calves. the acute disease is characterized by progressive dehydration and death, sometimes in as little as h. in the subacute form, diarrhoea may persist for several days and result in malnutrition and emaciation. several enteropathogens are associated with neonatal diarrhoea, but the most prevalent in most areas are escherichia coli, rotavirus, coronavirus and cryptosporidium parvum. in north america and europe, various maternal vaccines against calf diarrhoea have been developed. both mod-i¢ed-live and inactivated vaccines have been shown to enhance antibody titres in the colostrum and milk of vaccinated cows. in most cases, two primary injections are given several weeks before calving, followed by an annual booster injection just before subsequent calvings. the safety and e⁄cacy for the pregnant cow and new born calves is well established in the ¢eld. studies have been conducted to determine the amount of transferred igg required to provide protection against newborn calf infections (tyler et al., ) . in order to be fully protective, these maternal antibodies must cross the permeable intestinal barrier during the ¢rst h of neonatal life (moore et al., ) . e⁄cient uptake of colostrum will depend on several factors including: the genetic background of the cow, alimentation, sanitary status and calving conditions. a more controlled method of ensuring good passive transfer is to feed calves a concentrate of speci¢c antibodies, such as those in the commercial product locatim s (biokema anstalt, furstentum, liechtenstein) which confers good protection against neonatal enteritis. canine herpesvirus- (chv- ) is enzootic in dog populations all over the word. infection is associated with an acute and usually fatal disease in puppies during the ¢rst weeks of life.the pups become infected oronasally during whelping or in their ¢rst day of life from the bitch or their littermates. in adult dogs, the virus causes only a mild infection of the upper respiratory or genital tracts, but infection of the pregnant bitch may induce stillbirth, abor-tion or neonatal mortality. this virus is also strongly suspected to cause infertility. as a result of its di¡erent pathogenic roles, chv- may cause severe reproductive problems and high economic losses in breeding units. because chv may infect puppies very early in life, vaccination of the bitch represents the only option for actively preventing the disease. an inactivated chv- vaccine is available (poulet et al., ) and in both laboratory and ¢eld studies this vaccine has been shown to be safe for the pregnant bitch with no adverse e¡ects on reproductive performance. in all cases, vaccination resulted in uniform seroconversion and high neutralizing antibody titres in the bitches. no cases of chv disease were recorded in the puppies produced by vaccinated bitches. moreover, the results of ¢eld trials provided strong evidence of the e⁄cacy of the vaccine against other e¡ects, such as infertility, induced by the virus. the porcine circovirus type (pcv ) is now accepted as the major infectious agent involved in post-weaning multisystemic syndrome (pwms). pwms a¡ects pigs during the ¢rst weeks of life. clinical signs include progressive weight loss, dyspnoea, tachypnoea, anaemia, diarrhoea andjaundice. pwms is now endemic in many swine-producing countries, causing an economic impact on the swine industry worldwide. the e¡ects of pcv on the pig immune system are not fully understood but several studies have suggested that pcv might cause immunosuppression (shibahara et al., ; segales et al., ; vincent et al., ) . moreover, it has been reported that experimentally induced immune stimulation (e.g. by vaccination) early in life can induce the disease (grasland et al., ) . because of these features, maternal vaccination is regarded as the most favourable option to provide protection from pwms. piglets born from sows with high antibody titres to pcv were well-protected from a severe pcv challenge. by contrast, piglets of the same age but born from sows with low pcv antibody titres had higher viral load in lymph nodes, more serious clinical signs and lesions, and some of them developed pwms. a killed pcv vaccine has been developed recently. experiments conducted in a speci¢c pathogen-free model evaluated the e¡ect of maternal protection against a virulent pcv challenge. piglets born to vaccinated gilts expressed signi¢cantly fewer clinical signs and lesions, and had signi¢cantly lower viral load in serum, faeces and lymph nodes, compared with piglets born to non-vaccinated gilts. field studies reported a signi¢cant decrease of pwms and global mortality in both neonatal and ¢nishing pigs, suggesting that passive immunity could confer long-term protection. it is hypothesized that mild pcv exposure, in the face of maternally derived immunity, enables piglets to build e⁄cient active immunity speci¢c to the virus. many other examples of maternal vaccination of animals exist, for example the vaccination of sows has been widely used in the ¢eld to protect piglets and pigs from neonatal colibacillosis, necrotizing diarrhoea, erysipelas, atrophic rhinitis, swine in£uenza and aujesky's disease. in all cases these vaccinations have proven to be safe and e⁄cient. the protective e¡ect of passive vaccination has always been related to the presence of antigen-speci¢c antibodies in the vaccinated mother and colostrum. however, other mechanisms whereby maternal immunity confers protection may exist. numerous other constituents of colostrum, in addition to antibodies, are thought to potentially contribute to passive immunity. these include innate defence factors such as lysozyme, lactoferrin, peroxidase, complex oligosaccharides, mucins, cytokines, chemokines and leucocytes (kelleher and lonnerdal, ) . it has been established that colostrum-derived lymphocytes can migrate from the gut into the circulation and lymphoid organs of neonates (tuboly and bernath, ) . transferred lymphocytes could represent a source of cytokines and chemokines that exert regulatory e¡ects on neonatal antigen-presenting cells andtcells, or be a source of speci¢c armed cells able to ¢ght early infection. although maternally derived antibodies are generally considered to impair neonatal responsiveness to active vaccination, at least at the b-cell level, their potential positive e¡ects on the generation of speci¢c t-cell responses requires further detailed investigation (rowe et al., ) . the rational design of the most appropriate maternal vaccination programmes and strategies is linked to a better understanding of the di¡erent mechanisms by which maternal immunity confers protection to the newborn. veterinary models could help to address these fundamental questions for the bene¢t of human vaccination. neonatal and early life immune responses to various forms of vaccine antigens qualitatively di¡er from adult responses: predominance of a th -biased pattern which persists after adult boosting immunization of pregnant women: reproductive, medical and societal risks reproduction of pmws in immunostimulated spf piglets transfected with infectious cloned genomic dna of type porcine circovirus immunological activities associated with milk e¡ect of delayed colostrum collection on colostral igg concentration in dairy cows protection of puppies against canine herpesvirus by vaccination of the dams enhancement of vaccine-speci-¢c cellular immunity in infants by passively acquired maternal antibody changes in peripheral blood leukocyte populations in pigs with natural postweaning multisystemic wasting syndrome (pmws) porcine circovirus induces b lymphocyte depletion in pigs with wasting disease syndrome ultrastructural evidence of transplacental transport of immunoglobulin g in bitches intestinal absorption of colostral lymphoid cells in newborn animals detection of low serum immunoglobulin concentrations in clinically ill calves development of interleukin- -producing capacity throughout childhood silencing of natural interferon producing cell activation by porcine circovirus type dna key: cord- - es o authors: liao, qiuyan; cowling, benjamin j.; lam, wendy wing tak; fielding, richard title: factors affecting intention to receive and self-reported receipt of pandemic (h n ) vaccine in hong kong: a longitudinal study date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: es o background: vaccination was a core component for mitigating the influenza pandemic (ph n ). however, a vaccination program's efficacy largely depends on population compliance. we examined general population decision-making for ph n vaccination using a modified theory of planned behaviour (tbp). methodology: we conducted a longitudinal study, collecting data before and after the introduction of ph n vaccine in hong kong. structural equation modeling (sem) tested if a modified tpb had explanatory utility for vaccine uptake among adults. principal findings: among subjects who completed both the baseline and the follow-up surveys, % ( / ) reported being “likely/very likely/certain” to be vaccinated (intent) but two months later only . % ( / ) reported having received ph n vaccination. perception of low risk from ph n ( %) and concerns regarding adverse effects of the vaccine ( %) were primary justifications for avoiding ph n vaccination. greater perceived vaccine benefits (β = . ), less concerns regarding vaccine side-effects (β = − . ), greater adherence to social norms of vaccination (β = . ), anticipated higher regret if not vaccinated (β = . ), perceived higher self-efficacy for vaccination (β = . ) and history of seasonal influenza vaccination (β = . ) were associated with higher intention to receive the ph n vaccine, which in turn predicted self-reported vaccination uptake (β = . ). social norm (β = . ), anticipated regret (β = . ) and vaccination intention (β = . ) were positively associated with, and accounted for % of variance in vaccination planning, which, in turn subsequently predicted self-reported vaccination uptake (β = . ) accounting for % of variance in reported vaccination behaviour. conclusions/significance: perceived low risk from ph n and perceived high risk from ph n vaccine inhibited ph n vaccine uptake. both the tpb and the additional components contributed to intended vaccination uptake but social norms and anticipated regret predominantly associated with vaccination intention and planning. vaccination planning is a more significant proximal determinant of uptake of ph n vaccine than is intention. intention alone is an unreliable predictor of future vaccine uptake. influenza contributes significantly to worldwide morbidity and mortality [ ] . periodically, influenza viruses mutate into antigenically-different strains leading to global pandemics [ ] . the influenza pandemic (ph n ) was caused by a triple reassortment of human, swine and avian influenza viruses [ ] . vaccination is the most effective intervention for preventing influenza [ ] and a core part of national pandemic plans for pandemic mitigation. lead times of at least months in producing a vaccine against a novel strain means that while vaccines may be unavailable in time to prevent the first wave of a pandemic [ , ] , effective public uptake of a vaccine may mitigate subsequent waves [ ] . significant health promotion activities regarding influenza prevention have been prominent in hong kong since well before the onset of ph n , arising largely from the severe acute respiratory infection (sars) epidemic and a/h n bird flu outbreaks. seasonal influenza vaccination is widely promoted each year. hong kong's ph n epidemic started on june , peaking in september, and by early november had petered out ( figure ). by the end of december , the hong kong government had recorded , human ph n cases [ ] in a population of , million. to minimize any potential second wave, significant televised and other publicity was given to the launch of a ph n vaccination programme on december , initially for five priority groups: healthcare workers, persons with chronic illness and pregnant women, children aged months to years, adults aged years or above, and pig farmers and slaughtering industry personnel [ ] . on january ph n vaccination was extended to the general public. the vaccination was free for priority group members [ ] , but cost hk$ - (us$ - , - . % of hong kong's median monthly income of hk$ , / us$ , /j ) per dose for the general population. a study in july of respondents projected that vaccine uptake would be influenced by end-user cost, with %, of hong kong's general population being ''highly likely'' to take up ph n vaccine if free, and % if costing hk$ - (us$ [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ , ] . from november onwards, television, radio, newspaper and official websites strongly encouraged priority groups to have ph n vaccination [ ] . however, the hong kong government did not make recommendations for the general population, who were asked to judge for themselves whether to be vaccinated or not. shortly after the vaccine launch for priority groups, local media prominently attributed several adverse events to ph n vaccination, including, a case of guillain-barre syndrome (gbs) diagnosed a week after ph n vaccination, reported on th january , and an intrauterine death (iud) weeks following the mother's vaccination, reported on th january ( figure ). in both cases local health agencies presented convincing evidence challenging the link between vaccination and the two adverse events but were largely ignored. retrospectively, a drop in ph n vaccination uptake among priority groups was observed [ ] . it seems probable that the adverse media reports had impeded vaccination uptake among general population. we collected baseline data between - january, , immediately before ph n vaccine was made available to the general population and then two months later ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) march ) we recorded their reported vaccination status ( figure ) with the intention of modelling how general population decision-making regarding ph n vaccination might predict subsequent vaccine uptake. empirical studies have found that history of seasonal influenza vaccination [ , [ ] [ ] [ ] [ ] , perceived risk of pandemic influenza [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , worry [ , , , ] , and attitudes towards vaccine, such as vaccine efficacy and side-effects [ , , , [ ] [ ] [ ] were significantly associated with intention to receive a vaccine against the influenza pandemic. this is consistent with the findings related to determinants of vaccination against seasonal influenza [ ] [ ] [ ] [ ] [ ] . however, there are some common and significant limitations to these empirical studies. first, all except one [ ] relied on vaccination intention to predict the actual vaccination uptake. in one study, since only a few respondents reported having received the ph n vaccine, the authors combined those intending to get vaccinated with those who had already received the vaccine into one ''intending'' group and examined factors associated with this 'vaccination intention' [ ] . this is problematic because factors associated with vaccination intention and actual vaccination receipt probably differ. moreover, the reliability of intention as a predictor of actual behavior remains controversial. harris et al. found that only about half of ''intending'' recipients of seasonal influenza vaccination actually take it and almost all those who do not intend to take it remained unvaccinated [ ] . moreover, most studies conducted before the pandemic occurred or before the vaccine was available [ , , [ ] [ ] [ ] [ ] , ] of dutch respondents reported intending to take ph n vaccination prior to or at the onset of the (potential) pandemic phase, respectively [ ] . similarly, in hong kong % of respondents in july reported being ''highly likely'' to receive ph n vaccine if offered for free [ , ] . however, by the time vaccination became available intention appeared much lower with only - % of study respondents in france and in turkey intending to take the ph n vaccine [ , ] . second, all the studies are cross-sectional rather than longitudinal; none assessed subsequent actual vaccination status. thus, although associations have been identified, there is no way to infer causality. third, most of the studies are atheoretical. although some of the studies developed their study questions based on theoretical framework such as hbm [ , , ] , none have conducted model analysis and evaluated the model fit. therefore, due to these three reasons, there remains a significant concern about how valid such results are and a significant knowledge gap about how the observed pattern of influences could be explained. a major limitation of previous empirical studies [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , ] is failure to accommodate the intention-behaviour gap. although several behavioral theories such as protection motivation theory (pmt) [ , ] , theory of reasoned action (tra) [ , ] and theory of planned behaviour (tpb) [ , ] propose that intention is the proximal determinant of behaviour, intention does not necessarily translate into actual behaviour. empirical studies of the intention-behavior relationship showed that intention had a medium effect (a correlation of , . - . ) on behavior [ ] [ ] [ ] , but a recent review including experimental studies found that a medium-to-large change in intention induced by manipulated interventions caused only a small-to-medium change in behavior [ ] , where an effect size of . is medium and one of . is small [ ] . sheeran found that about % of those intending to take action fail to act [ ] , consistent with harris et al's findings [ ] . factors that are prime contenders to moderate/ mediate the relationship between intention and behaviour include behavioural control/efficacy, action planning and anticipation of consequences [ ] [ ] [ ] . perceived behavioural control/self-efficacy. the tpb is an extension of the tra incorporating the concept of perceived behavioural control (pbc) as an intervening variable predicting both intention and also actual behavioural change directly [ , ] . the direct effect of pbc on actual behavioural change partly explains why not all intention translates into behaviour. previous reviews suggested that intention-behaviour relationships could be moderated by perceived behavioral control, with higher levels of perceived behavioural control improving prediction of intention on behaviour [ , ] . although some researchers suggested that pbc differs from self-efficacy because selfefficacy emphasized perceived internal control more while pbc also considers external control factors [ ] , a systemic review on the efficacy of tbp found that pbc and self-efficacy had comparable effects on intention and behaviour [ ] . despite being a dominant theory of behavioural change, because the tpb is limited in predicting behaviour we sought to enhance its predictive power by replacing pbc with self-efficacy and incorporating enhanced social effects to accommodate external control factors. implementation of intention/planning. implementation of intention, termed ''planning'', is a potentially important factor facilitating translation of intention into behaviour [ , , , ] . planning is specific to situations (e.g., when, where, and how) within which one will perform the behaviour [ ] . it activates the situational context for goal attainment and thereby makes the goal become more accessible [ , ] . a meta-analytic review showed that implementation of intention as planning consistently caused a medium-to-large effect on behavioural change [ ] . anticipated regret. anticipated regret is the expectation of feeling regret or upset if one does or does not conduct certain behaviours. anticipated regret has been found to be a strong predictor of vaccine uptake against seasonal influenza [ , ] , playing the lottery [ ] and exercise [ ] . anticipated regret might also moderate the intention-behavior relationship: the higher anticipated regret for inaction, the better the prediction of intention on behaviour [ , ] . a robust theoretical framework comprehensively explaining behavior change that elucidates population decision-making for health protective and promoting behaviour has long been sought. as the main contender, the tpb explains , % of variance in health behavioural change related to addictive behaviour, automobile-related behaviours, clinical and screening behaviour, eating behaviour, exercising behaivour, hiv/aids-related behaviour and oral hygiene behaivour [ ] . the standard version of tpb proposes that attitudes towards the behaviour, subjective norm and pbc predict behavioral intention while intention and pbc predict the actual behavioural change [ , ] . additional predictors that significantly improve the model's predictive power are needed [ ] . two previous studies have examined modified versions of tpb to predict vaccination uptake against seasonal influenza [ , ] . one study used tpb plus two additional factors: influenza vaccination history and anticipated regret, to predict intention to receive vaccine against seasonal influenza among elderly from social clubs [ ] : vaccination history and anticipated regret respectively accounted for an additional . % and . % of total variance in influenza vaccination intention [ ] . however, again the study was cross-sectional and actual vaccination uptake was not assessed. a second study of healthcare workers [ ] adopted an extended version of tpb that included additional elements of anticipated regret, moral norm, descriptive norm and professional norm. the study found that controlling for the original tpb variables, moral norm and anticipated regret were significant determinants of actual receipt of seasonal influenza vaccine [ ] . the study provides useful information for future application of the extended version of tpb. however, since the study was conducted among healthcare workers, some of the variables such as moral norm and professional norm which emphasize obligation and professional convictions may not be applicable among the general population. factors influencing ph n vaccine uptake at the later stage of a pandemic might be more cognitively driven unlike behavioral responses during the early stage of a pandemic which might be more affect driven [ ] . therefore, taking into account prior work on seasonal influenza vaccination uptake [ , ] , extending the tpb could provide theoretical utility for understanding public decision on taking ph n vaccination. starting with tpb and existing literature, we therefore built a conceptual model of public decision-making for ph n vaccination ( figure ). in addition to the original tpb components, seasonal influenza vaccination history, anticipated regret and vaccination planning were included in the model. the model proposed that attitudes towards vaccination (perceived benefits of ph n vaccination and concerns regarding possible adverse effects of ph n vaccination), perceived social pressures from significant others and other people around regarding ph n vaccination (social norms regarding ph n vaccination), perceived self-efficacy in taking vaccination (perceived self-efficacy), anticipated regret for not taking the ph n vaccination (anticipated regret) and seasonal influenza vaccination history would predict vaccination intention, which in turn predicts vaccination planning and future vaccination uptake; anticipated regret and perceived self-efficacy could also predict vaccination status directly; finally, vaccination planning was proposed to bridge the intention-behavior gap and predict vaccination status directly ( figure ). we conducted a longitudinal study of influences on ph n vaccination behaviour in hong kong to test this model ( figure ) , and subsequently followed up participants to record their selfreported receipt of ph n vaccine. in this study, we aimed to answer the following research questions: how well does intention predict future uptake of ph n vaccine? does vaccination planning mediate the relation between intention and future vaccination uptake? and do the original tpb components and the additional components (extended social norms, anticipated regret and seasonal influenza vaccination history) contribute to peoples' decisions on vaccination uptake? the study obtained ethics approval from the institutional review board of the university of hong kong/hospital authority hong kong west cluster. written informed consent was waived by the irb because all the data were analyzed anonymously, but verbal consent was obtained from all the subjects before the interview started. hong kong has % landline telephone penetration, local calls are free and telephone interviews are common and representative methods of survey data collection [ ] . we conducted main cross-sectional telephone surveys of psychological and behavioural responses to the first wave of the influenza a/h n pandemic in hong kong from april through november (the parent study) [ ] in order to monitor these variables. as an extension, the present study re-contacted subjects from some of these surveys and sought to understand public decision-making regarding ph n vaccine uptake for mitigating the potential second wave of the pandemic. between - january, a baseline assessment for the present study was performed, immediately prior the local ph n vaccination campaign extending to the general community (vaccination for high risk groups started from december , ), and we again contacted participants for follow-up two months later, between - march . sample size determination. we estimated that a sample of at least was required to achieve % power at an a = . to reject a model of the specified complexity ( figure ) if the model fit index root mean square error of approximation (rmsea) exceeded . [ , ] . to allow for a response rate , % in the follow-up and the baseline surveys, we need to target at least , subjects in the baseline survey. subject selection and inclusion criteria. a flow chart showing subject selection is provided in figure . a total of , subjects participated in the parent study [ ] . all these subjects were cantonese-speaking adults (aged$ ) selected within households using a kish grid methodology, who were capable of and willing to answer a telephone interview. additional details about inclusion criteria are available elsewhere [ ] . respondents in the th , - th surveys of the surveys comprising the parent study who, in the parent study agreed to be re-contacted and who had not received ph n vaccine were invited to complete the baseline assessment for the present study. these five surveys (the th , - th surveys) were selected because participants in these surveys had not had any follow-up contact either in the parent study or otherwise. this minimizes interview fatigue thereby improving response rates. these surveys were all of a comparable sample size, between , - , [ ] . the five selected surveys were conducted between july and october , , and generated a representative [ ] pool of , respondents of whom . % ( , / , ) gave consent for further contact. from a list of the , subjects who agreed to be re-contacted, , calls were randomly selected and successfully made by a university telephone polling organization. unanswered calls were tried at least four times at different hours and weekdays before being replaced by new numbers. finally, a total of , ( %, , / , ) respondents agreed to participate in the baseline survey. of these ( %, / , ) reported already having received ph n vaccination and were therefore excluded as ineligible, leaving , respondents who completed baseline interviews. the interview questionnaire for the baseline survey was derived from literature review, our previous cross-sectional surveys [ ] and the theoretical framework constructed for this study (figure ). specialists in health psychology, statistics, infectious disease and public health jointly determined the measures comprising the final questionnaire, guided by the need to maintain low assessment load and parsimony to ensure good response rates. the finalized questionnaire consisted of five sections: section addressed respondents' self-rated health and their experience of influenzalike illness in the past six months; section addressed risk perceptions regarding ph n ; section addressed perceived trust in information related to ph n and ph n vaccination from different information sources; section addressed attitudes, beliefs and social norms regarding ph n vaccine/vaccination, vaccination intention and planning; section addressed key respondent demographics. overall, the baseline assessment consisted of questions, which took less than minutes to complete. other demographic data were obtained from the parent study [ ] . prior to baseline assessment for the present study, subjects were reminded of their prior participation and that they had agreed to participate in a further study. the study was introduced as a survey of attitudes towards swine flu vaccination. we sought their willingness to participate. those agreeing were asked about their vaccination status. subjects who reported that they had already received ph n vaccination were excluded. the remaining interview was performed. a follow-up survey was conducted months later wherein respondents were reminded of the earlier survey and asked about their vaccination status and reasons for having had or not having vaccination. all the data were collected through telephone interview in both baseline and follow-up surveys. the measures comprising the study instruments were used to build the conceptual model ( figure ) and are described below and in table . perceived benefits of ph n vaccination, and, concerns regarding adverse effects of ph n vaccination. these two constructs assessed attitudes towards ph n vaccination. perceived benefits of ph n vaccination was assessed by measuring agreement on five-point ordinal scales (from ''strongly disagree'' to ''strongly agree'') with three statements (table ) . a cronbach's alpha (a) of . indicated an acceptable internal consistency for this scale and these two items were treated as the indicators of a latent scale (perceived benefits of ph n vaccination). concerns regarding adverse effects of ph n vaccination were assessed by measuring agreement, using fivepoint scales, with two statements. the cronbach's a for these two items was . , considered acceptable by some researchers [ ] , though clearly less than desirable. we therefore treated the items as reflecting a latent variable (concerns regarding adverse effects of ph n vaccination). social norms regarding ph n vaccination. while tbp considers the influence of solely coercive social pressure from significant others to perform a behaviour, previous studies suggest that it is also important to consider the generalized tendency to adopt behaviours demonstrated by others encountered in daily life for imitative reasons [ , ] . we use the term social norms rather than subjective norm to represent these broader coercive and imitative social influences. social norms were assessed by agreement on a -point scale with two statements. the internal consistency for these two items was weaker, with a = . , which suggests each item appropriately measures different social influences. we initially incorporated these items separately in the structural equation model but except for the path weights dividing almost equally between the two items, no difference was otherwise seen. we therefore retained them as indicators of a combined latent construct in the model for purposes of model parsimony [ ] . anticipated regret. anticipated regret was assessed with two statements asking about respondents' likelihood of feeling regret. responses of these two items were on a -point categorical scale (from ''definitely not'' to ''certain''). the internal consistency a for these two items was . . the two items were used to indicate the latent variable ''anticipated regret'' in the modeling analysis. perceived self-efficacy. one item was used to measure selfefficacy, asking about respondents' agreement on a -point scale with the statement ''i am confident that i can go independently to get human swine flu vaccination''. a standard scale of self-efficacy was not adopted to minimize assessment load. however, a single item for self-efficacy has been shown elsewhere to have validity in predicting behavioural change [ , ] . seasonal influenza vaccination history. respondents were asked whether they had received any seasonal influenza vaccination in the past three years (yes/no/don't know). vaccination intention. respondents were asked how likely it was that they would get vaccinated against ph n during the winter flu season, using a -point likert scale (from ''definitely not'' to ''certain''). vaccination planning. we measured vaccination planning by assessing respondents' agreement on a -point scale with three statement items, such as ''i have planned when and where to get my human swine flu vaccination this winter''. the internal consistency a for these three items was . , though less than the most common acceptable level of above . , remaining at the minimal acceptable level (a ranged between . - . ) of reliability for preliminary research [ ] . these items were also treated as indicators of a latent variable for modeling purposes. reported vaccination uptake. in the follow-up survey, respondents were asked to confirm if they had received ph n vaccine within the past three months. respondents were also asked to indicate their major reasons for having or not having taken the ph n vaccination using open-ended questions. multiple reasons could be given by each respondent. we first compared demographic differences between follow-up and lost-to-follow-up respondents with pearson chi-square test while demographic differences of the respondents who completed both the baseline and follow-up survey and the general population [ ] were assessed using cohen's effect sizes [ ] . proportions were calculated to describe patterns of vaccination intention, reported vaccination uptake, and major reasons for taking or not taking ph n vaccination. structural equation modeling was then applied to examine the determinants of ph n vaccination, vaccination intention and vaccination planning based on the extension of tbp. mplus . for windows (muthén & muthén, - was employed because the model comprised dichotomous (vaccination status) and ordinal (vaccination intention) outcome variables. before testing the full structural model, zeroorder correlations between the measures of related constructs were calculated. confirmatory factor analysis was performed to assess the adequacy of the measurement model including perceived benefits of ph n vaccination, concerns regarding adverse effects of ph n vaccination, social norms regarding ph n vaccination, anticipated regret and vaccination planning. to test the full structural model, all variables were entered into the model simultaneously. mean and variance adjusted weighted least squares estimation was applied to evaluate the standardized parameters (beta, b). since chi-square test is very sensitive to sample size and non-normally distributed data, several other model fit indices were evaluated including the comparative fit index (cfi), the tucker lewis index (tli), and rmsea. a cfi. . and tli. . indicates a good fit. rmsea less than . and one ranging between . - . respectively indicate a good and acceptable model fit [ ] . misfitting models were respecified guided by theoretical soundness and modification indices [ ] . missing proportions ranged from . % for seasonal flu vaccination history to . % for the item ''i have planned when and where to get my ph n vaccination this winter''. there was no missing data for reported vaccination uptake. missing data were handled with multiple imputation [ ] . of the respondents who completed the baseline assessment, / ( %) respondents agreed to participate and completed the march follow-up survey (figure ). demographic characteristics of respondents in the baseline and followup surveys are shown in table . compared to respondents completing both baseline and follow-up surveys, respondents lost to follow-up were younger (x = . , p = . ) and more likely to be single (x = . , p, . ). overall, the low cohen effect sizes (, . ) showed that the demographics of respondents who completed both the baseline and follow-up surveys were comparable to those of the general population of hong kong [ ] . of the , respondents who completed the baseline survey, % ( / , ) reported that they would ''definitely not'' take ph n vaccination during the winter flu season; % ( / , ) reported being ''very unlikely/unlikely'' to take it; % ( / , ) reported their ph n vaccination likelihood as ''evens'' ( : /equal likelihood); and only % ( / , ) reported vaccination likelihood as ''likely/very likely/certain''. within the subset of / , respondents who completed both baseline and follow-up surveys, % ( / ) had reported at baseline that they would be ''likely/very likely/certain'' to receive ph n vaccination. however, in the follow-up survey, only / ( . %) respondents reported having received ph n vaccination in the intervening period, of whom had reported being ''likely/very likely/certain'' to receive ph n vaccination at baseline. reporting higher intention to receive ph n vaccination in the baseline was associated with greater likelihood to vaccinate by follow-up (fisher's exact test, x = . , p, . ). the respondents who reported taking ph n vaccination gave the major reasons for deciding on vaccination as follows: three choose vaccination because of the 'high risk of swine influenza' characterized by statements like ''swine flu is serious'', ''i am worried that swine flu will become more serious'', and ''i feel vulnerable to swine flu''; two reported that their decision was due to 'doctors' advice' and two reported 'belief of the vaccine efficacy'. other reasons provided by one respondent only were 'belief in the vaccine's safety', 'government recommendation', 'convenient availability', and 'protection of patients'. reasons for not having vaccination given by the respondents who did not receive ph n vaccination ( figure ) were, most frequently 'low risk of or from swine influenza' ( / , %) and 'concerns regarding adverse effects of the vaccine' ( / , %). around % ( / ) of the respondents reported both 'low risk of/from swine influenza' and 'concerns regarding adverse effects of the vaccine'. table for the final full structural model (figure ), two additional paths were added and estimated based on the modification indices including a path from social norms to vaccination planning and path from anticipated regret to vaccination planning while the path from perceived self-efficacy to vaccination and the path from anticipated regret to vaccination were removed, coefficients for these two paths being nonsignificant and too small to be meaningful. the final model indicated a good fit with cfi = . , tli = . and rmsea = . ( figure ) . the model showed that respondents perceiving greater ph n vaccination benefits (b = . ), less concerns regarding vaccine adverse effects (b = . ), greater sensitivity to social norms b = . ), higher anticipated regret if not vaccinated (b = . ), higher perceived self-efficacy in taking ph n vaccination (b = . ) and receiving seasonal influenza vaccination in the past three years (b = . ) reported greater intention to take ph n vaccination, and accounted for % of variance in vaccination intention scores. greater adherence to social norms (b = . ), higher vaccination intention (b = . ) and higher anticipated regret (b = . ) were associated with more vaccination planning, together accounting for % of variance in vaccination planning. both vaccination intention (b = . ) and vaccination planning (b = . ) significantly predicted actual ph n vaccination, accounting for % of variance in ph n vaccination ( figure ). the world health organization recommended a stepwise use of ph n vaccines for protecting people against the ph n influenza pandemic in july [ ] . however, a vaccination program's efficacy largely depends on the public's compliance. our study found that only % of , subjects reported having received ph n vaccination and of , subjects remaining unvaccinated, only % reported intending (being likely/very likely/certain) to take the ph n vaccine. two months later in the follow-up survey, an even smaller proportion, . % of the respondents who completed both the baseline and follow-up survey reported having been vaccinated against ph n . perceived low risk of ph n and concerns regarding vaccine-related adverse effects were the two most frequently cited reasons for refusing the vaccination. the extended tpb model suggests that both the original tpb components and the additional components contribute to people's decisions on vaccination uptake but that social norms and anticipated regret for not taking vaccination were the strongest determinants of vaccination intention and vaccination planning. finally vaccination planning partially-mediated the relation between intention and reported vaccination uptake. compared to previous studies, vaccination intention was much lower in our study than that found in surveys conducted prior to the influenza pandemic [ ] or before the vaccine was available [ ] , but was comparable to the findings of surveys conducted in france [ ] and turkey [ ] after ph n vaccination programmes were launched there. an earlier hong kong study that relied on expressed intent to predict vaccination uptake [ ] failed to accurately predict the subsequent meager population uptake of ph n vaccination by, at best, an order of magnitude [ ] , suggesting that intention alone is insufficient for predicting future vaccination uptake, consistent with empirical findings in other areas [ , ] . despite predictions that intended ph n vaccination uptake would decline if there was insufficient data on novel vaccine safety and efficacy [ ] , safety issues were not the predominant barrier to vaccination in the present study. while % of our study respondents who remained unvaccinated cited vaccine safety concerns, despite good evidence that the vaccine is effective with a risk profile similar to that of seasonal influenza vaccine [ ] , almost twice as many, %, cited 'low risk of/from swine influenza' as their reason for not getting vaccinated, suggesting that these respondents felt no advantage would be gained by vaccination. around % of respondents, cited both 'low risk of/ from swine influenza' and 'concerns regarding adverse effects of vaccine' as the reasons for not getting vaccinated, seemingly adopting a risk-benefit approach to vaccination decision-making. however, in the setting of low influenza risk, with the reports of vaccine related adverse events in the media after the vaccine was available for the priority groups (figure ) , people may shift their perceived risks away from influenza and towards vaccination, suggestive of availability bias (risk distortion by easily recalled events) [ ] . we believe that perceived vaccine risk would become progressively less of a barrier to vaccination as perceived influenza risk increases, and vice versa. moreover, despite recent reports that hong kong residents would be sensitive to vaccination pricing when considering whether to vaccinate [ , ] , only . % of our respondents cited high vaccine cost as the reason for rejecting vaccination. major reasons for taking ph n vaccination corresponded to reasons for not taking it, with perception of ph n risk most frequently cited. however, the few respondents receiving ph n vaccination prohibited meaningful comparison. the extended version of tpb model fits well to the survey data. the model showed that an expanded social norms and anticipated regret accounted for most of the variance in vaccination intention, rather than the more core elements of tpb. in turn, social norms independently accounted for more than twice the variance in vaccination planning than did intention, and vaccination planning accounted for more variance in vaccination uptake than did intention. thus it seems that social norms comprise the major influences on vaccination uptake through modifying vaccination intention and planning. a meta-analytic review of tpb efficacy concluded that the tpb variable subjective norm (perceived coercive social pressure from significant others) weakly predicted intention compared to other tpb components, mainly due to poor measurement [ ] . ''descriptive norm'' (perception of what other people do, imitation or conformity behaviour) is reportedly a more important predictor for intention [ , ] . here we combined table . correlations, means, standard deviations, and standardized factor loadings for the measurement model. measures of subjective and descriptive norms, treated as a latent variable (social norms), because they were found to have much the same predictive direction and weight. multiple item measures of norms should have better predictive power than single item measures [ ] . this model importantly informs public health approaches to population behaviour during respiratory epidemics. first, information uncertainty or untrustworthiness, for example regarding vaccine safety, is likely to prompt people look to others for their cues to action: the social environment, namely what other people believe and do powerfully influences decisions to action [ , ] . people often tend to imitate others, so establishing a ''vaccination trend'' may help uptake. for example, it could be effective to encourage those who remain unvaccinated with feedback from vaccinated peers and by providing an updated total of numbers vaccinated. what the general public think and do may prove to be as influential as information from scientists or health professional [ , ] . second, encouraging uptake of a new vaccine will be problematic if the associated threat element is low, irrespective of vaccine pricing, particularly for novel and untested vaccines. vaccine safety and efficacy data should be provided wherever possible at all levels including through health-care providers, media and the general public. to effectively communicate the risk and benefit of a novel vaccine, it is important to establish an effective surveillance system to monitor vaccination progammes and rapidly respond to any reported adverse events [ ] . the media have an important influence and both reactionary and opinionated news items should be recognized as potentially detrimental to vaccination uptake. in particular, the need to develop stories that generate revenue increasingly overrides balanced reporting in contemporary media. hence risk amplification remains a problem. public health agencies need to improve their liaison with influential media outlets to minimize this, where possible. third, omission bias, a phenomenon where people view vaccination as more risky than remaining unvaccinated, could be a barrier for vaccination [ ] . omission bias arises when there is anticipation of greater regret about adverse effects of vaccination, if taken, than the regret about being infected with influenza if vaccination is rejected [ ] . therefore, social marketing emphasizing the far greater likelihood of regret for consequences due to refusing vaccination than the regret over an improbably low adverse event due to taking vaccination may help to reduce this bias. for example, previous studies found that simply asking two questions about feeling regret for inaction could increase respondents' intention to play a lottery or do exercise [ , ] . finally, vaccination planning is a key intervening variable between vaccination intention and actual vaccination. this is to be expected given that it is more proximal to actual behaviour than intention is. in those who may be undecided, interventions facilitating planning may prompt action. this could include suggesting where, when and how to get vaccination, improving and publicizing accessibility of vaccination centres and opening times. even so, intention and planning explained only % of the variance in the reported vaccination behaviour, suggesting that other factors, such as intention stability [ ] , influencing vaccination behaviour await identification. study limitations include baseline attitudes/beliefs, vaccination intention and planning being measured at the same time point, prohibiting exploration of causality in observed associations. some study measures were constrained due to length of telephone interviewing, and while sub-optimal were necessary methodological compromises. although most researchers recommended cronbach's a of . as the minimal acceptable for internal consistency of multi-item scales, others accept . or . - . for preliminary research as the cut-off point [ ] . other than dimensionality concerns, lower a can reflect too few items comprising the putative scale [ ] . this is more likely for complex variables, such as social norms which have a broad spectrum of elements. though less than perfect, measurement errors can be reduced by incorporating the items as a latent variable in sem [ ] , an approach we adopted. additionally, collinearity between exogenous indicators, such as social norms and perceived benefit can be potentially problematic, perhaps lowering the accuracy of sem estimation. however, since high associations between measures of the constructs were not observed (table ) then collinearity-related error is probably small [ ] . despite being randomly selected for the parent study, subjects of this study were not randomly selected from the general population, although demographics suggest the current sample is comparable to the hong kong general population [ ] (table ). moreover, subject recruitment was based on voluntariness and all data were selfreported. all could cause social desirability and selection bias, so caution is needed before extrapolation to the general population. also refusal at follow-up could have influenced patterns of responses. our study examined public decision-making regarding a novel influenza pandemic vaccine. our findings may not apply to vaccination against seasonal influenza due to numerous differences in beliefs towards the vaccination. for example, although perceived low risk remains the major reasons for refusing vaccination against seasonal influenza as in our study, vaccine safety is seldom cited as a barrier [ , ] whereas we found that about one third of respondents had vaccine safety concerns. cultural differences in influenza and vaccination-related beliefs are possible [ ] , but these differences may gradually diminish with the increasing identical news information available through the three dominant news agencies and common public health strategies being increasingly universal. related stories, such as use of preservatives and adjuvants in vaccine manufacture may enhance knowledge and reduce trust in product safety [ ] . the role of media remains much under-researched in this regard. finally, data was insufficient to reliably report the reasons for ph n vaccination uptake among the population. nonetheless, compared with other cross-sectional studies [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , the longitudinal design of this study strengthens understanding of influences on population decision-making for pandemic influenza vaccination uptake and represents a step forward in this area of research. this study is novel in linking theoretically derived, vaccination-related cognitions to subsequent influenza vaccination behaviour, and exemplifies that within the hong kong chinese culture, social norms and action planning are far more influential than intention in predicting vaccination behaviour. the global impact of influenza on morbidity and mortality evolution and ecology of influenza a viruses emergence of a novel swine-origin influenza a virus (s-oiv) h n virus in humans efficacy and effectiveness of influenza vaccination pandemic influenza vaccine manufacturing process and timeline public health. will vaccines be available for the next influenza pandemic preparing for the second wave: lessons from current outbreaks number of notifications for notifiable infectious diseases human swine influenza vaccination programme human swine influenza vaccination acceptability of a/h n vaccination during pandemic phase of influenza a/h n in hong kong: population based cross sectional survey factors in association with acceptability of a/h n vaccination during the influenza a/ h n pandemic phase in the hong kong general population publicity plan for human swine influenza vaccination programme statistics on human swine influenza vaccinations press releases determinants of intention to get vaccinated against novel (pandemic) influenza a h n among health-care workers in a nationwide survey does receipt of seasonal influenza vaccine predict intention to receive novel h n vaccine: evidence from a nationally representative survey of u.s. adults factors in vaccination intention against the pandemic influenza a/h n influenza vaccination and intention to receive the pandemic h n influenza vaccine among healthcare workers of british columbia, canada: a cross-sectional study intent to receive pandemic influenza a (h n ) vaccine, compliance with social distancing and sources of information in nc low acceptability of a/h n pandemic vaccination in french adult population: did public health policy fuel public dissonance? public perceptions in relation to intention to receive pandemic influenza vaccination in a random population sample: evidence from a cross-sectional telephone survey risk perceptions, worry, or distrust: what drives pregnant women's decisions to accept the h n vaccine? which factors are important in adults' uptake of a (pre)pandemic influenza vaccine? why were turks unwilling to accept the a/h n influenza-pandemic vaccination? people's beliefs and perceptions about the swine flu outbreak and vaccine in the later stage of the epidemic demographic and attitudinal determinants of protective behaviours during a pandemic: a review relationship between intention of novel influenza a (h n ) vaccination and vaccination coverage rate the impact of communications about swine flu (influenza a h n v) on public responses to the outbreak: results from national telephone surveys in the uk influenza vaccine coverage rates and perceptions on vaccination in south korea influenza vaccination coverage rates in five european countries-a population-based cross-sectional analysis of two consecutive influenza seasons what factors affect influenza vaccine uptake among community-dwelling older chinese people in hong kong general outpatient clinics? emotions and preventive health behavior: worry, regret, and influenza vaccination risk perceptions: assessment and relationship to influenza vaccination do people who intend to get a flu shot actually get one? a protection motivation theory of fear appeals and attitude change cognitive and physiological processes in fear appeals and attitude change: a revised theory of protection motivation belief, attitude, intention, and behavior understanding attitudes, and predicting social behavior attitudes, personality and behavior the theory of planned behaivor the theory of planned behavior: a review of its applications to health-related behaviors efficacy of the theory of planned behaviour: a meta-analytic review intention-behavior relations: a conceptual and empirical review does changing behavioral intentions engender behavior change? a meta-analysis of the experimental evidence statistical power analysis for the behavioral sciences social foundataions of thought and action: a social cognitive theory implementation intentions: strong effects of simple plans implementation intentions and goal achievement: a meta-analysis of effects and processes augmenting the theory of planned behavior: roles for anticipated regret and descriptive norms acting on intentions: the role of anticipated regret determinants of older adults' intentions to vaccinate against influenza: a theoretical application determinants of influenza vaccination among healthcare workers situational awareness and health protective responses to pandemic influenza a (h n ) in hong kong: a cross-sectional study community psychological and behavioral responses through the first wave of pandemic (h n ) in hong kong power analysis and determination of sample size for covariance structure modeling principles and practice of structural equation modeling a meta-analysis of cronbach's coeffient alpha efficacy of an extended theory of planned behaviour model for predicting caterers' hand hygiene practices combining behavioral theories to predict recycling involvement an outbreak of the severe acute respiratory syndrome: predictors of health behaviors and effect of community prevention measures in hong kong, china psychosocial factors influencing the practice of preventive behaviors against the severe acute respiratory syndrome among older chinese in hong kong main tables of the population census. hong kong: government of the hong kong sar analyzing incomplete political science data: an alternative algorithm for multiple imputation who recommendations on pandemic (h n ) statistics on human swine influenza vaccinations as at safety of pandemic (h n ) perception of risk journey through an epidemic: some observations of contrasting public health responses to sars an evaluation of a belief hiv/aids prevention intervention for college students using normative feedback and goal setting reducing the risk of hiv transmission among adolescents in zambia: psychosocial and behavioral correlates of viewing a risk-reduction media campaign vaccine safety: risk communication-a global perspective omission bias and vaccine rejection by parents of healthy children: implications for the influenza a/h n vaccination programme omission bias and pertussis vaccination what is coefficient alpha? an examination of theory and applications multicollinearity and measurement error in structural equation models: implications for theory testing the - influenza pandemic: effects on pandemic and seasonal vaccine uptake and lessons learned for seasonal vaccination campaigns addressing parents' concerns: do vaccines contain harmful preservatives, adjuvants, additives, or residuals? we thank the hku public opinion programme for assistance in administering the telephone survey. we thank diane ng for coordinating the data collection and data management. analyzed the data: ql. contributed reagents/materials/analysis tools: ql bjc wwtl rf. wrote the paper: ql bjc wwtl rf. key: cord- -oqwbmyft authors: ammon, andrea; sasse, julia; riedmann, klaus title: early disease management strategies in case of a smallpox outbreak date: journal: poxviruses doi: . / - - - - _ sha: doc_id: cord_uid: oqwbmyft as a consequence of the threat of smallpox being potentially used as a means of bioterrorism, many countries have developed preparedness plans for smallpox in the past few years. this chapter summarizes some of the most important issues for the management of smallpox. usually, the strategy for the management of clinical cases of poxviruses includes the early detection of cases, rapid laboratory diagnosis, an assessment of the risk of further spread and containment measures. for the early detection, different systems are being tested to identify suspected cases before a diagnosis is confirmed (e.g., syndromic surveillance). also it is necessary to provide special training on the disease pattern, including differential diagnosis, to clinicians and practitioners. if a suspected case has been identified, rapid diagnostic tests are required. in addition to the national and international notifications based on given case definitions, certain measures are necessary to allow an initial risk assessment of the epidemic development. for a rapid risk assessment, the investigations should follow the algorithms of epidemiological outbreak investigation such as the tracing and identification of exposed contacts and the sources of infection. further decisions have to be taken on the basis of a continuous risk assessment. countermeasures can be divided into medical and non-medical ones. the choice of an adequate vaccination strategy as a medical countermeasure for the case of a re-emergence of smallpox very much depends on the epidemic scenario, and the general availability and quality of a vaccine. logistic aspects of the vaccination strategies have to be considered in preparedness planning (e.g., resources necessary for the implementation of mass vaccinations), and also the prioritization of groups to be vaccinated. in addition non-medical measures to prevent the spread of infection, such as the isolation of cases and quarantining of exposed persons (e.g., contact persons of confirmed cases) have to be foreseen. the effectiveness of other measures like prohibition of mass gatherings or closure of institutions is often assessed in the light of historical events. however, they have to be considered within today’s ethical and societal context, taking into account, in particular, the increased number of people who are immunocompromised. since our knowledge of how the virus would behave today is limited to extrapolations from historical data and is therefore imperfect, these measures are still under discussion. all relevant groups should be involved in exercises to assure the effective operation of the plan mainly regarding communication and cooperation. after the eradication of smallpox, it was possible to cease the most successful strategy against smallpox, namely vaccination. apart from rare events like the outbreaks of monkeypox in the democratic republic of congo or in the usa [ , ] , there has been no need to think about the management of this disease anymore. however, the threat of smallpox being used as a means of bioterrorism has forced reconsideration of the need for smallpox vaccinations and other measures to manage potential cases or outbreaks of smallpox. in the past few years, many countries have developed preparedness plans for smallpox. in the following chapter we have tried to summarize some of the most important issues for the management of smallpox. a full description of all the necessary parts of the preparedness plans would go beyond the space available here. the strategy for the management of clinical cases of poxviruses (occurring sporadically or in outbreaks) usually includes the early detection of cases, rapid laboratory diagnosis, an assessment of the risk of further spread and containment measures. early detection of a first smallpox case will be crucial for a successful management of any new outbreak. the earlier anti-epidemic countermeasures are initiated, the more likely the epidemic can be controlled or prevented in time and casualties can be limited. conventional surveillance systems like epidemiological surveillance of a well-defined set of clinically suspected diseases or laboratory confirmed agents are important to monitor and control the occurrence of infectious diseases. yet, these systems usually detect outbreaks or unusual epidemic developments only with a certain time delay. therefore, planning considerations include concepts that identify an attack as early as possible [ ] . among such systems are for example strategies to monitor the number of emergency department visits, over-the-counter medication sales or school absenteeism. also, environmental monitoring systems like air samplers, which permanently test the air for threat agents to detect a biological agent before it causes symptoms, have been suggested. since they only cover selected areas and have to be analyzed against a background noise, they do not necessarily guarantee a timely recognition of a biological threat [ ] . after th september , various models of syndromic surveillance have been established and tested in the united states for different syndromes (e.g., [ ] ), but they also still need to prove their value in detecting a bioterrorist attack in a timely manner. most likely a deliberate release of smallpox would not be detected unless one or more human cases with clinical symptoms of the disease occurred. the early clinical detection of a smallpox case requires familiarity with the disease pattern. the number of the actually practicing physicians who have clinical experience with smallpox patients is decreasing, and it is therefore necessary to provide special training on the disease pattern, including differential diagnosis to clinicians and practitioners. the emergence of highly contagious diseases with high mortality and morbidity rates pose an immediate threat to public health and ask for a real time detection of the onset. as a separate chapter in this book describes poxvirus diagnostics, we will not go into specific diagnostic techniques. a very important issue is the necessity to confirm any suspicion of smallpox as fast as possible to avoid false alarms with far-reaching consequences. to ensure the safety of staff involved in taking samples and performing the diagnostics, good cooperation and agreed procedures between health authorities, clinicians and laboratory staff are required. electron microscopy and nucleic acid detection are the fastest methods and can give results within h. for culturing the virus, biosafety level facilities are required. an initial suspected smallpox case triggers various notifications according to the requirements of national and international health legislation and regulations. furthermore, if a deliberate release of the virus seems possible, an actual threat to the affected state has to be presumed. in this case, disaster management and law enforcement agencies will assist the responsible health authorities to guarantee a comprehensive management in case of a confirmation and the likely spread of the disease. epidemiological and criminal investigation should be coordinated. in addition to the national and international notifications based on given case definitions, certain measures are necessary to allow an initial risk assessment of the epidemic development. these measures should follow the algorithms of epidemiological outbreak investigation, such as the tracing and identification of exposed contacts and the sources of infection. further decisions have to be taken on the basis of a continuous risk assessment. immediate anti-epidemic measures are of considerable importance. a permanent monitoring of the epidemic is necessary to guarantee that the effectiveness of the measures taken can be accurately evaluated, which in turn can lead to new measures or to a modification of the actual strategy. the following target groups for intervention measures can be distinguished: smallpox patients must be transferred immediately to a hospital with an isolation unit for further treatment. if no adequate infrastructure is available, isolation standards should be followed as well as possible (for requirements for isolation and isolation facilities see tab. ). most important is the vaccination of the contact persons as soon as possible within the first days after exposure and their isolation and observation either at home or in hospital. contraindications, e.g., history of severe eczema or immunodeficiency have to be weighed against the risk of disease. the treatment of complications resulting from vaccination must be also taken into account. even after a deliberate release, it is rather unlikely that a major epidemic or pandemic will occur if the appropriate countermeasures are taken in time. in the event of a smallpox outbreak the population can be protected by the prompt implementation of a vaccination campaign adapted to the epidemic realities. due to the historical experience, a second eradication of the smallpox disease is possible on the basis of the known eradication measures. the bigger challenge will be the identification and elimination of the sources of the intentional release. furthermore, the spread of a smallpox epidemic can be counteracted by limiting access to public facilities and events and by restricting freedom of movement. in addition, recommending appropriate protective measures and risk avoidance behavior to the population will be helpful. it is most important that all the measures taken are communicated to the public according to best practice of a consistent risk communication. the general public has to be given consistent information adapted to target groups and the situation via the available media. information of general relevance can be broadcast nationwide by television, for example, whereas information of regional or local relevance can be transmitted via other media (radio, local newspapers, cars with loudspeakers, leaflets, etc.). the information to be disseminated will include recommendations for protective measures as well as the announcement of restrictions on entry to events and facilities. the protection of the non-infected population will necessitate quarantine measures for suspect cases. as viruses do not recognize national borders, international cooperation is also of decisive importance. this may include technical and personnel support as well as the exchange and coordination of information but also coordinated action. in the revised international health regulations adopted by the world health assembly in , smallpox is one of the four diseases (the other three are poliomyelitis due to wild-type poliovirus; human influenza caused by a new subtype; severe acute respiratory syndrome, sars) for which just a single case case is considered unusual or unexpected with potentially serious public health impact, and thus must be notified (http://www.who.int/csr/ ihr/wha _ -en.pdf, accessed th may ). who member states have years to implement the necessary systems for surveillance and response including national focal points, which have to be accessible at all times for communication with the who focal points. the choice of an adequate vaccination strategy for the case of a re-emergence of smallpox in a country very much depends on the epidemic scenario one has in mind and the general availability and quality of a vaccine. at the same time, logistic aspects of the vaccination strategies have to be considered in preparedness planning, i.e., the facility and personnel resources necessary for the implementation of mass vaccinations have to be determined and identified. with the exception of the very unlikely situations of an accidental release or a natural re-emergence [caused, for example, by mutants of orthopoxviruses (camel-or monkeypox)], the only realistic scenario for a re-emergence of smallpox is a deliberate release of the agent, which does not necessarily have to follow historic patterns of epidemic spread. simultaneous and multilocal outbreaks are possible and have to be included as possible scenarios for a comprehensive preparedness planning. predictive modeling of the epidemic spread has to rely entirely on historic data and is of limited value. the availability and quality of a vaccine has the most significant influence on the strategy, as there is no evidence of an effective therapy with antiviral drugs against a smallpox infection in humans. the chosen strategy will be determined by the particular epidemiological situation and consideration of the threat of further releases and the risk of secondary infections compared with the well-known adverse effects of the currently available vaccines. unlike during a natural outbreak, the threat of additional intentional releases has to be considered for a vaccination policy. various models have been developed to assist in identifying the best use of the available vaccines (e.g., [ ] [ ] [ ] [ ] ), as well as other control measures like case isolation and contact tracing or combinations thereof [ , ] . since all these models have different assumptions for important parameters (like r ), the conclusions also vary. following historical data from the last natural, in this case imported, smallpox cases in europe in the decades before and during the eradication, the first step will be -after the immediate isolation measures have been initiated -the vaccination of contacts and simultaneous ring vaccinations. there are efforts to predict the best anti-epidemic measures on the base of mathematic modeling [ , , [ ] [ ] [ ] [ ] [ ] . such models are fitted in such a way that they can reproduce historical outbreaks very well and try to predict the effects of different anti-epidemic measures on the basis of historical data. the quality and predictive value are limited and depend very much on the inclusion of a sufficient number of necessary and correct parameters. a slight change in a parameter can lead to exaggerated effects that do not follow the common sense experience. a lot of the decisive factors can only be roughly estimated, like transmission rate, population immunity or the effectiveness of a post-exposure vaccination. furthermore, as the re-emergence of smallpox is most likely to result from a deliberate release and multiple geographically unlinked outbreaks may be possible, this historically based vaccination strategy might seem idealistic. public and political pressure and security considerations may quickly lead to the ultimate step, the mandatory vaccination of the entire population. nevertheless, this should be done after a careful risk-benefit-calculation considering the serious adverse effects of the available vaccines. vaccination priorities: first responders, other priority groups no matter which strategy is chosen the availability of vaccine is a key issue. most industrialized countries have acquired a certain stockpile of first or second generation vaccine. the sizes of the stockpiles vary from country to country. some countries have sufficient stockpiles to cover the whole population, some do not. therefore, priority population groups have to be identified for vaccination -in accordance with epidemiological, political, ethical and societal necessities and based on a public consensus. as long as there are no smallpox cases worldwide, obligatory prophylactic vaccinations especially of entire populations are not necessary. the re-emergence of smallpox has a limited likelihood, whereas the certainty of serious adverse effects due to vaccination is a proven fact. nevertheless, it can be necessary if there is an increased likelihood of occupational expo-sure. prophylactic vaccination may seem useful for the staff of special isolation units, which are most likely to treat the first smallpox cases or of those laboratories designated for confirmatory diagnostics. in this phase also members of infectious disease task forces (interdisciplinary teams on any administrative level for the initial risk assessment and subsequent investigations) may be offered vaccination on a voluntary basis. as soon as a first smallpox case is confirmed worldwide, and a real threat and exposure seem more likely, the offer of voluntary vaccination to all professional groups who are required to keep the necessary public services running during a smallpox epidemic has to be considered. these groups include mainly medical staff, fire brigades and disaster relief organizations, red cross etc., but also people working in critical infrastructures (power and water supply, public transportation and communication) or for public security and order or on the administration or political level, i.e. those population groups who are relevant for the maintenance of public life. once a smallpox case is confirmed, vaccination strategies should focus on the necessities of an anti-epidemic management. first of all the population being affected or at risk must be vaccinated. if the epidemic spread cannot be controlled, mandatory mass vaccinations will be necessary. smallpox can be spread by droplets and by direct or indirect contact with the pustules on the skin. this assumes that all primary contact persons of a confirmed smallpox case (see tab. ) may be infected and must be identified as soon as possible. the risk of infection for persons with an extended contact time or a close contact distance is much higher than for persons with a short contact time. according to historical data, the highest risk of infection exists for household members or hospital contacts. the european outbreaks between and showed that % of the infected persons contracted smallpox at a hospital, % in the family, % at their working place or school and % of the infected persons were working in a laundry, while % were unidentified contacts. none of the smallpox cases in europe since the second world war contracted it on an airplane, a train or a bus [ ] . yet, under special conditions, an airborne transmission may be possible. in a hospital in meschede, germany, patients and nurses from the two floors above the floor where a smallpox patient was treated were infected by air circulation [ , ] . based on publications on smallpox transmissions, table describes the risks of infection. it might be impossible to control an outbreak of smallpox using only vaccination, therefore isolation of cases and monitoring of the contacts may be necessary in addition [ , ] . quarantine in an isolation ward for all persons who were exposed seems to be the safest way, but it has some limitations, like the quantity of qualified isolation wards, the supply of the population with food, drinking water etc. and the cooperation of the population. therefore, it will be helpful to adjust the anti-epidemic measures to the likelihood of developing the disease (tab. ) [ ] . the isolation concept should be adapted to the epidemic situation, the requirements on effective isolation and the expected number of contact persons. the personnel in all hospitals/facilities must be vaccinated and trained, personal protective equipment (including gloves, masks, goggles, gowns) and means to follow the hygiene measures must be available. if pri- high risk -persons who are living in the same household with the patient and persons with a similar risk of infection (members of the family and household contacts, etc.) -persons who have had "face-to-face-contact" with a sick person, which includes all persons, who have been so close to the patient that they could be infected by droplets, or who have touched the efflorescence of the skin [e.g., friends or neighbors who have taken care of the patient, physicians who have been consulted before the hospital, hospital staff (medical doctors, nurses, cleaning staff), persons in a public traffic system with direct contact, i.e., less than ca. m to the infectious case of smallpox, etc.] -persons who have been longer in the same (confined) room with a patient (e.g., work colleagues, transport staff of the ambulance, etc.) -persons who have direct contact with the dead body of a smallpox patient (e.g., undertaker, pathologist, priest, etc.) -persons who have worked with infectious samples of a smallpox patient without appropriate protection -persons who have touched scabs of a smallpox patients without appropriate protection -persons who have had direct, non-protected contact with the personal clothes, bed linen or other personal belongings, materials that a smallpox patient wore or used after the onset of fever medium risk -persons who are in the same building as a smallpox case, if this building has a ventilation system, air conditioning or comparable installation systems that circulate the air between different rooms in the building -persons who have traveled in the same compartment of a public transportation system or airplane with a ventilation system, air conditioning or comparable installation systems to circulate the air low risk -persons with a short and/or not close contact to an infectious smallpox case (e.g., a short stay in the same room, or a longer stay in the same building without ventilation system, air conditioning or comparable installation systems to circulate the air; sharing the same public transportation system without ventilation system, air conditioning or comparable installation to circulate the air; distance to the index case > m) -medical staff, if they have used appropriate personal protection equipment mary contacts develop fever and other typical symptoms of smallpox, their transfer to a hospital with isolation ward is immediately necessary. for contact persons with a low risk of infection and a timely, successful vaccination, segregation at home seems to be appropriate as long as they have not developed fever, all household contacts have been vaccinated and the local health authority has the capacity to observe them daily. nevertheless, it must be kept in mind that a vaccination, even when administered in time, does not yield % protection. according to historical data, the risk of infection for vaccinated household contacts of a smallpox patient in the past was . % [ ] , in comparison to % of unvaccinated household contacts. these data did not give any information about when the contact persons had had their last vaccination. vaccination should also be offered to secondary contact persons. they must be registered because they will become primary contacts themselves if the originally primary contact develops the disease. since transmission of smallpox is favored by close distance between persons, so-called "social distancing" measures are considered as further intervention measures to stop the spread. whereas the isolation of cases or segregation of exposed persons (contacts) is not under debate, the effectiveness of other measures like prohibition of mass gatherings, closure of institutions or even curfews are often assessed in the light of historical events. however, they should be considered within today's ethical and societal context, taking into account differences in the society, in travel behavior, and the increased recognition of contraindications to vaccination [ ] . also, the number of people who are immunocompromised (due to hiv, chemotherapy, transplantations etc.) has increased [ ] . these measures are still under discussion, since we have limited knowledge of how the virus would behave today. according to the vaccination strategy described above, the majority of vaccinations would be carried out in the case of the real event. therefore, elaborate preparations have to be implemented in the pre-event phase. smallpox vaccine and bifurcated needles have to be procured and stockpiled. some governments have a national stockpile of smallpox vaccines, but not all of them have a stockpile covering the need of their entire population. therefore, multi-lateral support in the case of an event has to be assured in time. within the european union, a task force on bioterrorism was set up in may with the main objective of implementing the health security program [ ] . the world health organization (who) has to convince some states to contribute to an international stockpile at who level. for national stockpiles, the logistics for storage, transport and distribution have to be determined in advance as well. to allow immediate mass vaccinations, the required infrastructure, such as facilities or personnel, has to be identified and the latter informed and trained in time. the entire process should be tested and practiced in simulation exercises. when choosing vaccination facilities important aspects have to be considered to enable the vaccination of a large number of people in a very short time, such as: -number and size of vaccination facilities according to population density -transport connections -easy access, also for handicapped people -water and energy supply -toilets -possibility of separate treatment of suspected cases -availability of rooms for personnel, first aid, treatment -phone -furniture material for documentation of the vaccinations and checking of contraindications (questionnaires, vaccination list/card) as well as information for the public has to be produced in advance and distributed to the authorities. they take care of the implementation of preparedness measures on the regional and local level. other tasks have to be achieved or initiated in the pre-event phase as well: vaccination of the vaccinators, training of the necessary staff and provision of the material needed at the vaccination facilities. a survey of over million vaccinations in the usa in showed that per million vaccinations there were serious adverse effects, including death [ ] . some of the known adverse effects that may arise from smallpox vaccination are post-vaccination encephalitis, progressive vaccinia, eczema vaccinatum or generalized vaccinia. therefore, the production of modern and more compliant vaccines is under consideration. a way to minimize the adverse events of smallpox vaccination might be the use of modified vaccinia virus ankara (mva), which was developed in the s by more than passages in chicken embryo fibroblasts [ ] . however, smallpox had been eradicated before the efficiency of the protective effect of mva could be tested. experiments with animals indi-cate that there may be fewer complications after vaccination with mva [ ] [ ] [ ] , and show also that mva provokes a high antibody titer and a high concentration of ifn--positive cells. some data show that mva-vaccinated animals are protected against smallpox infection [ , ] , but other results allow the interpretation that a mva-vaccination alone can not guarantee a full protection against infection [ ] . mva might be a good candidate for a pre-immunization [ ] or for persons with strong contraindications [ , ] . other replication-deficient vacv strains have also been developed for immunization [ , [ ] [ ] [ ] . some mva strains currently under development require a higher virus titer as they do not replicate in the human body. vacv strains have the potential to inducing post vaccination encephalitis. derived from historical data with - cases per million, the vaccination of the entire population of a country like germany would lead to - cases of severest adverse effects. finally, a lot of research is being performed to develop new vaccines. experiments on a dna basis are very promising, even if these vaccines do not fully protect from infection yet [ , ] . all the vaccines under development are still in the pre-clinical state. usually, vaccination strategies are chosen on the basis of scientific evidence and national health legislation. for the special case of smallpox, the only vaccine which has proven its efficiency decades ago is known to produce serious side effects. therefore, legal regulations for the financial compensation of vaccination damages have to be agreed upon and guaranteed before the implementation of vaccinations, no matter if they are being recommended for occupational safety reasons in the pre-event phase or as antiepidemic measure in the case of an event. more than years after the eradication of smallpox only very few health professionals have practical experience with the management of this disease. therefore, all relevant professions involved in the management of a smallpox outbreak or epidemic have to be trained on the disease pattern and its specific consequences on their professional tasks. training must include the professional implementation of sampling techniques as well as safe transport, which have to be arranged in advance to avoid any unnecessary delay or hazard from improper handling or packaging. the laboratories selected for smallpox diagnostics have to guarantee that this can be done both rapidly and with assured quality. these labora-tories have to immediately report a suspected or confirmed laboratory diagnosis to the appropriate authorities. public health officers, clinicians and practitioners for example have to update their knowledge on the clinical picture to guarantee an early recognition of the disease and also get familiar with the treatment and therapy of smallpox cases. laboratory personnel have to be trained in the diagnostics of smallpox on the basis of the standard operating procedures. the validity of the diagnosis is improved by regular participation in a quality assurance system. in general, if preparedness plans exist, they have to be evaluated among all the relevant groups by exercises to assure the effective operation of the plan mainly in the field of communication and cooperation. public health services might test the implementation of mass vaccinations or the reporting systems for a smallpox alert; clinicians might check the clinics' preparedness plans for cases of highly contagious diseases, ambulance services might train for the transport of highly contagious patients and all together they might check the interaction between the relevant actors aiming at a harmonization of the preparedness planning. outbreak of human monkeypox update: multistate outbreak of monkeypox -illinois advances in detecting and responding to threats from bioterrorism and emerging infectious diseases syndromic surveillance in public health practice ring vaccination and smallpox control modelling responses to a smallpox epidemic taking into account uncertainty a model for a smallpox-vaccination policy effectiveness of a postexposure vaccination for the prevention of smallpox: results of a delphi analysis a first smallpox case or first smallpox cases would need "official" confirmation in one of the two laboratories designated by who (cdc and vector) case isolation and contact tracing can prevent the spread of smallpox surveillance and control measures during smallpox outbreaks towards a containment strategy for smallpox bioterror: an individual-based computational approach containing bioterrorist smallpox transmission potential of smallpox in contemporary populations modeling a safer smallpox vaccination regimen, for human immunodeficiency virus type -infected patients. in: immunocompromised macaques modeling potential responses to smallpox as a bioterrorist weapon smallpox in europe, - a different view of smallpox and vaccination an airborne outbreak of smallpox in a german hospital and its significance with respect to other recent outbreaks in europe the recent outbreak of smallpox in meschede, west germany begriffsbestimmungen seuchenhygienisch relevanter maßnahmen und bezeichnungen smallpox and its eradication the european commission's task force on bioterrorism complications of smallpox vaccination, /national surveillance in the united states der pockenimpfstamm mva: marker, genetische struktur, erfahrungen mit der parenteralen schutzimpfung und verhalten im abwehrgeschwächten organismus [the smallpox vaccinnation strain mva: marker, genetic structure, experience gained with the parenteral vaccination and immunogenicity of a highly attenuated mva smallpox vaccine and protection against monkeypox highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge modified vaccinia virus ankara protects macaques against respiratory challenge with monkeypox virus shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses modified vaccinia ankara; potential as an alternative smallpox vaccine immunogenicity and safety of defective vaccinia virus lister: comparison with modified vaccinia virus ankara induction of potent humoral and cell-mediated immune responses by attenuated vaccinia virus vectors with deleted serpin genes genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia lc m smallpox vaccines: looking beyond the next generation smallpox dna vaccine protects nonhuman primates against lethal monkeypox key: cord- -ry o xj authors: ciotti, john robert; valtcheva, manouela v.; cross, anne haney title: effects of ms disease-modifying therapies on responses to vaccinations: a review. date: - - journal: mult scler relat disord doi: . /j.msard. . sha: doc_id: cord_uid: ry o xj background: : development of long-term immunologic memory relies upon humoral and cellular immune responses. vaccinations aim to stimulate these responses against pathogens. several studies have evaluated the impact of multiple sclerosis disease-modifying therapies on immune response to vaccines. findings from these studies have important implications for people with multiple sclerosis who require vaccination and are using disease-modifying therapies. methods: : searches using pubmed and other engines were conducted in may to collect studies evaluating the impact of various disease-modifying therapies on immune responses to vaccination. results: : several studies demonstrated preserved immune responses in people treated with beta-interferons to multiple vaccine types. limited data suggest vaccine responses to be preserved with dimethyl fumarate treatment, as well. vaccine responses were reduced to varying degrees in those treated with glatiramer acetate, teriflunomide, sphingosine- -phosphate receptor modulators, and natalizumab. the timing of vaccination played an important role in those treated with alemtuzumab. humoral vaccine responses were significantly impaired by b cell depleting anti-cd monoclonal antibody therapies, particularly to a neoantigen. data are lacking on vaccine responses in patients with multiple sclerosis taking cladribine and high-dose corticosteroids. notably, the majority of these studies have focused on humoral responses, with few examining cellular immune responses to vaccination. conclusions: : prior investigations into the effects of individual disease-modifying therapies on immune responses to existing vaccines can serve as a guide to expected responses to a sars-cov- vaccine. responses to any vaccination depend on the vaccine type, the type of response (recall versus response to a novel antigen), and the impact of the individual disease-modifying therapy on humoral and cellular immunity in response to that vaccine type. when considering a given therapy, clinicians should weigh its efficacy against ms for the individual patient versus potential impact on responses to vaccinations that may be needed in the future. multiple sclerosis (ms) is an immune-mediated demyelinating central nervous system (cns) condition characterized by attacks of neurologic symptoms disseminated in space and time that often leads to disability. ms affects over , people in the united states with enormous costs to society. ms disease-modifying therapies (dmts) act on the immune system, by modulation or suppression. this review assesses the current evidence regarding the impact of ms dmts on immune responses to existing vaccinations, highlighting implications for response to a potential vaccine against sars-cov- . an effective immune response that provides long-term immunologic memory is driven primarily by the adaptive immune system, consisting of b cells (responsible for humoral, or antibody-mediated, immunity) and t cells (responsible for cell-mediated immunity). when stimulated in the presence of their target antigen, b and t cells clonally expand, with some transforming into memory cells, able to rapidly proliferate and become effector cells upon re-exposure to their target antigen. upon activation, b cells can also differentiate into plasma cells that generate initially igm and then igg antibodies specific to the antigen. table summarizes vaccine types and how the immune responses they generate differ. humoral responses to vaccines are generally measured using titers of igg antibodies against the particular antigen, though use of the hemagglutination inhibition (hi) assay is an exception. the hi assay reports the inverse of the dilution (the titer) at which a patient's antibody-containing serum is no longer able to inhibit the viral hemagglutination property. for inactivated influenza vaccine, an hi titer of ≥ is considered protective. cellular immune responses to vaccines are less well-studied, and measurement methods are highly variable. irrespective of vaccine type, immune responses to vaccination are generally more robust in women, in whom ms has a predilection. vaccine safety in ms was a subject of debate throughout the s and s, as seasonal influenza, measles/mumps/rubella (mmr), hepatitis b (hbv), h n influenza, and human papillomavirus (hpv) ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. vaccines were all implicated and subsequently refuted as being linked to ms development or worsening. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] vaccine efficacy in ms has been less controversial, as studies of untreated ms patients have not shown differences in responses compared to healthy controls (hc). regulatory bodies now recommend vaccinating people with ms on a normal schedule, with some caveats regarding live attenuated vaccines. [ ] [ ] [ ] the various immunomodulatory and immunosuppressive effects of different dmts add complexity regarding vaccinations. live vaccines are generally contraindicated in ms patients on immunosuppressive treatments. mechanistically, dmts that impact the adaptive immune system may decrease the efficacy of vaccines by impairing the development of long-term memory. this review evaluates the current evidence regarding the impact of dmts for ms on vaccine responses in humans. a pubmed search was performed on may , for english language articles that were published between january , and may , using the mesh terms multiple sclerosis and vaccine with each individual dmt. articles not focusing on vaccine response in the setting of dmt use, such as basic pathophysiologic reviews, author commentaries, reports of vaccines used as ms therapy, and animal studies were excluded. additional references were obtained from a google search of each individual dmt and immunization and vaccination (may - , ), secondary review of the articles discovered in these searches, searches of clinicaltrials.gov (may , ) and cdc.gov (may , ), and review of manufacturer prescribing information for each dmt. bias was qualitatively assessed for each study and funding sources are noted in table . levels of evidence for each study are assigned based on the oxford centre for evidence-based medicine levels of evidence. ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. table provides a summary of all published studies of vaccine responses in people using fda-approved dmts for ms. a prospective, non-randomized, open label study compared responses to an inactivated influenza vaccine in relapsing ms patients taking interferon beta- a mcg three times weekly and untreated relapsing ms patients. there was no difference in the proportion of patients in each group with seroprotective hi titers ( . % beta-interferon group vs. . % untreated group), or the proportions mounting -fold ( . % vs. . %) and -fold ( . % vs. . %) increase in hi titers. this study offers level evidence that ms patients taking high-dose, high-frequency beta-interferon mount an appropriate immune response to the influenza vaccine. another study compared immune responses after seasonal influenza vaccination in teriflunomidetreated relapsing ms patients to beta-interferon-treated relapsing ms patients. for all influenza strains used, > % of those in the beta-interferon group had protective hi titers days postvaccination. ratios of post-vaccination to pre-vaccination geometric mean titers (gmt) were all ≥ . , indicating an effective immune response. this study was limited by lack of an untreated ms control group. level evidence. a prospective observational study evaluated the effects of the inactivated influenza vaccine in patients taking a variety of beta-interferon preparations, comparing anti-influenza igm and igg titers to those in hc at multiple time-points post-vaccination. no significant difference between groups was found in the degree or duration of these humoral immune responses, with the exception of a significantly higher anti-influenza b igg titer at days and in the beta-interferon group. cellular immune responses were also compared by measuring the frequency of t cells secreting gammainterferon in response to influenza antigen, with no differences between groups. level evidence. the same investigator group performed another observational study of ms patients taking betainterferons and compared influenza vaccine responses at multiple post-vaccination intervals to hc. no differences in the proportion reaching a protective hi titer were observed between the two groups at any time, including at the peak antibody response time of months ( . % in the beta-interferon group vs. . % in hc). level evidence. another observational study evaluating vaccine responses in patients taking dimethyl fumarate included an arm of relapsing-remitting ms (rrms) patients taking beta-interferons. igg titers were assessed pre-and post-vaccination with vaccines to assess different types of immune responses: tetanus-diphtheria toxoid vaccine to assess t-cell dependent anamnestic humoral response, -valent pneumococcal polysaccharide vaccine (ppsv ) to assess t-cell independent humoral response, and quadrivalent meningococcal conjugate vaccine (mcv ) to assess neoantigen responses. those with a ≥ -fold rise in igg levels after vaccination were considered responders. for anti-tetanus/diphtheria, there was no difference in the responder proportion (dimethyl fumarate group % vs. beta-interferon group %). pneumococcal vaccination responses were not significantly different between the two groups, though there was considerable variability in gmt ratios across serotypes. neoantigen responses ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. to mcv were not different, with % of each group demonstrating a -fold rise in igg. post-to prevaccination gmt ratios were similar in the dimethyl fumarate and beta-interferon groups ( . vs . , respectively). level evidence. a prospective, multicenter, non-randomized study evaluated influenza vaccine responses in patients treated with a variety of dmts. patients taking beta-interferons showed a significantly greater proportional vaccine response as measured by hi titer than other dmt groups taking glatiramer acetate, fingolimod, and natalizumab. beta-interferon-treated patients reached seroprotective rates of > % for each strain, and reached protective hi titers to all strains ( . % of patients) more frequently than those treated with glatiramer acetate ( . % of patients), fingolimod ( . % of patients), and natalizumab ( . % of patients). this study was limited by lack of an untreated control group and low numbers, especially in the fingolimod and natalizumab groups. level evidence. together, these studies convincingly demonstrate adequate immune responses to a variety of vaccine mechanisms in ms patients treated with beta-interferons. although immune responses to influenza vaccines were observed in glatiramer acetate-treated patients in these studies, the results suggest that responses were reduced compared to hc and to those treated with beta-interferons. these studies regarding inactivated vaccination responses may not be generalizable to other vaccine types (such as live attenuated, nucleic acid, recombinant vector, or subunit vaccines), for which immune responses have not been reported in people on glatiramer acetate. a study already mentioned in the beta-interferon section investigated the effect of teriflunomide on influenza vaccination responses in ms patients. this non-blinded, nonrandomized, multicenter, multinational, parallel-group study included patients in groups: teriflunomide mg (n= ), teriflunomide mg daily (n= ), and beta-interferons (n= , the reference population). more than % of all patients in all groups achieved seroprotection (hi titer ≥ ) for the h n and influenza b antigens. seroprotection was lower in the h n teriflunomide mg group ( . %), compared to % ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. in the mg per day teriflunomide and beta-interferon groups. gmt ratios were reduced in the teriflunomide groups ( . - . ) compared to the beta-interferon group ( . - . ) . a limitation of this study is that it was not powered for comparisons of immune responses in the teriflunomide and betainterferon groups. level evidence. a prospective, randomized, double-blind, parallel-group, placebo-controlled study compared antibody responses to rabies vaccine (neoantigen) and delayed type hypersensitivity (recall) to candida albicans, trichophyton, and tuberculin in healthy people assigned to mg/day teriflunomide with healthy individuals assigned to placebo. gmts for rabies antibodies were lower with teriflunomide than with placebo, but all subjects assigned to teriflunomide achieved seroprotective antibody levels. teriflunomide had no adverse impact on the cellular memory response to recall antigens. level evidence. overall, these studies indicate modest negative effects of teriflunomide mg/day on immune response to influenza and rabies vaccinations. . . . dimethyl fumarate. a single open-label, multicenter, non-randomized study evaluated the effects of dimethyl fumarate treatment on vaccination responses. patients on dimethyl fumarate mg twice daily were compared to patients treated with beta-interferon after vaccination with vaccines to assess different types of immune responses. this study is discussed in detail in the section on betainterferons above and provided level evidence that dimethyl fumarate treatment did not reduce t-cell dependent and humoral immune responses. igm and igg, and the frequency of gamma-interferon secreting cells after immunization, were not significantly altered by fingolimod treatment compared to hc. however, the two groups were not well matched, with hc being younger (mean age , range - ) than the ms patients (mean age , range - ), and hc were % female compared with % female in the ms group. level evidence. a blinded, randomized, multicenter, placebo-controlled study of response to seasonal influenza vaccine and tetanus toxoid (tt) booster was performed in relapsing ms patients on either fingolimod . mg/day (n= ) or placebo (n= ). at weeks post-vaccination, responder rates (proportion achieving seroprotective hi titers or a -fold increase in antibody titers against at least one influenza strain) for fingolimod vs. placebo, respectively, were % vs. %. at weeks, responder rates were % vs. %. for tt, responder rates were % vs. % at weeks and % vs. % at weeks. although many fingolimod-treated ms patients were able to mount protective immune responses, this study provided level evidence that response rates were reduced in patients on fingolimod compared with placebotreated patients. fifteen patients on fingolimod were among the ms patients and hc included in a prospective study to measure antibody responses to the / influenza a h n and h n vaccine viruses. the fingolimod group developed reduced rates of seroprotection to h n compared with controls or ms patients on beta-interferons and glatiramer acetate. at months, months, and months, seroprotection rates were . %, . %, and . % in the fingolimod group vs. . %, %, and . % in hc. the response to h n was even poorer in those on fingolimod, with . % protected at months, . % protected at months, and % at months post-vaccination compared with . %, %, and . % for hc. level evidence. ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. a non-randomized, prospective, non-controlled study of ms patients who underwent seasonal influenza vaccination discussed in earlier sections of this review included people on fingolimod. a lower proportion of fingolimod-treated patients achieved protection to h n and influenza b compared to those on beta-interferons or glatiramer acetate. interpretation of these results is limited by the very small size of the fingolimod subgroup. level evidence. taken together, these studies indicate that concurrent fingolimod reduces immune response to influenza vaccinations. . . . siponimod. responses to seasonal influenza and ppsv vaccines were assessed in healthy persons treated with siponimod mg/day or placebo. the randomized, prospective study enrolled people per group into siponimod treatment groups and a placebo group. treatment groups were "preceding siponimod" (stopping days prior to immunization), "concomitant" (non-interrupted siponimod), and "interrupted siponimod" (treatment interrupted days prior to and for days after immunization). the durations of stopping or interrupting siponimod were based on the known time of - days for circulating lymphocytes to return after drug discontinuation. each person received seasonal influenza and ppsv vaccines, with blood samples obtained at baseline and multiple times after immunization. seroprotection rate > %, gmt increase of > . vs. baseline, and igg response rate of > % were examined. at days, each group exceeded the % response threshold and a gmt increase > . -fold for both influenza a antigens compared with baseline. for one of the two influenza b viruses, the seroprotection response threshold of > % was not met for the interrupted and concomitant siponimod groups. over % in each group responded to ppsv with > -fold increase in igg on day vs. baseline. compared to the placebo group, the proportions of people with titer increased > -fold at day were decreased in the concomitant and interrupted siponimod groups for h n , h n , and one of the influenza b viruses. gmts over time were lower for the concomitant siponimod group for both influenza a strains and one of the influenza b strains compared to the other ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. groups. this study provides level evidence of a lower response to influenza vaccines in those on siponimod at time of vaccination. stopping siponimod at least days prior to administration of a vaccine and resuming siponimod (after up-titration) or more weeks later is a potential strategy to improve vaccine response. . . . ozanimod. no relevant studies were found. no relevant studies have been reported in ms patients on oral cladribine. a vaccine study is being planned by the manufacturer. an early study of natalizumab-treated ms patients ( female) and hc ( female) examined antibody response to seasonal influenza vaccination. mean antibody titers to influenza a and b were not different between the two groups, with a non-significant trend towards lower titers to influenza a for the natalizumab group. this study was likely underpowered, and the study groups were not well matched. level evidence. a randomized, controlled, open-label study of people with relapsing ms was done to study the response to a recall antigen (tt) and the neoantigen keyhole limpet hemocyanin (klh). patients were randomized : to control or natalizumab groups. the control group received immunizations shortly after randomization and delayed starting natalizumab until after day , whereas those randomized to natalizumab were treated with natalizumab beginning months prior to immunizations. a lower proportion of those in the natalizumab group responded to tt and to klh at day . although the differences were not statistically significant, the study may have been underpowered. level evidence. ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. a previously mentioned real-world study of ms patients and hc examined response to the h n pandemic "swine flu" vaccine. seventeen of the ms patients in that study were on natalizumab. only of the ( . %) achieved seroprotective hi titers after immunization, compared to of controls ( . %) and of ( . %) of those on beta-interferon. level evidence. the same group of investigators performed a prospective study of responses to the seasonal influenza vaccination in / in ms patients on four different immunomodulatory therapies and hc at baseline and , , and months post-immunization. the proportion of those few patients on natalizumab (n= at months, n= at months, and n= at months) that had adequate response to the immunization was consistently % or more lower than hc and ms patients on beta-interferons. in the previously-discussed non-randomized, prospective, study of ms patients who underwent seasonal influenza vaccination, were on natalizumab. for h n and the influenza b antigen, only . % and . %, respectively, of those on natalizumab achieved sufficient response, compared to . % and . % for the people taking beta-interferon. level evidence. overall, these studies provide evidence that an inadequate response to some immunizations occurs in a sizeable proportion of people being treated with natalizumab. response to the seasonal influenza vaccine tested response to an inactivated vaccine, and immunization with klh tested the humoral response to a previously unknown antigen. the ocrelizumab group had a poorer humoral response to vaccinations. . % of the ocrelizumab group vs. . % of the control group had responded ( -fold increase in antigen-specific igg from baseline or development of protective antibody levels) to tt booster at weeks post-vaccination. positive response to ≥ serotypes in ppsv at weeks was . % in the ocrelizumab and % in the control group. the pcv booster did not enhance the response to serotypes in common with ppsv in the ocrelizumab group, whereas it did for the control group. the humoral response to klh was greatly decreased in the ocrelizumab group vs. the control group. after immunization with klh, the gmts for igm and igg for the control group were almost , and , , respectively, but were less than for igm and igg in those treated with ocrelizumab. seroprotective titers at weeks against five influenza strains (season / and / ) ranged from . % to . % in the ocrelizumab group, compared to . % to . % in the control group. level evidence. . . . rituximab. responses to vaccination were studied in non-ms populations treated with the b cell depleting chimeric monoclonal antibody, rituximab. in one study of rheumatoid arthritis patients, patients were randomized : to take rituximab mg iv twice two weeks apart in addition to methotrexate ( - mg po weekly) vs. methotrexate alone. patients in each treatment group were examined for response to tt, ppsv , and klh, and for dth to candida albicans. these two studies indicate that responses to neoantigens and t cell-independent antigens are greatly reduced by b cell depletion with anti-cd monoclonal antibody treatments. recall responses to the t cell-dependent tt antigen and dth responses were less affected by b cell depletion, with some differences noted in response to tt between the two studies which used different b-cell depleting agents. both studies were done in the first year after b cell depletion; responses might change after longer treatment duration. twenty-four people with ms taking alemtuzumab for median months (range . to months) took part in an investigation of the effects of alemtuzumab on vaccination responses. to test t-celldependent antigen recall responses, igg levels were measured before and weeks after vaccinations with diphtheria and tetanus in ms patients taking alemtuzumab, and in patients taking alemtuzumab before and weeks after inactivated polio , , and . pre-vaccination, all had protection to diphtheria and tt that was maintained after alemtuzumab. protection improved from % to % for polio and from % to % for polio after vaccination. at the time of vaccination, the median cd t-cell count was low and median cd t-cell and cd b-cell counts were normal. ppsv was used to test responses to t-cell-independent antigens. of the ms patients who were immunized, the proportion achieving seroconversion for serotypes and exceeded that of literature controls. similarly, the proportion protected against haemophilus influenzae type b and meningococcal group c (neoantigen) increased from % and %, respectively, to % and % post-vaccination, equivalent to published seroconversion rates for controls. the investigators noted that vaccination within months of treatment resulted in a smaller proportion of responders. this study provides level ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. evidence that response to prior vaccinations is maintained following alemtuzumab treatment, but suggests that vaccinations be delayed until at least at months after alemtuzumab treatment. several studies in non-ms patient populations (e.g. asthma, rheumatoid arthritis, systemic lupus erythematosus) have provided level evidence of minimal impact of chronic oral corticosteroids on vaccine responses. [ ] [ ] [ ] [ ] however, the doses of corticosteroids in these studies were all lower than those typically used for ms relapses. in their guidelines, the infectious diseases society of america recognized the lack of data on vaccine efficacy in people treated with high doses of corticosteroids (≥ mg prednisone equivalents for ≥ days). it is generally recommended to avoid administering live vaccines during treatment with and until at least weeks after discontinuing high-dose corticosteroids. , this research did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors. ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. responses to inactivated and toxoid vaccines were diminished in those taking fingolimod at the time of vaccination. responses to the inactivated influenza vaccine were diminished in those taking siponimod at the time of vaccination. the prevalence of ms in the united states: a population-based estimate using health claims data fundamentals of vaccine immunology measuring vaccine responses in the multiplex era standardization of hemagglutination inhibition assay for influenza serology allows for high reproducibility between laboratories sex and gender differences in the outcomes of vaccination over the life course vaccines and multiple sclerosis: a systematic review adverse effects of vaccines: evidence and causality influenza vaccination in ms: absence of t-cell response against white matter proteins effects of ms disease-modifying therapies on responses to vaccinations: a review a multicenter, randomized, double-blind, placebocontrolled trial of influenza immunization in multiple sclerosis quadrivalent hpv vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system seasonal and h n v influenza vaccines in ms: safety and compliance vaccinations and the risk of relapse in multiple sclerosis. vaccines in multiple sclerosis study group vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases acip altered immunocompetence guidelines for immunizations | recommendations | cdc immunization and multiple sclerosis: recommendations from the french multiple sclerosis society infectious complications of multiple sclerosis therapies: implications for screening, prophylaxis, and management. open forum infect dis effects of ms disease-modifying therapies on responses to vaccinations: a review vaccination against infection in patients with multiple sclerosis immune response to influenza vaccine is maintained in patients with multiple sclerosis receiving interferon beta- a preserved antigen-specific immune response in patients with multiple sclerosis responding to ifnβ-therapy immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy immune response to vaccines is maintained in patients treated with dimethyl fumarate effects of ms disease-modifying therapies on responses to vaccinations: a review immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial immune competence after alemtuzumab treatment of multiple sclerosis influenza vaccination in kidney transplant recipients: cellular and humoral immune responses antibody levels and response to pneumococcal vaccine in steroid-dependent asthma immunogenicity and safety of pneumococcal vaccination in patients with rheumatoid arthritis or systemic lupus erythematosus safety and efficiency of influenza vaccination in systemic lupus erythematosus patients idsa clinical practice guideline for vaccination of the immunocompromised host effects of ms disease-modifying therapies on responses to vaccinations: a review ciotti jr, valtcheva mv, cross ah. effects of ms disease-modifying therapies on responses to vaccinations: a review. key: cord- - hto qn authors: schoch-spana, monica; brunson, emily k.; long, rex; ruth, alexandra; ravi, sanjana j.; trotochaud, marc; borio, luciana; brewer, janesse; buccina, joseph; connell, nancy; hall, laura lee; kass, nancy; kirkland, anna; koonin, lisa; larson, heidi; lu, brooke fisher; omer, saad b.; orenstein, walter a.; poland, gregory a.; privor-dumm, lois; quinn, sandra crouse; salmon, daniel; white, alexandre title: the public’s role in covid- vaccination: human-centered recommendations to enhance pandemic vaccine awareness, access, and acceptance in the united states date: - - journal: vaccine doi: . /j.vaccine. . . sha: doc_id: cord_uid: hto qn given the social and economic upheavals caused by the covid- pandemic, political leaders, health officials, and members of the public are eager for solutions. one of the most promising, if they can be successfully developed, is vaccines. while the technological development of such countermeasures is currently underway, a key social gap remains. past experience in routine and crisis contexts demonstrates that uptake of vaccines is more complicated than simply making the technology available. vaccine uptake, and especially the widespread acceptance of vaccines, is a social endeavor that requires consideration of human factors. to provide a starting place for this critical component of a future covid- vaccination campaign in the united states, the -person working group on readying populations for covid- vaccines was formed. one outcome of this group is a synthesis of the major challenges and opportunities associated with a future covid- vaccination campaign and empirically-informed recommendations to advance public understanding of, access to, and acceptance of vaccines that protect against sars-cov- . while not inclusive of all possible steps than could or should be done to facilitate covid- vaccination, the working group believes that the recommendations provided are essential for a successful vaccination program. since its first appearance in the united states in february , the novel coronavirus (sars-cov- ) has infected over . million americans and killed over , (as of october , ) [ ] . responses to the virus, including closing venues where person-to-person spread was likely, and requiring the use of masks and physical distancing measures when social contact could not be avoided, have reduced virus spread. at the same time, these protective actions have radically transformed social life and disrupted national and household economies [ ] . as the health crisis continues to linger and a sense of pandemic fatigue starts to take hold, political leaders, health officials, and the general public are seeking solutions [ ] . one of the most promising, if successfully developed and deployed, is vaccines. this technology could provide individual and population-level immunity, and through these the eventual conditions for the resumption of routine social and economic activities [ ] . to facilitate the development and dissemination of such vaccines, the us government has committed over billion dollars (via operation warp speed) with the aim of delivering million doses of a safe, effective vaccine by january [ ] . while this timeline is likely overly optimisticvaccine development, especially against a class of pathogens for which no licensed vaccine currently exists, typically takes - years [ ] -progress is being made. as of october , , vaccines are in preclinical evaluation, are in phase i and ii safety trials, have entered phase iii efficacy trials, and five vaccines have been approved for limited use: two in china, two in the united arab emirates, and one in russia [ ] . despite these promising developments, operation warp speed manifests a key social gap. the program rests upon the compelling yet unfounded premise that 'if we build it, they will come.' past experience in routine and crisis contexts demonstrates that, for a variety of reasons, not all segments of the public will accept medical countermeasures including vaccines [ ] [ ] . a recent poll in the us suggests this is already the case for sars-cov- (covid- ) vaccines. about half of us adults ( %) reported they definitely or probably would accept the vaccine, while % said they would not [ ] . in the same poll, only % of black americans indicated they would definitely/probably accept the vaccine compared to % of white americans. a human factor-centered vaccination campaign is needed to address these issues, but this campaign must be effectively planned and implemented. if poorly designed and executed, a covid- vaccination campaign could undermine increasingly tenuous beliefs in vaccines and the public health authorities that recommend them. at the same time, the broad impacts of a successful vaccination program would be considerable. immediate benefits would include interrupted disease transmission; fewer cases, hospitalizations, deaths, and chronic sequelae; and the beginning of reinstated social and commercial exchanges. longer term effects would include improved institutional capabilities to foster vaccine confidence among diverse communities, enhanced public understanding regarding vaccination's value to society, and heightened public trust in government, science, and public health. the purpose of this article, which is based on a report on the same topic [ ] , is to outline the major challenges and opportunities associated with a future covid- vaccination campaign and to provide empirically-informed recommendations to advance public understanding of, access to, and acceptance of vaccines that protect against sars-cov- . with the current lag time in vaccine availability, vaccination planners and implementers in the us and around the world have the opportunity to exercise foresight and take proactive steps to overcome potential hurdles to vaccine uptake and maximize public acceptance. these steps, however, must be taken now before this critical window of opportunity closes. the research and recommendations presented in this paper are a product of the -person working group on readying populations for covid- vaccine (table ) . this group was convened in april by principal investigators from the johns hopkins center for health security and the texas state university department of anthropology with support from the national science foundation-funded converge initiative [ ] . the purpose of the working group was to develop and disseminate recommendations informed by design thinking and evidence from social, behavioral, and communication sciences, that would support realistic planning for a us covid- vaccination campaign. members of the working group-listed as authors on this paper-included national figures in public health and social science with research, policy, and practice expertise in vaccinology, vaccine hesitancy/confidence, health disparities, infectious disease, bioethics, epidemiology, bioinformatics, public health law, pandemic mitigation, public health preparedness, mass vaccination campaigns, community engagement, and crisis and emergency risk communication. a combination of literature reviews on vaccination, pandemic planning, and health crisis communication; an assessment of current news and social media trends regarding covid- vaccines; and key informant interviews with each working group member focusing on their respective expertise formed the basis of the research presented in this article. this research was refined, and the recommendations were developed, through an iterative process involving the development of draft reports by a core working group, feedback from the entire working group via email and comments provided during a virtual meeting on may , , and subsequent rounds of revisions and feedback (including a second virtual meeting on june , ). the final report from the working group, which forms the basis of the recommendations and best practices below, was finalized on july , . envisioned largely as a biotechnology and logistics challenge, covid- vaccination also poses complex human factors challenges. such challenges have been observed during past emergencies. in , for instance, many americans rejected the h n vaccine due to safety concerns [ ] , despite the fact that the vaccine only involved a strain change (i.e., it was not a new technology) and was fully tested before release. the h n vaccine also amplified perceptions of bias. in los angeles, for example, distrust in public health-resulting from both prior experimentation on blacks (e.g. the tuskegee syphilis study) and long-term discrimination of blacks in health care settings [ ] [ ] [ ] -led local faith-based leaders, radio personalities, and other community representatives to advise black community members to avoid vaccination [ ] . even though the los angeles county health department actively sought to address these concerns, these suspicions coupled with a lack of convenient access to h n vaccines ultimately resulted in many blacks in this community remaining unvaccinated [ ] . despite the existence and importance of such challenges, funding for research on human factors related to vaccine acceptance is not commensurate with its significance for vaccination success [ ] [ ] . this type of inquiry-practical research of a social and behavioral nature on a medical technology-generally falls between the priorities of the national institutes of health ([nih] which rarely funds social science research) and the national science foundation (which does not fund applied public health research). funding from other sources including the centers for disease control and prevention (cdc) and private foundations has also historically been limited. in addition, the existing funding infrastructure is not outfitted for rapid response research during dynamic crises like sars-cov- . while initiatives are underway to develop communities of practitioners and a supportive infrastructure for disaster science in the us, including professional networks, streamlined institutional review board processes, and joint responder-researcher training [ ] [ ] , more progress is needed especially in regards to rapid funding opportunities. in the case of sars-cov- vaccination, for instance, while an nih funding opportunity award that could support research on human factors related to vaccine acceptance was made possible in june , the earliest project start date is september , a full nine months after operation warp speed plans for covid- vaccines to become available [ ] . to ensure a successful covid- vaccination campaign, it is necessary for sponsors to invest in time-critical investigations on human factors related to vaccine acceptance, and for public health authorities and other stakeholders to act on the social and behavioral findings of this research. such efforts include:  reconfiguring existing research investments to include social, behavioral, and communication science. one possibility for this is to set aside a small portion of the operation warp speed budget for research on human factors related to vaccine acceptance. such an approach has been used with great success in the past with other cutting-edge scientific initiatives such as the human genome project and manned space flight [ ] [ ] [ ] .  embeding rapid social, behavioral, and communication science within the covid- response, helping to deliver timely data and empirically based advice. by including social scientists in planning and implementation efforts, their people-centered methodologies and specialized knowledge can be integrated in a timely manner to maximize critical insights [ ] [ ] [ ] [ ] [ ] .  transforming the vaccine research enterprise by involving communities as active partners not passive subjects. traditional "one-sided, top down" approaches to community engagement are not always effective. community partnerships during the west africa ebola outbreak, for example, were necessary to overcome issues of trust and produce needed behavioral changes [ ] [ ] .  applying human-centered design principles (aka "design thinking") to the planning and implementation of the covid- vaccination program. user-focused approaches can result in more usable, acceptable, and effective interventions compared with traditional expert-driven methods [ ] [ ] . such an approach has been very successful in promoting hpv vaccination [ ] . vaccines typically require years of development and testing before licensure. nonetheless, us political leaders have publicly promised to accelerate covid- vaccine development at "an unprecedented pace," with the aim of delivering million doses of a safe and effective vaccine by january [ ] . although the use of new technologies can potentially accelerate vaccine production, public expectations around vaccine availability may not align with the practical realities of vaccine development, licensure, manufacture, and distribution. by failing to deliver sars-cov- vaccines as promised, the us government could frustrate pandemic-weary communities, siphon away trust, and suffer a major loss of institutional legitimacy. this situation is further complicated by public perceptions of the risks and benefits of sars-cov- vaccines. recent polling suggests that increasing numbers of americans plan to reject covid- vaccines, even if they are available and affordable [ , ] . a review of news reports, blogs, and other social media suggests a variety of potential causes for this result, including nonchalance about the disease and concern about vaccine safety. public perception, however, is a moving target. new developments, for example, an emergency use authorization (eua)-a power granted to the food and drug administration (fda) to make unlicensed drugs, vaccines, or other therapeutics available during a public health emergency, provided sufficient evidence that the countermeasure in question "may be effective"-for covid- vaccines, could engender additional uncertainties around vaccine safety due to the public's lack of familiarity with this complex regulatory mechanism. whatever the public's beliefs about vaccine benefits, risks, and supply, they cannot be separated from the current cultural milieu. in the us this is currently characterized by division, partisanship, and eroding public trust in government institutions-including the biomedical and public health agencies tasked with overseeing vaccine development, licensure, and distribution. in relation to the latter, for example, the intellectual independence of the fda has come under scrutiny for its ability to objectively assess vaccine safety and efficacy amid immense political pressure to quickly approve a sars-cov- vaccine [ ] . this complicated social environment poses a distinct and unprecedented complication to all vaccine promotion efforts in the us. amid this increasingly complex social landscape, there are several measures that us public health and healthcare practitioners, political leaders and policymakers, and communication experts can implement to prime the general public for sars-cov- vaccines including:  tempering expectations of vaccines as a "quick fix." because covid- vaccines will not immediately be available to everyone who wants them, and time will be needed to develop immunity (especially given the likelihood of two-dose regimens), communicators must prepare the public to continue implementing a mix of protective actions and harm reduction strategies.  forecasting a range of vaccine possibilities: from best case to worst case scenarios regarding vaccine supply and effectiveness. from a position of openness and transparency, public health communicators should address inevitable roadblocks and bottlenecks at every stage of vaccine testing, licensure, distribution, and administration, and convey to the public how this could affect vaccine availability. in addition, it will be necessary to reframe the dialogue about the value of vaccines, given that future sars-cov- vaccines may be not be the public's hoped for silver bullet. a vaccine, for example, may prevent the most severe disease but not prevent sars-cov- infection. in this scenario, vaccination could keep hospitals from being overwhelmed, prevent declines into frailty after severe bouts of disease, and avert medical bankruptcies that may arise with the longer-term impacts of covid- , but not provide the community immunity necessary to halt the spread of sars-cov- .  persisting in transparency around vaccine safety systems and actively work to protect their integrity. health authorities should focus existing vaccine safety infrastructure on the use of sars-cov- vaccines. in this vein, health authorities should develop a robust system for post-licensure surveillance, including ascertaining background rates of anticipated adverse events prior to vaccine rollout to enable comparison with post-rollout incidence of adverse events. independent oversight of vaccine safety, as occurred during the - h n pandemic, should also be used [ ] .  early on, seeking the counsel and input of communities of color that may have historic reticence towards public health. vaccine promotion efforts should engage these communities early and as frequently as possible. as partners in the task, they must also empathize with legitimate concerns around vaccine safety, medical experimentation, and inequalities in health care [ ] [ ] , while also identifying and sharing salient information that can help assuage unwarranted worry. a profusion of true and false information, which the who recently referred to as an "infodemic" [ ] , is now circulating around covid- . in this crowded information landscape, the veracity of information can be difficult to determine and key messages can be lost. in the us, public discourse on the pandemic currently incorporates a panoply of topics including science, public health, social disruptions, political divisions, and economic fallout [ ] , each of which can be a vehicle for misinformation-information that differs from expert consensus at the time it is shared [ ] . while many reasons exist for this flood of misinformation, including the widespread public adoption of social media platforms as a tool for information seeking, the uncertain nature around covid- as a novel infectious disease, and the presence of disinformation campaigns aimed at deflecting blame and pushing false narratives around the global covid- response [ ] [ ] [ ] , no easy solutions exist to stem the tide [ ] [ ] . regarding covid- vaccination specifically, while the first vaccine is minimally months away from materializing, the topic has already commanded immense public attention and generated its own pool of misinformation [ ] [ ] . this ranges from rumors questioning vaccine safety to more complicated narratives suggesting that future covid- vaccines were created alongside the virus and that major organizations are planning to use a covid- vaccination campaign for financial gain [ ] [ ] . while not the sole factor in determining behavior adoption, effective communication is necessary to address these issues and build public confidence in covid- vaccination [ ] . such communication will require addressing the enduring problem of how to best engage, exchange information, and empower audiences who have diverse beliefs and life circumstances. past communication experience with vaccines has shown the importance of engaging with key audiences to understand their concerns, values, attitudes, perceptions, and beliefs [ ] [ ] [ ] [ ] , and using this understanding to develop messages that resonate [ ] [ ] . messages that do not do this are often ineffective and, worse, can move audiences further away from the desired behaviors [ ] . given the diverse nature of social identities in the us, covid- vaccination communications will need to be tailored to meet the needs of specific audiences including essential workers, parents, groups with high comorbidity rates, and communities of color.  investing in qualitative research to identify specific community concerns and hopes in relation to covid- vaccination. qualitative research can provide insight into "how" and "why" participants feel, think, or behave a particular way [ ] [ ] . such insight, in turn, is the basis for developing more meaningful, trusted, and influential communication strategies [ ] . the current climate of racial, political, and economic division in the us has created a charged environment that necessitates both a fair vaccination campaign and widespread, public recognition of its fairness. an initial test of this will be how limited, initial doses of vaccines are allocated. in past public health emergencies, including the - h n pandemic, allocation strategies have been used to prioritize delivery of medical countermeasures to specific groups like critical health care workers and those who are at particular risk [ ] . pervasive racial biases in the us healthcare system, including lack of insurance and a lesser quality of care for non-white, rural, and low-income populations [ ] [ ] [ ] . such disparities have long-term consequences. black populations in the us, for example, experience increased morbidity and mortality compared to their white peers, sometimes in ways that cannot be accounted for by access to health care and income [ ] . public health authorities will need to anticipate and mitigate public discourse regarding vaccine allocation and distribution along with prejudicial ideas about social worth, explaining that vaccinating individuals residing in the us, regardless of social or legal status, is critical to the public's health as a whole. finally, politicization of the pandemic-both real and perceived-may prime expectations of a partisan-based vaccine allocation and distribution rather than an equitable one. some americans, for instance, perceive the use of masks as a slight against president trump by his detractors [ ] . likewise trump has signaled his preference for having a vaccine available prior to the election (a projection not in keeping with expert assessments), prompting concerns about whether he could turn a potential but inadequately tested vaccine into a campaign tool [ ] . such polarized views of covid- raise concerns about whether vaccine allocation and distribution can and will be judged as fair by the majority of americans. people will judge a covid- vaccination campaign's integrity not simply on biomedical merits, but on matters of fairness and equity-that is, have people received their just portion of health services, and has disease prevention, ultimately, been fairly distributed? past experience suggests the following steps may contribute to a fair process:  the us government taking steps to make the vaccine available at no cost to all americans and publicly pledge that everyone who wants covid- vaccines will get covid vaccines. removing cost as a barrier is among the most significant ways to assure that all individuals benefit from the life-preserving benefits of sars-cov- vaccines, and that the public can have the utmost confidence that public health needs and not economics will determine access. in the time that exists before vaccines are produced it is critical that safe and accessible vaccination sites are identified. this process will require ramping up the use of sites that are already available and accessible, but are used less frequently for vaccination efforts. community pharmacies, for example, are widespread and have been mobilized for past vaccination efforts [ ] . to fully utilize pharmacies in covid- vaccination efforts, however, it will be necessary to address state-level policies that may currently preclude pharmacists from administering these vaccines without standing orders from physicians. other nontraditional, potential vaccination settings that should be considered include grocery stores, senior citizen centers, workplaces, and schools [ ] [ ] [ ] [ ] [ ] . in some cases, it also may be acceptable and feasible to deliver vaccination via home visits by community health nurses when vaccination is bundled with delivery of other preventive health services; this approach has received a strong recommendation in the past from the community preventive services task force [ ] . for marginalized populations, including racial and ethnic minorities, additional consideration must be given to what constitutes a "safe" vaccination site. during the - h n pandemic, for example, mistrust and fear among marginalized communities posed a challenge. latino farmworkers were at greater risk for h n -related morbidity and mortality. however, reports of bullying and harassment within and outside of local healthcare settings led many members of this population to be fearful and hesitate to seek out h n vaccination [ ] . while national patterns may exist, assessments of what constitutes safe vaccination sites for marginalized populations should be conducted at local levels. once vaccination sites are identified, it will be essential for public health authorities to disseminate up-to-date, comprehensible, and trustworthy information about vaccination opportunities. much of this communication work will be done by local and state health departments, which may be challenging in light of budget cuts and strained local public health infrastructure. an additional complication will be the likely complex covid- vaccination environment, characterized by multiple manufacturers, multiple vaccine doses, and differently timed follow-up doses. making vaccines widely accessible is a complex endeavor. past experience suggests that this is possible with proactive, thoughtful coordination and clear communication like the following:  utilizing nontraditional vaccination sites like schools, pharmacies, places of worship, workplaces, grocery stores, health departments, mass vaccination clinics, senior centers, home visits, and others. utilizing these sites, as well as clinical sites that already serve vulnerable or underserved populations (e.g., free/low cost community health care clinics, std clinics, substance use treatment centers) will be important to improve uptake in populations that outreach efforts have failed in the past.  preparing, in advance, all necessary educational materials and training that may be needed for those tasked with vaccination at nontraditional sites. training may include information on how to look up immunization records in state immunization registries, how to safely store vaccines, and how to safely recommend vaccines for targeted populations, keeping in mind any contraindications.  anticipating hesitancy among marginalized populations who may be fearful or wary of seeking vaccination at sites that have historically caused mistrust, and plan to either expand sites to better serve these populations or engage these populations early to earn and build trust. this may require using novel sites to better serve marginalized populations (e.g., places of worship, schools, culturally specific community centers or senior centers, mobile clinics). these nontraditional settings will also require those administering vaccines to be culturally competent. vaccination sites should not be heavily policed or send any signals that they may be somehow unsafe for vulnerable persons.  fostering collaboration among interagency and nongovernment partners to make vaccination available alongside provision of other safety net services. bundling services that address individuals' broader needs during the pandemic (e.g., food security, rent assistance, workforce development) could be a way to build trust, streamline vaccine provision, and enhance more convenient access for community members. the protracted covid- pandemic has placed multiple stresses on the american people: the threat of illness and death, the isolating effects of physical distancing measures, and the uncertainties and hardships associated with disrupted economic and schooling activities. the public's patience is understandably wearing thin. operation warp speed is taking revolutionary steps to develop sars-cov- vaccines as swiftly as possible and, along the way, to inspire hope that relief from the pandemic's multiple burdens is coming. despite vaccination's promise of release from the confines of the pandemic, some members of the us public-including those most at risk of covid- 's impacts-are already reluctant to embrace this public health measure [ ] . likewise, current protests against nonpharmaceutical interventions to the sars-cov- crisis, including criticisms about government over-reach, encroachment on individual freedoms, and a clash of personal values, have the potential to further erode public trust in future sars-cov- vaccines. under these circumstances, bold measures are necessary to instill public trust and to change the reality and the perception that covid- vaccination is a top-down program administered without regard to public sentiment, concerns, or priorities. one potential solution to these issues is the formation of public oversight committees at state and, in large metropolitan areas like new york and los angeles, local levels. governance structures that incorporate public oversight and community involvement have the potential to inspire greater public confidence in, and a sense of ownership over, public health interventions. such "ownership" can fortify the intent to vaccinate and strengthen distribution systems to reach throughout communities, thus helping to assure the fitting and fair use of a public good. this type of community engagement entails the collaboration of affected and at-risk populations with policymakers and practitioners in the generation, implementation, and evaluation of measures to safeguard public health and safety [ ] [ ] [ ] . an accountability mechanism and metrics will be necessary to ensure that allocation is fair, target groups receive vaccine, and underserved populations that have been disproportionately affected during the pandemic are justly attended. while vaccines represent a promising solution to the covid- pandemic, the development of vaccines is only part of the answer. widespread acceptance of vaccines is also needed. this acceptance, in turn, requires more than just making safe and effective vaccines available. it is a complex social endeavor that necessitates deep engagement around the human element, and requires the efforts of us policymakers; federal, state, and local public health officials; private funders; professional and community organizations; university researchers; and nontraditional partners. while the content provided in this article is not all-inclusive of what can, or should, be done to support widespread acceptance of covid- vaccines, the recommendations and best practices outlined here are important for such a vaccination program to be successful. as experts in a wide variety of vaccination-related topics, we fear that unless these critical steps are taken, any future covid- vaccination campaign will be less than hoped for. a worst-case scenario would involve an inability to stop the ravages of the disease and its cascading social and economic effects; further erosion of public trust in government, public health, and vaccine science; and potential threat to other life-preserving and live-enhancing vaccination efforts. that said, a successful covid- vaccination endeavor promises an alternative future: a return to a sense of normalcy, major innovations in vaccine research and operations, and the investment of us society as a whole in making vaccines a public good in which all can share and derive value. establish public oversight committees to review and report on systems affecting public understanding, access to, and acceptance of covid- vaccines usg should sponsor a national panel entity (e.g., nasem) to review, synt best practices for engaging communi allocation, deployment, and commun achieve equity, solidarity, and good h each state (and the most populous cit committee that is demographically re incorporates diverse sectors of societ and faith communities. abbreviations: hcd = human centered design; nih = national institutes of health; nsf = national science foundation; cdc = centers for disease control and prevention; activ = accelerating covid- centers for disease control and prevention. coronavirus disease cases in the us the evidence and tradeoffs for a 'stay-at-home' pandemic response: a multidisciplinary review examining medical, psychological, economic and political impact of 'stay-at-home' implementation in america post-abc poll finds. the washington post department of health & human services. fact sheet: explaining operation warp speed the college of physicians of philadelphia. vaccine development, testing, and regulation coronavirus vaccine tracker. the new york times group on vaccine hesitancy. vaccine hesitancy: definition, scope and determinants understanding vaccine hesitancy around vaccines and vaccination from a global perspective: a systematic review of published literature widespread declines the shares who say they would get a covid- vaccine on behalf of the working group on readying populations for covid- vaccine. the public's role in covid- vaccination: planning recommendations informed by design thinking and the social, behavioral, and communication sciences converge. covid- working groups for public health and social sciences research the public's response to the medical apartheid: the dark history of medical experimentation on black americans from colonial times to the present more than tuskegee: understanding mistrust about research participation implicit racial/ethnic bias among health care professionals and its influence on health care outcomes: a systematic review pandemics and health equity: lessons learned from the h n response in los angeles county public trust in vaccines: defining a research agenda the need for a multi-disciplinary perspective on vaccine hesitancy and acceptance science during crisis: best practices, research needs, and policy priorities converge. converge training modules department of health and human services. nih director's emergency transformative research awards human genome project information archive - . ethical, legal, and social issues the ethical, legal, and social implications program of the national human genome research institute: reflections on an ongoing experiment national aeronautics and space administration preparedness for a high-impact respiratory pathogen pandemic protecting humanity from future health crises: report of the high-level panel on the global response to health crises will ebola change the game? ten essential reforms before the next pandemic. the report of the harvard-lshtm independent panel on the global response to ebola world health organization. implementation of the international health regulations: report of the review committee on the role of the international health regulations in the ebola outbreak and response community-centered responses to ebola in urban liberia: the view from below implementing a novel community engagement system during a clinical trial of a candidate ebola vaccine within an outbreak setting a design thinking approach to effective vaccine safety communication design thinking in health care user-centered design for developing interventions to improve clinician recommendation of human papillomavirus vaccination trump administration announces framework and leadership for 'operation warp speed cnn poll: most americans would be uncomfortable returning to regular routines today could trump turn a vaccine into a campaign stunt national vaccine advisory committee (nvac). h n vaccine safety risk assessment working group coronavirus disease (covid- ) situation report - coronavirus: the us resistance to a continued lockdown. bbc news defining misinformation and understanding its bounded nature: using expertise and evidence for describing misinformation european external action service strategic communications and information analysis division. eeas special report update: short assessment of narratives and disinformation around the covid- /coronavirus pandemic addressing health-related misinformation on social media weaponized health communication: twitter bots and russian trolls amplify the vaccine debate press freedom critical to countering covid- 'pandemic of misinformation': un chief surge of virus misinformation stumps facebook and twitter the new york times anti-vaccination leaders seize on coronavirus to push resistance to inoculation antivaccination activists are growing force at virus protests. the new york times there isn't a covid- vaccine yet, but some are already skeptical about it the epic battle against coronavirus misinformation and conspiracy theories anti-vaccine movement could undermine efforts to end coronavirus pandemic, researchers warn. nature news social construction of the valuebehavior relation the jossey-bass health series. health behavior and health education: theory, research, and practice a comparison of the theory of planned behavior and the theory of reasoned action vaccine education spectrum disorder: the importance of incorporating psychological and cognitive models into vaccine education preserving civility in vaccine policy discourse: a way forward boomerang effects in science communication: how motivated reasoning and identity cues amplify opinion polarization about climate mitigation policies researchers say that the debate over the coronavirus may become more violent focus group methodology: principle and practice qualities of qualitative research: part i american indian/alaska native and russian/ukrainian communities the impact of social networks on parents' vaccination decisions h n influenza vaccination campaign: summary of a workshop series fair allocation of scarce medical resources in the time of covid- the equitable distribution of covid- therapeutics and vaccines racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites racial disparities in exposure, susceptibility, and access to health care in the us h n influenza pandemic national research council (us) panel on race, ethnicity, and health in later life understanding racial and ethnic differences in health in late life: a research agenda state-of-healthcare-in-the-united-states/racial-disparities-in-health-care/; californians required to cover their faces in 'most settings outside the home'. the washington post cdc's h n vaccine pharmacy initiative in the united states: implications for future public health and pharmacy collaborations for emergency response safety and acceptability of pneumococcal vaccinations administered in nontraditional settings national survey of pharmacy-based immunization services safety of influenza vaccinations administered in nontraditional settings centers for disease control and prevention. national and state-level place of flu vaccination among vaccinated adults in the united states flu season polio: an american story increasing appropriate vaccination: home visits to increase vaccination rates stigma, health disparities, and the h n influenza pandemic: how to protect latino farmworkers in future health emergencies community engagement, organization, and development for public health practice community participation for transformative action on women's, children's and adolescents' health on behalf of the working group on community engagement in health emergency planning. community engagement: leadership tool for catastrophic health events key: cord- -xzgfwu a authors: kamin-friedman, shelly title: would it be legally justified to impose vaccination in israel? examining the issue in light of the detection of polio in israeli sewage date: - - journal: isr j health policy res doi: . /s - - -z sha: doc_id: cord_uid: xzgfwu a background: the detection of wild poliovirus in israeli sewage in may led the health authorities to decide that children who had been vaccinated with ipv would also be vaccinated with opv. the decision sought to protect vulnerable israeli individuals who were either not vaccinated with ipv or who suffered from an immune deficiency, to preserve israel’s status as a polio-free country, to prevent the virus’ “exportation” into vulnerable polio-free countries, and to participate in the global efforts toward the eradication of polio. after a massive public persuasion campaign, % of the children born after were vaccinated as well as % of the children residing in central israel. a state comptroller report stated that the ministry of health should draw conclusions from the low compliance rates in certain israeli regions. goals: the article seeks to examine the legal legitimacy of mandatory vaccination in the service of eradicating a contagious disease (as opposed to preventing a pandemic outbreak), which was one of the objectives in the polio case. it more specifically relates to current israeli law as well as to a hypothetical new public health law which would authorize health officials to oblige vaccination and enforce this through the use of criminal sanctions. method: qualitative content analysis through the interpretation of court judgements, laws, legislative protocols, health ministry guidelines and documented discussions of the advisory committee on infectious diseases and immunization. main findings and conclusion: a mandatory vaccination backed by criminal sanctions in the service of the eradication of contagious diseases would probably be perceived as infringing on the constitutional right to autonomy to a greater extent than necessary according to israeli law and case law precedents. there may be some added value inherent in a new public health law which would authorize health officials to oblige vaccination where nonrestrictive measures have been ineffective. however, the law should also specify a variety of sanctions to accompany the enforcement of mandatory vaccinations which would be formulated from least to most restrictive according to the “intervention ladder” concept. the law should also describe the circumstances which would justify the implementation of each and every sanction as well as the procedural safeguards designed for established decisions and fairness toward the individual(s) whose rights are infringed by the application of these sanctions. polio is a severe disease which may cause paralysis. two types of vaccines have been used against it since the s and s: ipvinactivated polio vaccine, which induces humoral immunity but does not prevent intestinal infection, and opvan attenuated oral polio vaccine which induces a local and mucosal immune response in the intestinal mucous membrane and is later excreted. it thus not only protects the individual but can also be spread to others in close contact with the vaccinated individual and induce the "incidental" immunization of people who have not been directly vaccinated. a recipient of an opv or an unimmunized close contact may rarely develop paralytic polio as a result of the vaccine. however, giving an opv to someone already immunized with an ipv is very safe [ ] . israel started vaccinating children against polio in . the immunization schedule changed according to developments in both opv and ipv vaccines and according to epidemiological considerations. after the outbreak of the disease, israeli children were routinely vaccinated with a combination of opv and ipv. the vaccine did indeed significantly reduce polio morbidity. a total of cases of vappvaccine associated paralytic poliomyelitis have been reported between the beginning of monitoring in and , when the last recorded case of vapp was diagnosed. of these were diagnosed in vaccine recipients and in people who were in contact with vaccines [ ] . since there have been no cases of polio in israel for years, and since the who recognized israel as a poliofree country, israeli children have, in accordance with who guidelines [ ] , been vaccinated with ipv alone since . in may , and due to the consistent detection of wild poliovirus in israeli sewage in several sample and growing concentrations, israeli health authorities made efforts to reach unvaccinated children and vaccinate them with ipv. however, these efforts did not stop the environmental spread of the virus. in june , a who delegation to israel, the cdc and the israeli polio committee advised that children who had been vaccinated with ipv since should also be vaccinated with opv. on august , the parents of children in southern israel who were born after were asked to vaccinate them with opv. the recommendation was later extended to cover all israeli parents of children born after since the wild poliovirus had been detected in other areas too [ ] . the objectives of adding opv to israeli children already vaccinated with ipv were the protection of vulnerable israeli individuals who were not vaccinated with ipv or who suffered from immune deficiency, the preservation of israel's status as a polio-free country, the prevention of the virus' "exportation" to vulnerable polio-free countries, and participation in the global efforts toward the eradication of polio. it should, however, be noted that the ipv had been routinely administrated to more than % of israeli children by the time the wild poliovirus was detected in israeli sewage. as ipv decreases both the risk of infection and infectiousness [ ] , its high coverage prevented a polio outbreak in israel [ ] [ ] [ ] . in order to promote compliance with opv, and proceeding from an understanding that the main policy communication challenge would lie in persuading parents to vaccinate their children for the sake of others, the ministry of health initiated a campaign which called on parents to vaccinate their children in order to protect unvaccinated family members using the slogan "two drops and the family is protected" to this end. the ministry of health chose to provide the public with information about the vaccine without sanctioning parents who decided not to vaccinate their children. in choosing this policy, the ministry of health sought to preserve the parents' right for autonomy. a petition against the vaccination campaign later was submitted to the supreme court by an anti-vaccination group. the petitioners claimed that the ministry of health was not providing sufficient information about the nature and the dangers of opv including the fact that the vaccine does not benefit the children who receive it. the court heard the case on august , and recommended that the petitioners withdraw their petition, which they did [ ] . the global polio eradication initiative's independent monitoring board noted that "israel faced a real policy and communications challenge, compounded by the fact that there is a sizable body of anti-vaccination sentiment within the population" [ ]. following a public persuasion campaign, % of the children born after were vaccinated with opv as well as % of children born after and residing in central of israel [ ] . a state comptroller report stated that the ministry of health should draw conclusions from the low compliance rates in certain israeli regions [ ] . achieving optimal vaccination uptake rates troubles health policy makers in both israel and in other countries. the detection of wild polio in israeli sewage demonstrates the necessity for interventions aimed at promoting vaccination compliance in cases where persuasion alone has not given rise to an optimal uptake rate. as was mentioned above, the promotion of compliance with opv had several objectives. however, the following discussion will focus on the legal legitimacy of mandatory vaccination (enforced by criminal sanctions) in the service of the global eradication of polio. this examination is especially important in light of the current public health policy makers' ambition to eradicate contagious diseases as opposed to past interventions which sought to prevent epidemics. the legal issues raised by the analysis would be relevant to interventions in other cases which seek to attain complete eradication. from a wider perspective, the discussion would be relevant to public health interventions in additional fields, as many of them contain an inherent tension between the ambition of promoting public health and the legal obligation to protect individual rights: "achieving a just balance between the powers and duties of the state to defend and advance the public health and constitutionally protected rights poses an enduring problem for public health law" [ ] . a qualitative content analysis research was conducted on relevant court decisions, laws, legislative proceedings, and legislative protocols (all issued or produced between and ). a further analysis was carried out on health ministry guidelines and on documented discussions of the advisory committee on infectious diseases and immunization. the study was initiated by analyzing the aforementioned data which was then linked to the relevant theoretical literature such as to attain a cohesive entity. credibility was established through persistent observation. the justification for government intervention in the service of promoting vaccination compliance and the legal means for such interventions according to l.o. gostin the public in a democratic society authorizes the government to act for the common welfare. the government thus possesses the sole authority to empower, regulate, or carry out activities designed for the protection or promotion of the general health, safety, and welfare of the population [ ] . the iom emphasizes that "there are solid legal, theoretical, and practical grounds for government in its various forms to assume primary responsibility for the public's health" [ , ] . the israel supreme court (justice barak-erez) addressed the issue in the adalah decision which will be described in detail below [ ] , and held that the market failure which derives from individual nonvaccination decisions grounded in the notion of "herd immunity" justifies government intervention. moreover, the israeli basic law: human dignity and liberty ( § ) provides that the government has an obligation to protect the life, body, and dignity of every individual. although the right for health has not been recognized as a basic right, an intervention meant for the eradication of a contagious disease may be considered essential to the protection of human dignity as well as human life and the human body [ , ] . in attempting to promote vaccination compliance, public health authorities can employ such intervention strategies as client reminders or recalls, the enhancement of access to vaccination services, and the provision of information to target populations or vaccination providers [ , ] . however, sanctions against individuals who refuse vaccination require specific legislative authorization. all us states have laws that require vaccination for school admissions. exemptions vary from state to state, although all school immunization laws grant exemptions to children for medical reasons, and almost all states grant religious exemptions for people who have religious beliefs that prohibit immunizations. states also currently allow philosophical exemptions to those who object to immunization on account of personal, moral or other beliefs [ , ] ; in canada, three provinces require proof of immunization for school admissions: ontario, new brunswick and manitoba. exceptions are permitted on medical or religious grounds and for reasons of conscience. australia's new tax system (family assistance) act states that family tax benefits, child care rebates and child care benefits can only be paid for children who meet immunization requirements. a person may have a medical exemption from vaccination if they are undergoing treatment that compromises their immune system. religious or conscientious objection is not an exemption category [ ] [ ] [ ] . israel's advisory committee on infectious diseases and immunization (which advises the israeli ministry of health) discussed the possibility of requiring children's vaccination prior to their admission to the education system in . the committee advised that less intrusive measures should be adopted in order to increase vaccination compliance, and also stated that a mandatory vaccination requirement would not be effective due to enforcement difficulties and the expected number of exemptions that would be granted to parents opposing vaccination. it was therefore decided that a vaccination reminder would be given to all parents who registered their child in an educational institution but that no measures aimed at compelling them to do so would be taken. the possibility of using preschool registration to promote vaccination compliance was re-discussed by the advisory committee on infectious diseases and immunization in january . among other things, the committee discussed the suggestion of requiring a confirmation from a mother and child clinic that the child entering preschool had been vaccinated in the manner recommended by the ministry of health. it also discussed a suggestion requiring parents who oppose vaccination to sign an objection form. both suggestions were rejected by the committee for several reasons: first, israeli law does not permit the requirement of vaccinations as a precondition for education; second, the committee believed municipalities would encounter difficulties in implementing the requirement; and third, there was insufficient evidence to indicate that the implementation of such policies would be efficient and that it would promote vaccination compliance [ ] . the committee agreed that the central vaccination registry (which did not exist at the time) would be used to remind parents to vaccinate their children and to promote vaccination compliance. furthermore, the israeli social security law of was amended in such as to require vaccination in accordance with ministry of health recommendations in order to receive an additional child allowance. ministry of finance representatives supported the financial sanction and emphasized that it had been proven its effectiveness in other countries. ministry of health representatives added that israel's unvaccinated population is the reason for disease outbreaks, and that providing parents with a vaccination incentive might promote compliance [ ] . a petition against the amendment was later submitted to the israeli supreme court in adalah legal center v. the israeli ministry of social affairs and social services ( ). the petitioners claimed that depriving families with an unvaccinated child of the additional child allowance is a violation of constitutional rights. in a decision delivered on . . all three judges agreed that the constitutional right to dignity and the constitutional right to autonomy were not being violated in this case. justice arbel held that the question of whether the right to autonomy was violated should be answered with respect to the nature of the choice being deprived from the individual and the extent of the coercion applied to this end. the law's amendment deprives the families of a small financial benefit and does not impose a criminal sanction on parents who refuse to vaccinate their children [ ] . justice barak-erez clarified that a financial sanction (unlike a criminal sanction) allows parents the freedom of choosing their actions [ ] . as for the constitutional right to equality, justice hayut held that legislators are authorized to relate differently to parents who vaccinate their children as opposed to those who refuse to do so [ ] . justice arbel, on the other hand, was of the opinion that the above distinction is immaterial to the child allowance's initial purposethe assurance of minimal financial conditions for survival, meaning that the right to equality is indeed being violated in this case. nonetheless, justice arbel also concluded that this constitutional right violation complies with the stipulations laid down in the limitation clause ( § of the basic law: human dignity and liberty) specified hereunder [ ] . justice barak-erez did not positively hold that depriving the additional child allowance from families with an unvaccinated child represents a violation of the right to equality, but agreed with justice arbel that the law's amendment complied with the stipulations provided in the limitation clause: the amendment has a proper purpose (to protect unvaccinated children and promote public health); there is high probability that a financial sanction would be effective and promote vaccination compliance; and the intervention is both minimally infringing and proportionate since it has been balanced by the parents' right to opposition and appeal [ ] . however, the additional child allowance was later cancelled, and the amendment to the israeli social security law was repealed by the israeli parliament before its implementation [ ] . the public health ordinance enacted in , is currently the only reference in israeli law to public health interventions. according to § of the ordinance (which was translated from palestine gazette extraordinary no. of th december, -supplement no. ) "in any town, village or area where an infectious disease assumes or is likely to assume an epidemic character or where there exists in the neighborhood infectious disease such as in the opinion of the director constitutes a danger to the public health of such town, village, or area, the director or medical officer may proceed to take such measures to protect the inhabitants thereof from infection as he considers necessary and may for this purpose inter alia subject the inhabitants of such town, village or area to such prophylactic inoculation or vaccination as in his opinion is necessary to limit the spread of infection. any person who willfully refuses to submit to inoculation or vaccination under this section…is guilty of an offence and is liable to a fine not exceeding five pounds or imprisonment for a term not exceeding one month." § of the ordinance is an emergency powers provision which relates to a formidable epidemic, or to an endemic or infectious disease which threatens "any part of palestine" and empowers the high commissioner to order "any such matters or things as may appear advisable for preventing or mitigating such disease", including "the prophylactic inoculation or vaccination of the general public" [ ] . such mandatory vaccination as provided by the ordinance was only imposed twice in israeli history: once in , when israel faced a smallpox outbreak, and once in when a measles outbreak occurred (mainly in the negev region) [ ] . in light of the above, government intervention in the service of promoting vaccination compliance is thus theoretically justified. however, current israeli law does not follow other jurisdictions with respect to the imposition of sanctions on those who refuse routine vaccination but rather only allows the imposition of sanctions in the specific circumstances provided by the ordinance. was it legally legitimate to impose opvs in in accordance with the public health ordinance, ? as mentioned above, the detection of wild poliovirus in israeli sewage led the ministry of health to initiate a massive public health campaign aimed at persuading parents to vaccinate their children with opv. considering the state comptroller's disapproval of the low compliance rates in certain israeli regions, could the ministry of health have legally considered more intrusive measures of imposing opvs in accordance with the ordinance? the term "epidemic," which justifies the implementation of the public health ordinance and the imposition of mandatory vaccination, refers to "the occurrence in a community or region of cases of an illness, specified health behavior, or other health related events clearly in excess of normal expectancy" [ ] . given that the majority of the israeli population was previously immunized against polio with either opv or ipv, and since no morbidity incidences had occurred since , it may be argued that even one case of morbidity would be "in excess of normal expectancy." the question of whether the detection of wild poliovirus in israeli sewage was also a threat to public health is difficult to answer, as the ordinance does not specify the severity of the risk to public health required for its implementation. according to l.o. gostin, only a "significant" risk should be perceived as a threat to public health, as opposed to a speculative, theoretical or remote risk [ ] . the risk of polio contamination in israel in could have been perceived as significant, as polio viruses are highly contagious and spread by the fecaloral route. although the probability of harm as a result of a polio infection is low, the severity of harm that an unvaccinated individual or an individual with a suppressed immune system may suffer (permanent paralysis) is high. nonetheless, it seems that both § and § of the ordinance authorize the health authorities to impose mandatory vaccination when there is a significant risk to the local population and thus they do not relate to legitimate interventions required for the global eradication of a disease. almost all individuals in israel were protected from the clinical polio disease in [ ] , and there was no risk to the local population (as opposed to the risk of a single case of morbidity). hence, both sections of the ordinance could not provide a legal basis for compulsory opv. would it be legally legitimate to impose opvs in accordance with a new public health law? the israeli association of public health physicians along with the israeli medical association recently made efforts toward the legislation of a new public health law which would replace the antiquated sections of the ordinance (in a manner akin to public health law reforms in other countries as "existing statutes are outdated, contain multiple layers of regulation, and are inconsistent" [ ] ). moreover, the minority opinion in the adalah case held that the entire domain of vaccination should be addressed by new legislation [ ] . it is therefore essential to examine the legitimacy of legislation that would authorize the health officials to not only impose mandatory vaccination where there is a significant risk to the local population (or the risk of an epidemic) but also where the intervention seeks to promote the eradication of a disease. the present examination relates to an obligation which, like § of the ordinance, would be enforced by the criminal sanctions of a financial penalty or imprisonment for no longer than a month. any authorization granted to health officials under a new public health law must comply with the provisions of the basic law: human dignity and liberty. this basic law states that no violation of the life, body or dignity of any person should occur except in accordance with the limitation clause, which will be discussed later. the constitutional right to dignity includes, according to israeli supreme court judgements, the right to autonomy [ ] . one aspect of the right to autonomy is parental autonomy, which refers to parents' right and obligation to take care of their minor children. the rational for parental autonomy is the natural bond between parents and children, and the underlying presumption is that parents will generally make the best decisions for their children. moreover, it is appropriate to let parents decide when they are the ones who will bear the consequences of their decisions [ , ] . do mandatory opvs enforced by criminal sanctions violate the right to parental autonomy? the right to autonomy in the medical context is implemented through the requirement of "informed consent" prior to medical interventions. the "informed consent" doctrine consists of two components: the physician's duty to disclose information about the prospects and risks of the procedure (informed participant) and the patient's right to freely consent or refuse to the treatment (informed choice) [ , ] . it may be argued that this liberal interpretation of bioethics which regulates curative medicine and proceeds from an assumption of absolute bodily autonomy does not apply to public health interventions. childress et al. stated that "it would be a mistake to suppose that respect for autonomy requires consent in all contexts of public health" [ ] . while curative medicine deals with the health of an individual, public health interventions deal with the health of a population. a population's interests may sometimes contradict individual interests and justify interventions which do not assure an individual's consent or despite her or his refusal [ ] [ ] [ ] . moreover, it is unrealistic to obtain informed consent to a public health intervention when the health professional cannot predict whether a specific unvaccinated individual will benefit from the intervention in the future. this is because those members of the population who would stand to gain from the intervention are unknown, and their number can only be estimated in advance [ ] . the legitimacy for exercising state power without receiving "informed consent" derives from social contract theory, which suggests that people agree to accept certain obligations by choosing to live in a society. the presumption of obligation acceptance is based on the "tacit consent" of an individual who resides in the state to government rule in exchange for the benefits of society. other sources for the presumption of obligation acceptance are the "hypothetical consent" of an individual to be bound by the state which is necessary for social functioning, as well as a fairness of balancing the state's benefits to the individual against the limits that are necessary for maintaining those benefits [ , , ] . the israeli supreme court decision in the case of juhar aturi v. the israeli ministry of health ( ) related to the duty to disclose vaccine risks, and held that informed consent for vaccination does not require the disclosure of remote and rare side effects. latter israeli court decisions expanded the duty of disclosure in curative medicine but did not relate to preventive medicine and vaccinations. a limited disclosure requirement might lead to a limited requirement for individual consent to vaccination (or a limited implementation of the informed consent doctrine in public health interventions) as any discussion on the duty of disclosure cannot be separated from a discussion on the right to free consent [ ] . nonetheless, the israeli patient's rights law of espoused the "informed consent" doctrine with respect to both the curative medical context as well as preventive treatment. according to the law, medical treatment, which includes preventive treatment, shall not be given to a patient without her or his "informed consent." a decision by the israeli district court related specifically to vaccination and clearly stated that the "informed consent" requirement applied to a decision on vaccination just as it applied to a decision on any other medical procedure [ ] . the supreme court's decision in the adalah case addressed the circumstances in which the parental autonomy to determine whether or not their children should be vaccinated was violated. the court related to obligatory vaccination enforced through criminal sanctions (whose legitimacy is examined here in the opv context) as hard paternalism (unlike the deduction of an additional child allowance which is soft paternalism). as such, the court held that it violated the right to parental autonomy [ ] . can the violation of parental autonomy be justified in the circumstances? according to john stuart mill, the right to autonomy or parental autonomy (although applicable in public health interventions) is not unlimited: persons should be free to think, speak and behave as they wish, provided they do not interfere with a like expression of freedom by others ("the harm principle") [ ] . l.o. gostin interprets this as suggesting that personal freedoms extend only so far as they do not intrude on the health, safety and other legitimate interests of other individuals. persons, according to gostin, are entitled to live without the risk of serious injury or disease [ , ] . the famous u.s. court decision in jacobson v. massachusetts ( ) followed the millian doctrine and justified a law that mandated vaccination despite restricting liberty: in , massachusetts was the first state in the u.s. to compel vaccination against smallpox. according to the state law, any refusal to the smallpox vaccination resulted in penalties ranging from fines to imprisonment. henning jacobson refused both the vaccination and the payment of a $ fine. jacobson argued before the u.s. supreme court that the massachusetts law violated the due process and equal protection provisions of the fourteenth amendment ("nor shall any state deprive any person of life, liberty or property without due process of law.") jacobson further alleged that it was unreasonable for the state to interfere with his liberty when he had not been taken with any illness. the us supreme court decided in favor of massachusetts in , declaring that the state had the authority to enact health laws of every description to guard the common good in whatever way the citizens, through their elective representatives, thought appropriate: "even liberty itself, the greatest of all rights, is not [an] unrestricted license to act according to one's own will" [ ] . the violation of parental autonomy can be justified according to israeli law if it complies with the stipulations mentioned in the limitation clause ( § of the basic law: human dignity and liberty): the infringement is carried out according to a law befitting the values of the state of israel, is enacted for a proper purpose and to an extent no greater than is required. is a law which authorizes health officials to mandate opvs in order to eradicate polio enacted for a proper purpose? health economists have justified interventions aimed toward increased vaccination coverage through cost-benefit, cost-effectiveness and cost-utility analysestechniques for quantifying and measuring the value of an intervention by weighing the likely costs, including the consequences of adverse events, against the potential positive outcomes. given that the eradication of contagious diseases reduces medical care expenses and adds years of productive life to members of society for a small per-person cost, an increased compliance with opvs with a view to the eradication of polio is considered a proper purpose according to the aforementioned economic-theoretical methods [ , ] . however, economic methods, which help in the determination of public health policy, and especially in cases of limited public health resources, do not reflect moral considerations and preferences that may also justify the violation of individual autonomy. one of these moral considerations is social justice, which is a commitment to the attainment of a sufficient level of health for all [ , ] . the eradication of polio such as would protect the unimmunized population correlates with these social justice values. moreover, the syrian civil war that was still raging in made it increasingly more difficult for syrians to access medical services and vaccines. many syrian residents and refugees were not vaccinated against polio and were at risk of poliovirus infection. the promotion of polio eradication in the region under these circumstances would have the potential of protecting the vulnerable syrian population. protecting population health (as opposed to community health) without national or geographical limitations correlates with the "global justice" which is required in a globalized world where communicable diseases can easily cross borders [ ] . the promotion of polio eradication in israel may also be considered a proper purpose that would justify the infringement of individual autonomy given that the gpeithe global polio eradication initiative spearheaded by national governments, the who, rotary international, the u.s. cdc and unicef supported by the bill and melinda gates foundation have striven toward the eradication of the disease since [ ] . israel is thus morally and politically obliged to participate in the global effort toward the eradication of polio. another case in which a disease was declared as a global health threat by the who was when severe acute respiratory syndrome (sars) was diagnosed in people in countries and caused deaths. china, in which the disease had first been diagnosed, was criticized by the who and by other countries for delays in reporting cases and for a lack of cooperation with the who [ , ] . israel would thus not be able to risk its position as a developed country which cooperates with the global effort toward the eradication of polio. the term "no greater than required," which justifies an intervention despite potentially violating the right to autonomy relates to sub-terms: the effectiveness of the intervention (rational connection); the least infringing intervention, and the proportionality between the benefits from the intervention and the concomitant infringement of human rights. would a mandatory opv be an effective intervention and promote the eradication of polio? in order to determine whether a mandatory opv enforced by criminal sanctions would be an effective intervention, it is necessary to clarify when an intervention meant for the promotion of opv compliance would be considered "effective". as was mentioned above, the ministry of health advised all israeli parents to vaccinate children who were born after with opv in . the public health campaign which followed this recommendation sought to attain maximum compliance. however, the state comptroller criticized the ministry of health for low compliance rates since % of the children born after were vaccinated as well as only % of those children born after and residing in central israel. this begs the question of whether an intrusive intervention would result in higher compliance rates. in this respect, it should be noted that israeli case law suggests that there is no need to prove that the intervention would surely attain its objective, and that it suffices to prove reasonable probability [ ] . the effectiveness of compulsory opvs in israel depends by and large on the reasons for low compliance. low compliance rates which derive from the vaccination hesitancy of israeli parents who seek an open and trusting relationship with their health care providers and who wish to make autonomous decisions regarding vaccination would not be increased by sanctions [ , ] . sanctions would also be certain to provoke israeli parents who already believe that the government is too intrusive with respect to their freedoms as well as parents who are convinced that the vaccine would endanger their child . beside concerns that sanctions would not stimulate hesitant parents as well as parents who oppose government interference, the sanctions' effectiveness would likely be reduced by enforcement difficulties: imposing the obligation to follow, register and report the immunization status of every israeli child would require additional budgetary allocations to the health system. the lack of such an additional budget would interfere with the attainment of the stated objective. over and above budgetary shortfalls, the imposition of sanctions on parents who refuse to vaccinate their children also involves legal and ethical issues associated with the registration of unvaccinated children. the israeli privacy protection law ( ) forbids the disclosure of an individual's private matters (including medical information), although a violation of this privacy is permitted when it is done in accordance with a valid legal provision. the public health ordinance (in § b) authorizes the minister of health to establish a national immunization registry and thus legitimizes the disclosure of vaccination statuses [ ] . however, the ethical dilemma that exists between the violation of healthy people's medical confidentiality and the promotion public health remains and requires an in depth discussion in and of itself. moreover, the registry's legal objectives were the supervision of vaccines administered at public mother and child clinics, hmos (health maintenance organizations) and schools as well as the implementation of § of the national insurance law, which deprived an additional child allowance from the nonvaccinated. the implementation of child allowance reductions is no longer relevant as the associated legal amendment has been repealed. the registry's sole objective at present is thus the supervision of the vaccines administered to the population. using these records in order to impose sanctions on unvaccinated children would deviate from this objective and would very likely provoke opposition [ ] . is a mandatory opv enforced by criminal sanctions the least autonomy-infringing intervention? if we were to overcome parental opposition and enforcement difficulties, and conclude that a mandatory opv would be an effective intervention for promoting compliance and eradicating polio, we must examine whether the enforcement of opvs through criminal sanctions would also be the least autonomy-infringing intervention from an effectiveness perspective. according to childress et al. [ ] , "the fact that a policy will infringe a general moral consideration provides a strong moral reason to seek an alternative strategy that is less morally troubling". reviews of evidence regarding interventions which sought to improve vaccination coverage in children, adolescents and adults, hold that strong scientific evidence supports the assumption that non-intrusive interventions (i.e. client or provider reminder/recall or expanded access to health care settings) can be effective enough in improving vaccination coverage [ ] . in the adalah case [ ] , both justice arbel and justice barak-erez held that deducting an additional child allowance from parents who refuse to vaccinate their children is the least infringing intervention that would promote vaccination compliance, and that a criminal sanction would surely be more intrusive. however, the aforementioned reviews of evidence and the adalah decision relate to routine vaccinations which aim to protect the individual and ensure herd immunity, and do not relate to vaccines recommended for disease eradication where there is no risk of a local outbreak. expecting parents to expose their children to vaccination in order to eradicate a disease worldwide has low prospects given the extent of the expected opposition for an intervention with such remote outcomes. it may therefore be argued that a mandatory opv backed by criminal sanctions would be the least autonomy-infringing intervention necessary for attaining a high degree of compliance. nonetheless, the health authorities must conclude that educating the public regarding all aspects of the importance of polio eradication, including the negative political outcomes of a refusal to participate in the global polio eradication initiative, is ineffective before implementing sanctions (let alone criminal sanctions) against parents who refuse to vaccinate their children with opv. the obligation to use non-intrusive measures before enforcing vaccinations through sanctions accords with the concept of therapeutic jurisprudence (tj), which suggests that legislation should be the last resort after the public has been provided with relevant information such as to build trust and promote compliance [ ] . the requirement of proportionality the discussion above relates to a new public health law that would authorize health officials to enforce a mandatory vaccination in the service of promoting disease eradication and to enforce this obligation throughout a financial penalty or imprisonment of no longer than a month. a financial penalty (unlike the deprivation of freedom) might be considered as a tool for prompting action. however, the proportionality of a decision to convict an individual who refuses vaccination requires a clearing of this individual's criminal record once she or he complies with the obligation to vaccinate. moreover, this provision must also include a procedure which would discuss requests for exemptions. in this respect the granting of exemptions in cases of medical contraindications alone would not diminish the law's proportionality (as the granting of religious or philosophical exemptions might render the law ineffective). nonetheless, a decision to enforce a mandatory opv by a financial penalty in the service of globally eradicating polio even if the aforementioned stipulations are met, might be perceived as incompatible with the violation of the parental autonomy to refuse to altruistically vaccinate a healthy child who is not at risk for a clinical disease (not only was there no risk of a polio outbreak in israel in , but the opv vaccination recommendation was also given to children who had already been vaccinated with ipv and had possessed humoral protection against polio). enforcing the vaccination through a "softer" sanction (i.e. the deprivation of some child benefitsas was suggested in in order to promote compliance with routine vaccination in israel), might not attain a maximum degree effectiveness but would provide parents with the genuine discretion of deciding whether or not to participate in the global eradication efforts, and may thus be considered as proportionate to the concomitant violation of parental autonomy [ ] . the global ambition of eradicating contagious diseases and totally preventing morbidity requires health authority interventions in order to promote vaccination compliance. an examination of the legal legitimacy for a mandatory opv accompanied by criminal sanctions in the service of polio eradication reveals that such intervention would infringe autonomy to an extent greater than required: although eradication is a proper purpose, criminal sanctions might not be effective and may even provoke resistance. moreover, and even if we were to overcome parental opposition and enforcement difficulties, criminal sanctions would still not be the leastinfringing intervention when a public education campaign would achieve the intervention's objectives, and would not be proportionate when the recommended vaccine has remote benefits. the appropriate intervention for promoting vaccination compliance in the service of eradicating contagious diseases should start with nonrestrictive measures such as enhancing the accessibility of vaccination, providing the public with complete and relevant information about the vaccine, or offering incentives to parents who comply with vaccination recommendations. however, in situations where nonrestrictive measures would not suffice in the attainment of health authority objectives, there may be some added value inherent in a law which would authorize it to enforce a mandatory vaccination. such a law should also include several sanctions meant for the enforcement of obligatory vaccination, i.e., tiers of financial sanctions, and the establishment of a criminal record or the quarantine of individuals who refuse vaccination. according to the "intervention ladder" theory [ ], these sanctions should be formulated from least restrictive to most restrictive. such a formulation would in turn require the evaluation of the extent of intrusiveness inherent in every such sanction by experts in law and ethics. the suggested law should further describe the circumstances which justify the implementation of every sanction: a disease in close proximity represents a risk to public health as a significant part of the population is unimmunized; it is necessary for the promotion of compliance with routine vaccination; or the who recommends that the population be vaccinated in the service of promoting global objectives. health authorities should also be granted the discretion to decide on the least restrictive sanction in unexpected circumstances. the terms employed by legislators must also be interpreted. in this respect, and if the law only justifies criminal sanctions when the virus represents a risk to the population, then the term "risk" requires the clarification of its severity and nature, and the term "population" requires the clarification of its geographic borders. the core of the new law should also contain a description of the decision-making process which must be based on facts and which must assure fairness to the individual whose rights are being infringed [ ] . finally, the public should be entitled to participate in the decision-making process or at least be allowed to follow its fully transparent proceedings, since the acquisition of public justification would diminish public resistance to the intervention and consequently increase its effectiveness [ ] . endnotes in environmental samples taken in egypt, israel, the west bank and gaza strip following a polio outbreak in syria. it was noted that a multi-country response was needed despite the fact that polio cases had only been detected in syria, given the ongoing civil war in this country and the mass displacement of its population into neighboring countries. "the primary goal is to ensure that oral polio vaccine (opv) is urgently delivered into all communities" [ ] . sanctions applied against those who refuse vaccination (depriving the right to education) in the us resulted in increased immunization rates [ , , ] . however, given that the majority of the population in israel complies with vaccination recommendations voluntarily, and in light of israeli parents' motivation toward making autonomous decisions, the imposition of a mandatory vaccination may result in resistance and attain the opposite of its intended purpose [ , ] . the enactment of the vaccination act in england ( ), which imposed fines on parents who failed to allow their children to be vaccinated, led to riots in the streets and to serious protests made not only by those opposing the vaccination itself but also by opponents of government intrusion on personal autonomy [ , ] . the work of ensuring that all us students were vaccinated according to school admission laws required the cooperation of both health and education administrators with different priorities. school principals had difficulty keeping track of students' medical records and claimed that budget shortages prevented the implementation of enforcement measures [ ] . gostin suggests that adoption of equally effective and less restrictive alternatives would also encourage voluntary compliance [ ] . imposing tort liability on parents who refuse to vaccinate their children may also encourage vaccination. however, such liability may only be imposed when the parents' choice of non-vaccination results in harm to others. proving that a particular unvaccinated child transmitted a disease to another and caused harm can be a difficult and in some cases an even impossible task [ ] . in the adalah case, justice barak-erez (in ¶ of the court's decision) held that public education was essential to promoting compliance with vaccination, and referred to alberstein m, davidovitch n. .therapeutic jurisprudence and public health: israeli perspectives. bar ilan studies. ; : , which called for the implementation of therapeutic jurisprudence in public health [ ] . the minority opinion in the adalah case considered the partial deprivation of child benefits as a financial sanction which would be legitimate as part of a general piece of legislation that would address vaccination issues [ ] . according to the nuffield council of bioethics, the "intervention ladder" relates to public health interventions in general, and includes both intrusive and nonintrusive interventions which do not require legislation. the law should clarify the risk which justifies a certain sanction according to the mode of transmission, the risk's duration, the probability of harm and the severity of harm [ ] . the israeli mental healthcare law , which replaced a former law passed in , is an example of a statute that balances society's interest in protecting the individual or the public from the symptoms of mental illnesses against the need to promote human rights and individual autonomy. among other things, the law provides for limited psychiatric discretion in the imposition of forced hospitalization, and further provides for the option of appealing a psychiatric decision, as well as the entitlement to legal counseling (for the individual facing hospitalization). introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. recommendations of the advisory committee on immunization practices (acip) cdc -mmwr the epidemiology of polio in israel -a historical perspective position paper on polio vaccines and polio immunization in the preeradication era the two drops campaign against polio which was conducted in israel in herd immunity: a rough guide gamzo: if it was up to me an unvaccinated child would be expelled from nursery school nevo legal database isr. -state response to the petition and attached who document -wild poliovirus tranmission in southern israel: assessment and response options -main findings and recommendations of a who support mission - polio vaccination completion. israel ministry of health the israeli public health response to wild poliovirus importation report on child, adult and health care workers immunization. state comptroller's public health law power, duty, restraint the future of the public's health in the st century. institute of medicine. the national academies press the israeli ministry of social affairs and social services. nevo legal database isr in search of the right to health in israeli constitutional law reviews of evidence regarding interventions to improve vaccination coverage in children, adolescents, and adults financial incentives for childhood immunization national conference of state legislatures -\ states with religious and philosophical exemptions from school immunization requirements state of immunity: the politics of vaccination in twentiethcentury america compulsory vaccination and conscientious or philosophical exemptions: past, present and future australian government department of social services. strengthening immunisation for young children advisory committee on infectious diseases and immunization. using registration to state-run nursery schools as a tool for promoting compliance with routine vaccination. ministry of health hcj / adalla legal center v. the israeli ministry of social affairs and social services. nevo legal database isr hcj / adalla legal center v. the israeli ministry of social affairs and social services. nevo legal database isr hcj / adalla legal center v. the israeli ministry of social affairs and social services. nevo legal database isr hcj / adalla legal center v. the israeli ministry of social affairs and social services. nevo legal database isr hcj / adalla legal center v. the israeli ministry of social affairs and social services. nevo legal database isr palestine gazette extraordinary no. of therapeutic jurisprudence and public health when is an epidemic an epidemic? public health law reform hcj / ganem v. the israel bar association. nevo legal database isr lca / attorney general of israel v. zeev acer and beverly cohen. nevo legal database isr a history and theory of informed consent all for one and one for all: informed consent and public health public health ethics: mapping the terrain public health and bioethics public health ethics: from foundations and frameworks to justice and global public health ca / juhar alturi v. the israeli ministry of health ( ) pd isr dc (bs) / haliva eyal v. the israeli health department. nevo legal database isr on liberty private choice versus public health: religion, mortality and childhood vaccination law retaining, and enhancing, the qaly. value health economic analyses of vaccine policies social justice -the moral foundation of public health and health policy what does social justice require for the public's health? public health ethics and policy imperatives challenging inequities in health: from ethics to action strategic plan for polio outbreak ethical and legal challenges posed by severe acute respiratory syndrome hcj / hasan v. the national insurance institute. nevo legal database isr controversies in vaccine mandates. current problems in pediatric and adolescent health care analysis of public responses to preparedness policies: the cases of h n influenza vaccination and gas mask distribution searching eyes -privacy, the state and disease surveillance in america public health: ethical issues the future of communicable disease control: toward a new concept in public health law public health law in a new century part i: law as a tool to advance the community's health low measles incidence: association with enforcement of school immunization laws childhood immunization: laws that work should the uk introduce compulsory vaccination? tort liability for parents who choose not to vaccinate their children and whose unvaccinated children infect others. university of cincinnati law review acknowledgements i gratefully acknowledge the assistance of the vaccination policy research group at tel aviv university's edmond j. safra center as well as prof. nadav davidovitch for comments that greatly improved the manuscript. i also thank the reviewers of this manuscript for their important comments as well as the editors of israel journal of health policy research. no financial support was provided in the preparation of this paper. the dataset that supports the article's conclusions is included within the article itself. • we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord- - gekjgr authors: kilich, eliz; dada, sara; francis, mark r.; tazare, john; chico, r. matthew; paterson, pauline; larson, heidi j. title: factors that influence vaccination decision-making among pregnant women: a systematic review and meta-analysis date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: gekjgr background: the most important factor influencing maternal vaccination uptake is healthcare professional (hcp) recommendation. however, where data are available, one-third of pregnant women remain unvaccinated despite receiving a recommendation. therefore, it is essential to understand the significance of other factors and distinguish between vaccines administered routinely and during outbreaks. this is the first systematic review and meta-analysis (prospero: crd ) to examine the strength of the relationships between identified factors and maternal vaccination uptake. methods: we searched medline, embase classic & embase, psycinfo, cinahl plus, web of science, ibss, lilacs, africawideinfo, imemr, and global health databases for studies reporting factors that influence maternal vaccination. we used random-effects models to calculate pooled odds ratios (or) of being vaccinated by vaccine type. findings: we screened , articles and identified studies from countries for inclusion. of these, studies were eligible for meta-analysis. the odds of receiving a pertussis or influenza vaccination were ten to twelve-times higher among pregnant women who received a recommendation from hcps. during the influenza pandemic an hcp recommendation increased the odds of antenatal h n vaccine uptake six times (or . , % ci . – . , i( ) = . %). believing there was potential for vaccine-induced harm had a negative influence on seasonal (or . , % ci . – . i( ) = . %) and pandemic influenza vaccine uptake (or . , % ci . – . , i( ) = . %), reducing the odds of being vaccinated five-fold. combined with our qualitative analysis the relationship between the belief in substantial disease risk and maternal seasonal and pandemic influenza vaccination uptake was limited. conclusions: the effect of an hcp recommendation during an outbreak, whilst still powerful, may be muted by other factors. this requires further research, particularly when vaccines are novel. public health campaigns which centre on the protectiveness and safety of a maternal vaccine rather than disease threat alone may prove beneficial. a a a a a maternal vaccination aims to reduce maternal and neonatal morbidity and mortality caused by infection [ ] . the world health organisation (who) recommends the inactivated influenza, tetanus-toxoid-containing vaccine (ttcv), and combined tetanus, diphtheria, and acellular pertussis (tdap) vaccines for pregnant women in settings where the disease burden is known [ ] . historically, maternal tetanus vaccination was limited to areas of significant transmission. in areas where there is ongoing maternal to neonatal transmission of tetanus, two doses of ttcv (preferably tetanus-diphtheria) are recommended in pregnancy in addition to tdap or dtap (for pertussis) and seasonal influenza vaccines. [ ] pertussis vaccination was limited to childhood, however the resurgence of pertussis during outbreaks that disproportionately affected younger infants led to national policy changes between and in countries such as the united kingdom and the united states, that introduced routine maternal pertussis vaccination. [ , ] similarly, the widespread influenza immunisation programs during the h n pandemic resulted in public health bodies particularly in europe, the united states and australia introducing guidance to implement recommendations for routine antenatal seasonal influenza vaccination during the subsequent decade. the united states healthy people campaign sets a target to achieve influenza vaccination coverage of % among pregnant women [ ] . suboptimal maternal vaccination coverage (estimated between - %) of seasonal influenza and pertussis vaccines globally represents a missed opportunity to improve maternal and neonatal health [ ] [ ] [ ] [ ] . understanding the features that contribute to reduced uptake of vaccines used in outbreaks is also of particular importance given the increased morbidity and mortality seen with infections contracted during the vulnerable period of pregnancy [ ] . in the last decade, the world health organisation has declared multiple public health emergencies of international concern for diseases including outbreaks of the ebola virus (west africa, north kivu), zika virus, and the novel coronavirus (wuhan) [ , ] . ebola and zika are known to cause significant morbidity and mortality if contracted during pregnancy, whereas the effect of the covid- is unknown [ ] . a vaccination strategy has been developed for ebola, and vaccine research is underway for zika virus and covid- . the concern of disease risk may be amplified during an outbreak, but concerns about using a novel vaccine may also be enhanced. it is important to identify factors that appear to affect antenatal vaccine uptake during routine use (pertussis and influenza) versus vaccinations recommended during an outbreak setting (h n influenza) to help prepare for future outbreaks. understanding the influence of personal beliefs and experiences on maternal vaccination uptake is key to designing, testing and deploying interventions that are tailored to improve vaccine acceptance and coverage in routine and outbreak settings. researchers have investigated the underlying reasons for low coverage using surveys, focus group discussions, and indepth interviews to explore the perceptions and experiences of pregnant women. previous reviews have established a narrative of evidence that suggests a broad range of factors (vaccine cost, accessibility, maternal knowledge, social influences, context, healthcare professional (hcp) recommendation and the perception of risks and benefits) all contribute to vaccine uptake. consensus within the field and across four prior literature reviews indicate that receiving a recommendation from an hcp for vaccination is the most important factor in maternal decision-making, irrespective of geographic or social context [ ] [ ] [ ] [ ] [ ] . in general, there is limited data on maternal vaccination uptake and records of hcp recommendations at a national level. however, for the united states of america (usa), which monitors antenatal seasonal influenza and pertussis vaccination coverage, data suggest approximately one-third of women who receive an hcp recommendation for the vaccine will choose to remain unvaccinated [ ] . in , the centers for disease control and prevention (cdc) found that . % of pregnant participants received a recommendation or an offer for tdap vaccine, but . % of them chose to remain unvaccinated [ ] . for seasonal influenza, fewer women chose to vaccinate when recommended to do so; . % received a recommendation or an offer yet . % of pregnant women surveyed remained unvaccinated [ ] . understanding why women remain unvaccinated despite an hcp recommendation is key. we also sought to discriminate factors that influence specific vaccines since seasonal influenza vaccination coverage is lower than other routine vaccines (tdap, tetanus) during pregnancy. prior literature and systematic reviews tend to characterize the factors influencing maternal vaccination decisions as either barriers or facilitators [ ] [ ] [ ] [ ] [ ] . we sought to quantify the association between beliefs, attitudes and prior behaviours that influence maternal vaccination uptake. we selected the h n influenza vaccine, deployed globally and recommended to pregnant women during the pandemic of , to be included alongside our analysis of other who routinely recommended vaccines, the pertussis and seasonal influenza vaccine. thus, we performed a systematic review and meta-analysis of qualitative and quantitative literature to provide comprehensive evidence on the magnitude of effect that factors influence maternal vaccination decisions globally with the aim to inform policy makers, public health strategists and researchers involved in designing vaccine interventions to increase uptake. we conducted a systematic review of literature, unrestricted by language or location, to identify qualitative and quantitative studies that reported on the cognitive, psychological, and social factors associated with maternal vaccination among pregnant and recently pregnant women (within two years of birth). we searched medline, embase classic and embase, psycinfo, cinahl plus, web of science, ibss, lilacs, africawideinfo, imemr, and global health for studies published by november (appendix p - in s file). additional studies were identified by screening reference lists (ek, sd) of previous reviews and through suggestions by experts in the field. titles and abstracts were independently screened and agreed upon (ek, sd) for potential eligibility. a final arbiter (pp) resolved any conflicts of agreement on inclusion. we excluded pre-clinical research, behavioural intervention studies, and any research that exclusively examined experimental vaccines in pregnancy or sociodemographic variables (appendix p - in s file). to be included in the meta-analysis, studies had to report an estimated odds ratio (or (or could be calculated from raw data)) for the association between a specific factor and vaccination status (excluding intention to be vaccinated). research groups from studies in which the data were unclear or had not been reported were contacted for clarification (appendix p in s file). the data from included studies were extracted (ek, sd) and input into microsoft excel (microsoft corporation, redmond, wa, usa) and a coding template was developed by authors to categorise factors influencing maternal vaccination uptake (expanded methodology appendix p - in s file details why established frameworks were not used). coding into broad themes (e.g. accessibility and convenience) using grounded theory was completed independently (ek, sd) with nvivo (qsr international, melbourne, australia) (inter-rater reliability kappa score . ). the quantitative studies were independently assessed (ek, mrf) for inclusion in the metaanalysis based on first cycle broad codes to capture data that could be synthesized (appendix p - in s file). qualitative data underwent a second round of coding to identify specific patterns within the broad themes (inter-rater reliability kappa score . ). a third round of coding (subdividing the first cycle codes) was conducted to ensure that only data that was directly comparable were included in each meta-analysis (appendix p in s file). twentythree narrow definitions were agreed upon by two authors (ek, mrf) to ensure consistency of the data included (appendix p - in s file). these definitions were used to pool studies for specific vaccines (seasonal influenza, pandemic influenza, and pertussis) generating separate meta-analyses (ek, mrf). any discrepancies in data extraction were resolved by both authors. quality appraisal was performed (ek, sd) using checklists for cross-sectional, cohort, and qualitative research studies from the joanna briggs institute quality assessment tools (appendix p - in s file). [ ] studies were ranked based on a framework developed by authors with an attributed quality score. where authors disagreed on final point allocation, the arbiter (pp) intervened to resolve the disagreement. quality analysis was not used to define inclusion or exclusion. however, pre-specified sensitivity analyses were performed investigating the robustness of results to the inclusion of only high-quality studies (joanna briggs institute scores > ) (appendix: p , p in s file). we wished to conduct a sensitivity analysis assessing the robustness of results by gross domestic product of countries included to assess the influence of geographic context. when two or more studies reported ors for a specific factor, random-effects models were used to calculate a summary or [ ] with heterogeneity assessed with i . funnel plots were used to examine the potential for publication bias. specific factors reported by only one study are summarised in the appendix (appendix p in s file). a secondary analysis was performed to assess factors associated with intention to be vaccinated during pregnancy. all meta-analyses were conducted in stata (statacorp, college station, tx, usa) [ , ] . the prisma checklist (preferred reporting items for systematic review and meta-analysis checklist) (appendix p - in s file) [ ] was used and the study was registered with prospero (international prospective register of systematic reviews) (crd ). an expanded methodology can be found in the appendix (appendix p - in s file). countries (appendix p - in s file). the majority of studies were quantitative only (n = ), then qualitative only (n = ) with three studies using mixed methods (table ) . studies were predominantly from the usa ( studies), australia ( ), and canada ( ) . seasonal influenza vaccine was the most commonly investigated vaccine, either independently or as part of a study of factors influencing the uptake of multiple vaccines ( % of studies n = ), followed by vaccines against pertussis ( % n = ), pandemic influenza ( % n = ), tetanus ( % n = ), and antenatal vaccines generally ( % n = ). we identified eight categories of factors that influence maternal vaccination across both qualitative and quantitative studies: accessibility and convenience ( studies), personal values and lifestyle ( ), awareness of information regarding the specific vaccine or disease of focus ( ), social influences on vaccine use ( ) , emotions related to vaccination ( ), perceptions of vaccine risk ( ) , perceptions of vaccine benefit ( ), and personal vaccination history ( ). from these eight categories, five could be synthesised quantitatively (appendix p - in s file). results from all meta-analyses are presented in fig . no data for tetanus vaccination were suitable for meta-analysis. a list of the most common barriers or facilitators cited in studies excluded from meta-analysis is available in the appendix (appendix p - in s file). from the qualitative studies, we identified sub-categories of factors that appear to influence maternal vaccination decision-making (table ). for our primary analysis we conducted meta-analyses which assessed the relationship between a specific belief or behaviour and maternal vaccination status ( - , participants (average , ) included in each meta-analysis)) (appendix p - in s file for individual meta-analyses and summary table) (fig ) . for our secondary analysis we conducted metaanalyses assessing the relationship between a specific belief or behaviour and maternal vaccination intentions, rather than prior behaviour ( - , participants (average , ) included in each meta-analysis)) (appendix p in s file when the number of studies included in the meta-analysis exceeded seven, funnel plots were used to assess the potential for publication bias (appendix p in s file). although based on a small number of studies, there was incomplete agreement between the primary and secondary analyses (intention to be vaccinated meta-analysis results are provided in appendix p - in s file). sensitivity analyses including studies with joanna briggs institute scores > were conducted for both vaccination status and intention to be vaccinated outcomes (appendix: p , p in s file). whilst results were generally consistent, differences were difficult to interpret due to the low number of higher-quality studies. all qualitative studies reported on the perceived effect of hcp influence on decision-making, and to a lesser extent the influence of other social networks or the internet. often an offer (or lack of an offer) of vaccination during an antenatal visit was a key factor in final behaviour [ ] [ ] [ ] . participants also expressed willingness to receive information from hcps, but were disappointed with a perceived overuse of leaflets to convey information in lieu of direct conversation with an hcp [ , , ] . other studies reported that some pregnant women sought vaccination information through media or the internet, but these avenues were not regarded as the most reliable for accurate information [ ] [ ] [ ] [ ] [ ] . almost all qualitative studies indicated that being aware of maternal vaccination and/or the respective disease, regardless of information source, was key to receiving the vaccine but rarely sufficient ( studies in eight of the qualitative studies that examined perceptions of disease severity, participants were unaware of the additional risks of influenza to pregnant women [ , , , - , , ] . qualitative studies also highlighted differences in participants' perceptions of severity for different diseases. for example, h n or pandemic influenza was perceived as more severe than seasonal influenza [ , ] . additionally, pertussis was correctly seen primarily to present danger to infants, whereas influenza was viewed as a significant risk to the pregnant woman [ ] . whilst the disease risk was used as a contributing factor to final decision other factors were weighed against it. whilst factors such as convenience, personal values, and emotions related to vaccinations during pregnancy were not captured in our meta-analyses, they were highlighted in qualitative analyses. [ , ] , and pain [ , , ] . one study reported that vaccinated and unvaccinated pregnant women expressed similar fears, but unvaccinated women often described their fears in more detail [ ] . the fear of perceived vaccine harms (including the ideas of unknown risks for novel vaccines) were used to explain the rejection of maternal vaccination despite a connected fear of the disease it was aimed to protect against [ , - , - , ]. despite the challenges of synthesizing an extensive and varied body of research, we have been able to quantify the relative effect size for a large number of specific beliefs and behaviours around maternal vaccination uptake. prior attempts to weight factors influencing maternal vaccination uptake have largely been confined to ranking the most commonly cited barriers or facilitators within studies, listing the latter as predictors. this approach is likely to conflate several individual factors which are important to designing better interventions aimed at increasing maternal vaccination acceptance and uptake. our major finding is that vaccine-specific factors and previous vaccination behaviour have a strong influence on antenatal vaccine uptake. disease-related perceptions have a modest effect on final vaccination uptake. beliefs that vaccine would benefit the mother or cause no harm to the pregnancy were associated with four-to-nine-times greater odds of vaccination-acceptance during pregnancy. prior systematic reviews were unable to characterise the nature or strength of effect of vaccine safety concerns on maternal vaccination decisions. lutz et al. described that . to % of pregnant women had safety concerns for their foetuses [ ] . wilson et al. reported that safety concerns were the most frequently cited barriers ( of studies) but the relationship of this concern to final vaccination uptake was not defined. the underlying vaccination status of pregnant women was unreported in this prior study, limiting the interpretation of this finding [ ] . in our study, beliefs that vaccine could cause birth defects or general harm in pregnancy served as strong deterrents to both seasonal and pandemic influenza vaccination (seasonal or . , % ci . - . ; pandemic or . , % ci . - . ). similarly, perceptions of vaccine utility had a strong positive influence on uptake. for the seasonal influenza vaccine, perceiving the vaccine as beneficial in general was an important factor associated with pregnant women's vaccination status (or . , % ci . - . ). for pandemic influenza vaccination, despite the wide confidence intervals, our data suggest that perceptions that vaccine can protect pregnant women (or . % ci . - . ) is strongly associated with vaccine uptake. our study did not find clear evidence that a belief of susceptibility to pandemic or seasonal influenza was associated with increased maternal pandemic influenza vaccination (or . , % ci . - . ) or seasonal influenza (or . , % ci . - . ) vaccine uptake. there was some evidence to support an association between perceptions of the severity of pandemic influenza and pregnant women's vaccination status (or . , % ci . - . ) with the belief that pandemic influenza can result in hospitalisation increasing vaccine uptake threefold (or . , % ci . - . ). we would recommend additional studies to explore the role of disease severity and susceptibility in greater detail to clarify their importance when other factors are present. for seasonal influenza, the data is inconclusive since women who believed that the disease could be harmful to their pregnancy or baby had four-times greater odds of being vaccinated than those who did not (or . , % ci . - . ) yet there was no evidence to suggest belief in the risk of the disease generally (or . , % ci . - . ) or its ability to result in hospitalisation (or . , % ci . - . ) were related to vaccine uptake. this was mirrored by our qualitative research which indicated that the influence of a belief in the severity and susceptibility to a disease does not in isolation determine vaccination decision [ , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . this has important implications for public health communication strategies around maternal vaccination since campaigns, particularly during an epidemic or influenza outbreak, have centred around disease threat. based on our findings we caution any communication approach which highlights only the threat of disease when publicising vaccination. we suggest this requires further review of the messaging strategies comparing those with and without explicit details of vaccine safety to the public and/or a discussion of disease threat with attention to language which might inadvertently promote fear [ ] . the global communication strategies during the h n pandemic have been widely criticised as lacking an evidence-base and not appropriately targeting specific vulnerable groups [ ] . we suggest that future research investigates disease-focused communication strategies versus vaccine-centred communication when discussing maternal vaccination to help prepare for future pandemics. our study was conducted prior to the north kivu ebola vaccine deployment among pregnant women in . this study precedes vaccine candidate deployment for sars-cov- with immediate implications for future studies analysing potential acceptance of a maternal vaccine and the associated communication strategy. this is an important area of investigation to analyse the factors that influence maternal uptake when the vaccine is still in an experimental part of outbreak control. whilst the analysis of purely experimental vaccines was outside the remit of this work, we suggest further investigation into assessing the importance of factors identified in this review (including fear-conflict, anxiety and specific safety concerns) and their influence on uptake of vaccine during its developmental phase at the time of an outbreak. our findings also have potential implications for future study design. many studies included in this systematic review and meta-analysis were designed using the framework of the health belief model [ - , , , , , , , - , , , - ] . in brief, the health belief model describes final vaccination acceptance or rejection based on the interacting beliefs of seriousness and susceptibility to the target disease of the vaccine, benefits of the intervention, and barriers in order to predict health behaviour. our study suggests that the model should be adapted to highlight the importance of the latter two categories in maternal vaccination behaviour predictions. consistent with the extensive body of evidence on this topic, an hcp recommendation for routine vaccinations (seasonal influenza and pertussis vaccination) was a very strong factor influencing maternal vaccine acceptance that is associated with ten-times greater odds of being vaccinated over those who did not receive an hcp recommendation (pertussis or . , % ci . - . ; seasonal influenza or . , % ci . - . ). although based on a small number of studies, our meta-analysis suggests that the influence of an hcp recommendation for pandemic influenza vaccination moderately-to-strongly influences uptake. pandemic vaccine uptake was closely related to prior vaccination behaviour. vaccination (with a different vaccine) during a prior pregnancy (or . % ci . - . ) had a strong influence on pandemic vaccine uptake. interestingly, this did not appear as evident for receiving an antenatal seasonal influenza vaccine in a subsequent pregnancy (or . , % ci . - . ). this suggests a possibility that decision-making for seasonal influenza vaccines made in second and third pregnancies may not be consistent with the decisions in the first pregnancy [ ] . whilst studies have often included a sample of second-or third-time mothers, there is less extensive evidence of temporal changes in decision-making factors for maternal vaccines. whilst a general awareness about maternal vaccination did not increase the odds greatly of pandemic vaccine uptake, it appeared key for routine antenatal vaccines. policy awareness was strongly associated with seasonal influenza vaccination uptake. national recommendations from the authoritative health bodies appear to carry weight in maternal vaccination decision-making at a population level [ ] . this is important for the rollout of new maternal vaccines, as vaccinations not endorsed by national policy may be less accepted. publicising such policies could improve trust in maternal vaccination programmes and facilitate improved uptake. qualitative findings from focus group discussions and in-depth interviews were generally consistent with the quantitative results: an unambiguous recommendation from an hcp to vaccinate against seasonal influenza or pertussis is key to pregnant women being vaccinated [ - , , , , , ] . it is difficult to draw conclusions about which specific hcp (e.g. obstetrician, general practitioner, and midwife) or service provider (e.g. community or hospital-based practitioners) is the most influential. similar to the quantitative literature, qualitative studies have shown that a recommendation by an hcp was not always sufficient [ , , , , , , , , ] . reasons for refusal despite hcp recommendation from the qualitative analysis provide insights into the effects of fear, mistrust, and a feeling of accountability [ , , , , ] . in the face of uncertainty about a vaccine, a guarded state prevails despite concern for disease risk [ , , , , ] . this was most notably captured by meharry et al. as, ". . .fear if i do (vaccinate), fear if i don't (vaccinate), and do nothing when i fear both" [ ] . this analysis, combined with the finding of a very strong relationship between the belief of vaccine harm and reduced uptake indicates that the perceived risk of self-intervening (i.e. taking a vaccine) can be very powerful. this can overshadow the belief in environmental risk (e.g. contracting a severe disease). this suggests that mothers feel accountable for a perceived risk when choosing to vaccinate during pregnancy, which can result in inaction if the disease is also feared. whilst it is essential that pregnant women are informed about the risks of the disease in order to be appropriately consented, the manner in which this is communicated should be evaluated. it appears that, in some cases, fear may be counter-productive. this has been seen in childhood vaccines: if parents already fear the vaccine, making them fear the disease leads to decision conflict, and hesitancy [ ]. by including qualitative analysis, we were also able to unravel specific, participant-driven concerns that ranged from possible adverse events such as narcolepsy, infertility, and autism spectrum disorder as well as pregnancy-related concerns such as suspected risks of miscarriage, preterm birth, and birth defects. since the non-pregnancy related health concerns occur rarely in the general population or require long-term follow up over decades, post-marketing surveillance studies are used to measure if there are any vaccine-related effects [ ] . however, data on these specific concerns during pregnancy are often unavailable to general practitioners or midwives during counselling. we recommend that hcps are given ready access to clear and concise language on the safety of vaccines during pregnancy. the cdc has launched an extensive response to the relationship between antenatal vaccines and guillain barre syndrome, autism, febrile seizures and sudden infant death syndrome (sids) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, discussions on narcolepsy are made in reference to childhood rather than prenatal vaccination. additionally, there is limited availability of summarized reports for the public or general practitioners that synthesize the abundance of safety evidence on miscarriage, infertility, and birth defects. health bodies should make this widely generated safety evidence more accessible to the public and to hcps to facilitate uptake where concerns in practice arise [ , ] . it is reassuring that our meta-analysis reinforces some of the existing evidence surrounding factors that influence maternal vaccine uptake. attempting to quantify an effect size adds a useful summary measure. however, our study has a number of limitations that potentially impact inferences drawn from these data. the evidence-base exploring the factors determining antenatal vaccination decisions is extensive but of mixed quality, and synthesis of the results was complicated by the contextual and methodological heterogeneity between studies. a particular challenge was synthesizing questionnaire data which used variable phrasings and posed different assortments of questions limiting the volume of data that could be synthesised. ninety-seven percent of quantitative studies pooled employed a cross-sectional design. we acknowledge that in some settings, where data are obtained using variable questionnaires, examining a different number of factors, pooling information may obtain inconsistent results. however, in practice, it is unclear how these differences are likely to influence the obtained summary estimates. this has highlighted the need for more standardised procedures for data collection and reporting for individual studies. this is of particular importance during outbreaks when research is delivered in a timely manner. whilst we intended to compare results from the meta-analyses with vaccination status and intention to be vaccinated as outcomes, data were insufficient to draw meaningful comparisons. all the data for vaccine intention is found in the appendix p in s file. this is important since the majority of data available for pertussis vaccination in pregnancy focused on beliefs associated with vaccination intentions only [ , , , ] . whilst previous literature has shown intention to vaccinate can be a proxy for actual vaccination status, this may not always be the case with maternal vaccination and additional research is needed [ , ] . our findings were largely consistent across countries; however, we recognize that the majority of data come from high-income settings where national vaccine policies exist and, therefore, the generalisability of these findings may be limited. we were unable to conduct a sensitivity analysis to stratify results by gross domestic product of each country as there were too few studies included in each meta-analysis. additionally, data from many studies relied on self-reported vaccination status and did not verify medical records or vaccine registry data which may have introduced a recall bias (reflected in the jbi quality assessment scoring). however, previous research in the field has indicated that this bias is unlikely to be substantial [ , ] . a number of studies recruited participants using purposive or convenience sampling (table ) . thus, we applied the joanna briggs institute (jbi) critical appraisal tools (jbi) to assess potential biases among individual studies. based on our results, we then performed a pre-defined sensitivity analysis (of high quality/low quality) presented in the appendices (appendix , appendix p , p in s file). we were unable to detect an influenced study quality on our pooled analyses. a final limitation is that the exposures in our meta-analyses were dichotomized, whereas in reality beliefs exist on a spectrum. vaccine refusal is undoubtedly multifactorial. however, our study has demonstrated that factors specific to the vaccine, perhaps more so than the disease are highly influential. interventions recommended to improve maternal vaccination uptake have ranged from text reminders for prospective mothers to educational videos and motivational interviewing techniques for hcps [ ] [ ] [ ] . based on the results of this review, interventions designed to impact maternal vaccine uptake should continue to encourage individualised hcp recommendations. additionally, personalised counsel on the benefits and safety of a vaccine should emphasize the vaccine's protective effect on the pregnancy as well as discuss implications for foetal and childhood development. this is in contrast to traditional communication on disease threat in isolation. readily accessible information that synthesizes the large body of evidence that may otherwise appear contradictory to the general public, will facilitate healthcare consultations in addressing pregnancy and long-term concerns, such as those identified in our review. cause of neonatal death. child mortality data. unicef.org [cited current challenges and achievements in maternal immunization research organisation wh. who vaccine-preventable diseases:monitoring system immunization and infectious diseases healthy people healthypeople.gov. influenza and tdap vaccination coverage among pregnant women-united states seasonal flu vaccine uptake in gp patients: monthly data pandemic influenza and pregnant women: summary of a meeting of experts the truth about pheics. the lancet what next for the coronavirus response? the lancet viral infections in pregnancy: a focus on ebola virus understanding factors influencing vaccination acceptance during pregnancy globally: a literature review predictors of maternal vaccination in the united states: an integrative review of the literature understanding barriers and predictors of maternal immunization: identifying gaps through an exploratory literature review. vaccine a systematic review of barriers to vaccination during pregnancy in the canadian context determinants of uptake of influenza vaccination among pregnant women-a systematic review joanna briggs institute reviewer's manual meta-analysis in clinical trials systematic reviews in health care statacorp. stata statistical software: release preferred reporting items for systematic reviews and meta-analyses: the prisma statement knowledge, attitudes and practices about influenza vaccination among pregnant women and healthcare providers serving pregnant women in managua understanding pregnant women's attitudes and behavior toward influenza and pertussis vaccination vaccination against pertussis and influenza in pregnancy: a qualitative study of barriers and facilitators perceptions of hong kong chinese women toward influenza vaccination during pregnancy increased awareness and health care provider endorsement is required to encourage pregnant women to be vaccinated exploring pregnant women's views on influenza vaccination and educational text messages message framing strategies to increase influenza immunization uptake among pregnant african american women identifying ways to increase seasonal influenza vaccine uptake among pregnant women in china: a qualitative investigation of pregnant women and their obstetricians reasons why pregnant women did not vaccinate against influenza a h n attitudes and beliefs of pregnant women and new mothers regarding influenza vaccination in british columbia assessing the acceptability of a maternal tdap vaccine based on mothers' knowledge, attitudes, and beliefs of pertussis and vaccinations in lusaka, zambia. vaccine a qualitative study of vaccine acceptability and decision making among pregnant women in morocco during the a (h n ) pdm pandemic biography, pandemic time and risk: pregnant women reflecting on their experiences of the influenza pandemic attitudes towards antenatal vaccination, group b streptococcus and participation in clinical trials: insights from focus groups and interviews of parents and healthcare professionals reasons why women accept or reject the trivalent inactivated influenza vaccine (tiv) during pregnancy pregnant and recently pregnant women's perceptions about influenza a pandemic (h n ) : implications for public health and provider communication pandemics and vaccines: perceptions, reactions, and lessons learned from hard-to-reach latinos and the h n campaign vaccination against seasonal flu in switzerland: the indecision of pregnant women encouraged by healthcare professionals. revue d epidemiologie et de sante publique implementation of maternal influenza immunization in el salvador: experiences and lessons learned from a mixed-methods study. vaccine influenza vaccination during pregnancy: a systematic review of fetal death, spontaneous abortion, and congenital malformation safety outcomes. vaccine surveillance of adverse events after seasonal influenza vaccination in pregnant women and their infants in the vaccine adverse event reporting system adverse events in pregnant women following administration of trivalent inactivated influenza vaccine and live attenuated influenza vaccine in the vaccine adverse event reporting system safety of influenza vaccination during pregnancy: a review of subsequent maternal obstetric events and findings from two recent cohort studies. vaccine vaccine safety datalink team. inactivated influenza vaccine during pregnancy and risks for adverse obstetric events influenza vaccination in pregnancy: information for healthcare professionals vaccine recommendations and safety information: tetanus, diphtheria, and pertussis intention to accept bordetella pertussis booster vaccine during pregnancy in mexico city knowledge attitude and practice toward pertussis vaccination during pregnancy among pregnant and postpartum italian women do people who intend to get a flu shot actually get one validation of self-report of influenza and pneumococcal vaccination status in elderly outpatients validation of influenza and pneumococcal vaccine status in adults based on self-report motivational interviewing: a powerful tool to address vaccine hesitancy enhancing uptake of influenza maternal vaccine. expert review of vaccines strategies for increasing uptake of vaccination in pregnancy in high-income countries: a systematic review maternal and neonatal tetanus: a case study of pakistan acceptance of a pandemic avian influenza vaccine in pregnancy vaccination rates for pandemic influenza among pregnant women: an early observation from chennai, south india failure of the vaccination campaign against a(h n ) influenza in pregnant women in france: results from a national survey attitudes to immunisation in pregnancy among women in the uk targeted by such programmes influence of health literacy on acceptance of influenza and pertussis vaccinations: a cross-sectional study among spanish pregnant women determination of vaccination status of pregnant women during pregnancy and the affecting factors factors associated with intention to receive influenza and tetanus, diphtheria, and acellular pertussis (tdap) vaccines during pregnancy: a focus on vaccine hesitancy and perceptions of disease severity and vaccine safety trends in reasons for non-receipt of influenza vaccination during pregnancy in georgia vaccination knowledge and acceptability among pregnant women in italy influenza vaccination coverage among pregnant women-national h n flu survey (nhfs) sustained high influenza vaccination rates and decreased safety concerns among pregnant women during the - influenza season risk perceptions, worry, or distrust: what drives pregnant women's decisions to accept the h n vaccine? maternal & behaviors and perceptions regarding seasonal and h n influenza vaccination during pregnancy vaccination of pregnant women in france uptake of influenza vaccine in pregnant women during the h n influenza pandemic frequency of tetanus toxiod vaccination in pregnant women attending a tertiary care hospital factors that influence uptake of vaccination in pregnancy maintaining the momentum: key factors influencing acceptance of influenza vaccination among pregnant women following the h n pandemic causes of low tetanus toxoid vaccination coverage in pregnant women in lahore district tetanus vaccination status and its associated factors among women attending a primary healthcare center in cairo governorate knowledge and attitiudes of pregnant women and their providers towards recommendations for immunization during pregnancy factors influencing women's decisions about having the pertussis-containing vaccine during pregnancy acceptance and rejection of influenza vaccination by pregnant women in southern iran: physicians' role and barriers assessment of the vaccination status of pregnant mothers and their infants after birth with tetanus toxoid in district rawalpindi of pakistan attitudes, intentions, and barriers toward influenza vaccination among pregnant korean women. health care for women international vulnerable groups within a vulnerable population: awareness of the a(h n )pdm pandemic and willingness to be vaccinated among pregnant women in ivory coast poor uptake of influenza vaccination in pregnancy in northern india disparities in tdap vaccination and vaccine information needs among pregnant women in the united states knowledge, attitudes, beliefs, and behaviors of pregnant women approached to participate in a tdap maternal immunization randomized, controlled trial missed opportunities for tetanus immunization of pregnant women in juiz de fora knowledge, attitudes, beliefs, and barriers associated with the uptake of influenza vaccine among pregnant women improving influenza vaccination coverage in pregnancy in melbourne increasing uptake of influenza vaccine by pregnant women post h n pandemic: a longitudinal study in antenatal vaccination against group b streptococcus: attitudes of pregnant women and healthcare professionals in the uk towards participation in clinical trials and routine implementation an assessment of missed opportunities for immunization in children and pregnant women attending different health facilities of a state hospital seasonal influenza vaccination in pregnant women: knowledge, attitudes, and behaviors in italy status of pandemic influenza vaccination and factors affecting it in turkish pregnant women the perspective of pregnant women on pandemic influenza vaccine before pandemics trends in seasonal influenza vaccine uptake during pregnancy in western australia: implications for midwives pregnant women's perception of risk with use of the h n vaccine influenza vaccination among pregnant women: patient beliefs and medical provider practices patient attitudes toward influenza and tetanus, diphtheria and acellular pertussis vaccination in pregnancy vaccination of pregnant women in the valencian community during the - influenza season: a multicentre study exploring patients' awareness and healthcare professionals' knowledge and attitude to pertussis and influenza vaccination during the antenatal periods in cavan monaghan general hospital pandemic (h n ) influenza vaccine uptake in pregnant women entering the influenza season in western australia influenza and pertussis vaccination in pregnancy: portrayal in online media articles and perceptions of pregnant women and healthcare professionals. vaccine determinants of influenza and pertussis vaccination uptake in pregnancy: a multicenter questionnaire study of pregnant women and healthcare professionals pregnant women's intention to take up a post-partum pertussis vaccine, and their willingness to take up the vaccine while pregnant: a cross sectional survey acceptability of tetanus toxoid vaccine by pregnant women in two health centres in abidjan (ivory coast) pregnant women's knowledge of influenza and the use and safety of the influenza vaccine during pregnancy survey of attitude toward immunization of h n influenza a vaccine of pregnant women in guangzhou key: cord- -zmna ovl authors: lim, dwee wee; lee, lay tin; kyaw, win mar; chow, angela title: psychosocial determinants of influenza vaccination intention: a cross-sectional study on inpatient nurses in singapore date: - - journal: american journal of infection control doi: . /j.ajic. . . sha: doc_id: cord_uid: zmna ovl nurses have the closest interaction with inpatients and could transmit influenza to patients. from a self-administered questionnaire survey among inpatient nurses at a tertiary hospital, we observed that the strongest factors associated with intention for future vaccination were perceived benefits of and motivations for vaccination (adjusted odds ratio [aor], . ; % confidence interval [ci], . - . ), and perceived nonsusceptibility to influenza and preference for vaccination alternatives (aor, . ; % ci, . - . ). these factors need to be addressed to increase vaccination uptake and prevent nosocomial transmission. influenza can be transmitted in health care settings by infected health care workers (hcws), causing nosocomial outbreaks. the u.s. advisory committee on immunization practices recommends annual influenza vaccination for hcws for transmission prevention and reduction in work absenteeism. however, influenza vaccination in hcws has remained suboptimal. determinants of influenza vaccination intention differ across countries, hospitals, and occupational groups. nurses make up most of hcws in hospitals and have the closest interaction with patients in inpatient settings. it is crucial to understand the psychosocial factors associated with the intention for vaccination uptake among inpatient nurses to tailor effective vaccination promotion interventions. we conducted a cross-sectional study of inpatient nurses in a , -bed adult tertiary hospital in singapore, from october-november , prior to the hospital's annual seasonal influenza vaccination program, which provides vaccination free-of-charge to hcws via a mobile clinic. we developed a -item ( -point likert scale), self-administered questionnaire covering content on personal knowledge, attitudes, and beliefs toward influenza vaccination, and the barriers and facilitators of vaccination in the hospital. we also collected data on sociodemographics, vaccination uptake in the last influenza season, and intention for future influenza vaccination. ethical approval was obtained from the domain specific research board, national healthcare group (singapore). principal component analysis with varimax rotation was performed to derive the latent factor structure. internal consistency of each factor was measured using cronbach α coefficient. the χ test was used to compare differences in proportions. stepwise multiple logistic regression analysis was performed to assess for independent factors. a total of , out of , inpatient nurses responded to the survey. there were nurses with incomplete data who were excluded from analysis, resulting in a total of subjects in the study. half ( . %) of the nurses had received influenza vaccination in the previous season (year ). approximately % of the participants intended to receive influenza vaccine in the next influenza season (table ) . principal component analysis revealed latent factors on influenza vaccine, including ( ) perceived benefits of and motivations for influenza vaccination, ( ) global threat of emerging infectious diseases, ( ) effectiveness of hospital's influenza vaccination promotional efforts, ( ) personal nonsusceptibility to influenza and preference for alternatives to influenza vaccination, ( ) local threat of emerging infectious diseases, ( ) reinforcement and cues to action, ( ) fear of adverse effects, and ( ) accessibility. the cronbach α coefficient ranged from . to . (table a ). one item was removed from factor (fear of adverse effects), and the cronbach α improved to . . a composite score for the remaining items for factor was calculated. for factors (reinforcement and cues to action) and (accessibility), with poor internal consistency, individual items were included in the final multiple logistic regression model, along with the composite score for factor and the factors with good internal consistency. on univariate analysis, age, ethnicity, workplace, job title, past vaccination uptake, and psychosocial factors were significantly associated with future vaccination intention. in the multivariate model, the strongest predictor for vaccination intention was perceived benefits of and motivations for vaccination (adjusted odds ratio [aor], . ; % confidence interval [ci], . - . ) ( table ). this was followed by awareness of easy access to influenza vaccination at the occupational health clinic (aor, . ; % ci, . - . ), knowledge that vaccination was provided free-of-charge, (aor, . ; % ci, . - . ), the perceived effectiveness of the hospital's influenza vaccination promotional efforts (aor, . ; % ci, . - . ), and the perceived global threat of emerging infectious diseases (aor, . ; % ci, . - . ). perceived local threat of emerging infectious diseases was also associated with vaccination intention (aor, . ; % ci, . - . ). nurses who perceived themselves to be nonsusceptible to influenza and who preferred alternatives to vaccination (aor, . ; % ci, . - . ), and those who feared the adverse effects of vaccination (aor, . ; % ci, . - . ), were % and % less likely to express the intention for future influenza vaccination (table ) . the strongest determinants for future influenza vaccination intention among inpatient nurses were perceived benefits of and motivation for vaccination, awareness of easy access to vaccination at the occupational health clinic, and knowledge that the vaccine was free-of-charge. our findings corroborate with findings from other local and international studies. [ ] [ ] [ ] [ ] in addition, our study found that the perception of global threat of emerging infectious diseases also positively influenced nurses' intention for future influenza vaccination. this could explain the behaviors of hong kong nurses whose influenza vaccination uptake declined after the severe acute respiratory syndrome outbreak in until the avian influenza outbreak in neighboring china in and the influenza pandemic in . on the other hand, nurses who perceived themselves to be nonsusceptible to influenza and who preferred alternatives to vaccination were less likely to intend to be vaccinated in the future. this is of concern, because hcws often perceived themselves to be healthy and not at risk of influenza infection. , furthermore, singapore is a multiracial country where the use of complementary and alternative medicine is prevalent. these beliefs, which could greatly reduce the uptake of vaccination, would need to be addressed. despite the demonstration of vaccine safety, hcws continue to be concerned about the adverse effects. , , , our study found that nurses who feared the adverse effects of influenza vaccination were less likely to intend to receive future vaccination. more targeted interventions would have to be implemented to address these fears. our findings have several implications. first, influenza vaccination promotional efforts for nurses should address both the positive and negative determinants of vaccination intention. local epidemiology of influenza and hcws' risk of infection, benefits and safety of influenza vaccination, and precautions against potential adverse effect should be clearly communicated to support vaccination uptake. second, early dissemination of information on impending international and local outbreaks can increase influenza vaccination uptake among nurses ahead of epidemics. finally, accessibility to vaccination should be increased. this could include extension of vaccination clinic hours and encouragement of peer administration of vaccination. this study has shown that personal psychosocial and organizational factors are determinants of nurses' intention for influenza vaccination. promotional efforts should include disseminating information on infection risk and vaccination benefits, addressing fear of adverse effects, and increasing vaccination accessibility. factors loadings and cronbach α coefficient for psychosocial factors generated from principal component analysis questionnaire items factor loadings cronbach α the flu vaccine is effective in preventing flu. routes of transmission during a nosocomial influenza a(h n ) outbreak among geriatric patients and healthcare workers immunization of health-care personnel: recommendations of the advisory committee on immunization practices (acip) declining influenza vaccination coverage among nurses sociocognitive predictors of the intention of healthcare workers to receive the influenza vaccine in belgian, dutch and german hospital settings survey of healthcare workers' attitudes, beliefs and willingness to receive the pandemic influenza a (h n ) vaccine and the impact of educational campaigns attitudes and practices towards pandemic influenza among cases, close contacts, and healthcare workers in tropical singapore: a cross-sectional survey high coverage of influenza vaccination among healthcare workers can be achieved during heightened awareness of impending threat seasonal influenza vaccination predicts pandemic h n vaccination uptake among healthcare workers in three countries complementary and alternative medicine use in multiracial singapore influenza vaccination in paediatric nurses: cross-sectional study of coverage, refusal, and factors in acceptance we thank all the nurse managers in the ward who helped in data collection. key: cord- -cgkhip j authors: mcmillen, g. l.; briggs, d. j.; mcvey, d. s.; phillips, r. m.; jordan, f. r. title: vaccination of racing greyhounds: effects on humoral and cellular immunity date: - - journal: veterinary immunology and immunopathology doi: . / - ( ) -d sha: doc_id: cord_uid: cgkhip j abstract greyhound kennel owners frequently employ multiple vaccination schedules in an attempt to reduce financial losses incurred as a result of infectious diseases. in order to determine the effects of multiple vaccination schedules on the immune system of racing greyhounds, three litters of greyhound pups raised in laboratory conditions were divided into two groups and subjected to either a maximum or a minimum vaccination schedule. blood samples were collected biweekly for months beginning at weeks of age and analyzed to establish ‘baseline’ values for the lymphatic system of greyhounds. lymphocyte transformation, total and differential leukocyte counts, and flow cytometry were used to evaluate cellular immunity. humoral immunity was evaluated using serum neutralization and hemagglutination inhibition tests. proliferation of peripheral blood lymphocytes in response to the mitogen concanavalin a (con a) was higher for the maximum vaccination groups. the frequency distribution of circulating cd and igg labeled lymphocytes was higher in the minimum vaccination groups. a significant treatment by time interaction in cd , igg, and igm labeled cells was observed. this interaction, however, was not significant at any point in time for cd and igg labeled cells. the percentage of lymphocytes expressing surface igm was significantly higher in the minimum vaccination groups at and weeks of age. no significant differences were detected in humoral immunity between the maximum and minimum groups of each litter. results of this study indicate that maximum vaccination schedules do not appear to be more effective or more immunosuppressive than minimum vaccination schedules. months beginning at weeks of age and analyzed to establish 'baseline' values for the lymphatic system of greyhounds. lymphocyte transformation, total and differential leukocyte counts, and flow cytometry were used to evaluate cellular immunity. humoral immunity was evaluated using serum neutralization and hemagglutination inhibition tests. proliferation of peripheral blood lymphocytes in response to the mitogen concanavalin a (con a) was higher for the maximum vaccination groups. the frequency distribution of circulating cd and igg labeled lymphocytes was higher in the minimum vaccination groups. a significant treatment by time interaction in cd , igg, and igm labeled cells was observed. this interaction, however, was not significant at any point in time for cd and igg labeled cells. the percentage of lymphocytes expressing surface igm was significantly higher in the minimum vaccination groups at and weeks of age. no significant differences were detected in humoral immunity between the maximum and minimum groups of each litter. results of this study indicate that maximum vaccination schedules do not appear to be more effective or more immunosuppressive than minimum vaccination schedules. viral pathogens, in particular canine parvovirus (cpv) and canine distemper virus (cdv), cause a significant financial loss to the greyhound industry. in order to circumvent these losses, kennel owners attempt to elicit an early and continuous immune response by administering multiple doses of vaccines. simultaneous administration of cpv and cdv vaccines has been reported to decrease the number of circulating lymphocytes which may in fact produce a temporary state of immunosuppression (kesel and neil, ; mastro et al., ; phillips et al., ) . the host defense system is traditionally divided into two functionally overlapping categories: the humoral immune system and the cellular immune system (schultz, a) . the humoral immune system consists of b-lymphocytes which produce immunoglobulins, helper t-lymphocytes, macrophages, killer cells, and effector molecules. this aspect of the immune system is evaluated through the use of antigen-antibody interactions, effector cell assays, and through the evaluation of complement-mediated activity. the cellular immune system consists of t-lymphocytes, macrophages, and cytokines. lymphocyte proliferation, phenotyping, and delayed type hypersensitivity are commonly used to evaluate cellular immunity. the correlation between antibody titer and protective effect after immunization with cpv and cdv vaccines indicates that humoral immunity is important in the host defense to these pathogens. the role of cellular immunity in particular to cpv vaccination has received less attention. current vaccination protocols in the greyhound industry administer viral antigens more frequently and at a younger age. the response of pups less than weeks of age to viral antigens is reported to be lower than that of adult dogs and their lymphocyte proliferation in response to mitogen stimulation reaches adult values between weeks and months of age (banks, ) . the following study was designed to determine the effect of extensive vaccination protocols on the developing immune system of racing greyhounds. at weaning, greyhound pups from three different dams and the same sire were randomly divided into two groups. the vaccination history of the dams was unknown except that one dam was vaccinated with a multivalent vaccine (da,lp + pv) prior to breeding. each group was housed in a separate pen and vaccinated with either a maximum or a minimum vaccination schedule (table ). the maximum vaccination schedule was modeled after current vaccination protocols being used in the racing greyhound industry. the minimum vaccination schedule more closely resembled recom- of the american veterinary medical association (avma council on biologic and therapeutic agents, ). all vaccines were administered subcutaneously with the exception of rabies (intra-muscular) and parainfluenza-bordetella (intra-nasal). blood samples were collected from adults weeks prior to whelping and from pups every weeks beginning at weeks of age and ending at months of age. blood samples were collected in untreated, preservative-free heparinized, and edta treated tubes. cpv serum antibody titers were assayed biweekly using the hemagglutination inhibition (hai) test as previously described (carmichael et al., ) . hai titers were recorded as the reciprocal of the highest serum dilution showing complete inhibition of hemagglutination. cdv serum antibody titers were assayed biweekly using the serum-neutralization (sn) test as previously described (appel and robson, ) . the sn titer was recorded as the reciprocal of the highest serum dilution that neutralized viral cytopathic effect on vero cells (atcc ccl ). canine herpesvirus (chv), canine coronavirus (ccv), and infectious canine hepatitis (ich) virus serum antibody levels were assayed monthly using a sn test on primary dog kidney, swine testicle (st) (atcc ccl ), and mandin-darby canine kidney (mdck) (atcc ccl ) cells respectively. peripheral blood mononuclear cells (pbmc) were isolated using density gradient centrifugation (fletcher et al., ) . heparinized blood was diluted :l in . m phosphate-buffered saline (pbs) ph . , layered onto histopaque- (sigma), and centrifuged at x g for min. the leukocyte layer was collected, washed twice in rpm media (gibco laboratories), and resuspended to a concentration of x lo cells ml-' in rpm containing % heat inactivated fetal bovine serum (fbs) (hyclone laboratories), l-glutamine ( mm), penicillin ( units ml-' ), streptomycin ( . mg ml-'), kanamycin ( pg ml-'), and gentamicin ( . pg mll'). lymphocyte responsiveness to mitogen stimulation was assayed as previously described (schultz, b) with minor modifications. briefly, pbmcs were dispensed in . ml amounts ( cells per well) into -well flat bottom tissue culture plates (corning glass works) and subjected to the following experimental conditions: cells only; cells + . pg per well phytohemagglutinin-p (pi-ia) (sigma l- ); cells + . pg per well concanavalin a (con a) (sigma c- ); cells + cpv (atcc vr- ) at a multiplicity of infection (moi) of ; cells + cdv (onderstepoort strain, kindly donated by the james a. baker institute for animal health) at a moi of . . all tests were conducted in replicates of four. tritiated thymidine c htdr) at a concentration of . &i per well was added after h incubation at °c in a % co, incubator. cells were harvested - h later using a phdtm cell harvester (cambridge technology, inc.) and counts per minute (cpm) were determined on a beckman ls scintillation counter. the blastogenic response of lymphocytes was expressed as a stimulation index (sz) which was defined as the ratio of experimental to control cpm. leukocyte differential counts were performed on wright-stained smears made from edta blood samples. total white blood cell (wbc) and red blood cell (rbc) counts were determined on a coulter model s-plus iv (coulter electronics, inc., hialeah, fl). pbmcs were dispensed into ml tubes at a concentration of x lo cells per tube and washed once with . m pbs ph . . cell suspensions were analyzed by one-color flow microfluorometry using monoclonal antibodies. staining was conducted in either a direct or an indirect method with the following fluorescein isothiocyanate (fitc) conjugated antibodies: . pg anti-dog igm fitc conjugated (bethyl laboratories, inc.); . pg anti-dog igg fitc conjugated (bethyl laboratories, inc.); . pg mouse anti-feline cd fitc conjugated (fisher biotech); . pug biotinylated mouse anti-feline cd (fisher biotech) followed by . pug avidin-fitc (boehring mannheim biochemi-cal& . pg h a (class i major histocompatibility complex (mhc) antigen, vmrd) followed by . pg goat anti-mouse igm,,-fitc (bethyl laboratories, inc.); . pg th a (class ii mhc, vmrd) followed by . pg goat anti-mouse iggc, + l) -fitc (bethyl laboratories, inc). our laboratory has demonstrated that anti-feline cd and cd antibodies (fisher biotech) selectively bind mutually exclusive populations of canine peripheral blood lymphocytes (d.s. mcvey, unpublished data, ) in proportions similar to canine specific cd ( . / . ) and cd ( . / . ) antibodies reported by gebhard and carter ( ) . antibodies were incubated at °c for min. after staining, cells were washed twice with ml of . m pbs ph . , fixed with ~ of % paraformaldehyde, resuspended in ~ of sheath fluid and read at a wavelength of nm on a becton dickinson facscantm flow cytometer equipped with a w argon laser. unstained, avidin-fitc stained, anti-mouse igm-fitc stained, and anti-mouse igg-fitc stained cells served as controls. forward light scatter gates were set on the lymphocyte fraction to exclude dead cells and erythrocytes and lymphocytes were analyzed for each test. filter systems were used to measure light emitted at nm for detection of fitc. analysis was performed using the lysis version . program. the percentage of positive cells was expressed as the percent positive staining for each cell marker minus the control. analysis was conducted using a mixed model analysis of variance and the procglm program of the statistical analysis system with significance at p < . . comparisons were made between treatments within litters and within treatments over time. the two dams that were not vaccinated pre-breeding had average antibody titers of : for cpv and : for cdv. the dam that was vaccinated pre-breeding had cpv and cdv antibody titers of : and : respectively. maternally derived antibody levels to cpv were non-protective (hai < : ) (pollock and carmichael, in pups as early as weeks of age and in all pups by weeks of age (table ) . average maternally derived antibody levels to cdv were less than : by - weeks of age (table ) . although antibody titers varied over time, no significant difference was detected between the maximum and minimum vaccination groups in the antibody response to cpv and cdv vaccination. average cpv antibody titers were near protective values (ha : - : ) by - weeks of age. antibody titers subsequently declined in two of the litters at - weeks of age then increased to protective levels in all litters by months of age (fig. ) . average cdv antibody titers were over : by - weeks of age (table . maximum cdv antibody titers were observed at - weeks of age (fig. ) . .$. . cellular immunity lymphocyte proliferation in response to con a stimulation was generally higher (si = . - . ) than response to pha (sz = . - . ) stimulation (table ). ( ) ( ) ( ) ( ) x ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) lo ( ) ( ) ( ) < lo ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) lo ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ioo ( ) ( ) ( ) ( ) ( ) ( ) ( ) nd nd nd a litter from dam vaccinated immediately prior to breeding. numbers in parentheses are the numbers of pups tested. litter , n = ; litter , n = ; litter , n = . nd, test not done. weeks of age proliferation in response to antigens cpv (si = . - . ) and cdv (sz = . - . ) was lower than response to mitogen stimulation (table ). there was no significant difference between the two vaccination groups in response to pha, cpv, and cdv. a significant difference was detected (p = . ) in response to con a stimulation with the (tables and . no significant differences were detected in the expression of class i and class ii antigens of the major histocompatibility complex or in the percentage of cd labeled cells between the two vaccination groups (table ) . a significant treatment effect was detected for cd (p = . ) and igg (p = . ) labeled cells (table ). in addition, a treatment by time interaction was observed for cd (p = . ) and igg ( ' = . ) labeled cells with the maximum vaccination groups being higher at and weeks of age followed by the minimum vaccination groups being equal or higher from weeks of age on (figs. and , table ). at no specific point in time, however, was this interaction significant. a treatment by time interaction was observed for igm labeled cells (p = . with the maximum vaccination groups having a higher percentage of positive cells at weeks of age followed by the minimum vaccination groups being equal or higher from weeks of age on. at and weeks of age the minimum vaccination groups had a significantly higher percentage of lymphocytes expressing surface igm than the maximum vaccination groups (p-values . and . respectively) ( fig. and table ). data presented here indicate that no significant difference occurred in the humoral immune response between racing greyhounds subjected to multiple vs. minimal vaccination schedules. antibody levels to cpv and cdv did not increase at an earlier time period in greyhounds vaccinated at weeks of age compared with those vaccinated at weeks of age. in addition, antibody levels did not reach higher levels in greyhounds vaccinated with multiple vaccination schedules (figs. and ). this suggests that there was no apparent increased protection against disease in greyhounds that were vaccinated both at an earlier age and more frequently. maternal antibody levels to canine parvovirus were non-protective at the time of whelping in two of our adult greyhounds even though they were obtained from track or kennel environments where exposure to natural cpv was likely. our third female was vaccinated pre-breeding but only achieved a cpv antibody titer of : at the time of whelping. the reason for these poor antibody levels in our adult greyhounds is unknown but could be attributed to environmental stresses. average antibody titers to cpv vaccination were poor in both experimental groups with all puppies not achieving protective antibody titers until weeks of age. although the reason for this poor antibody response to cpv is unknown, it should be noted that both schedules initially used killed parvo vaccines. a recent report (blythe et al., ) advocating the use of killed parvo vaccines until - weeks of age in kennel situations states that modified live parvo vaccines can lower the immune status of pups for up to days. recent work in this laboratory investigating the use of modified live parvo vaccines in greyhound pups beginning at weeks of age and then vaccinating every weeks have recorded higher cpv antibody titers than when killed vaccines are used (unpublished data). modified live vaccines typically give a better immune response than killed vaccines by virtue of their ability to undergo limited replication in the host which stimulates both cell-mediated and antibody-mediated immunity (ellis, ) . since killed vaccines do not replicate in the host they are inherently less efficient inducers of the cell-mediated immune system. it is possible that the killed parvo vaccine administration to these young greyhounds resulted in enough seroconversion to inhibit the ability of the modified live vaccine to replicate. consequently, lower antibody titers to cpv resulted. a decline in cpv antibody titers was observed in two litters at - weeks of age. a similar decline in cdv antibody titers post-vaccination has been reported in greyhounds (webster, ) . cpv and cdv vaccinations have been reported to be immunosuppressive in that they cause a decrease in the number of circulating lymphocytes and their ability to respond to mitogens (povey, ; mastro et al., ; krakowka et al., ; phillips et al., ) . another study, however, found no evidence of immunosuppression as a result of cpv vaccination (phillips and schultz, ) . a recent study (miyamoto et al., ) reported a decrease in leukocyte and lymphocyte counts on day post vaccination in both puppies and adult dogs. this study also demonstrated an increase in the blastogenic response of lymphocytes after vaccination in puppies and no change in adult dogs. consequently, suppression as indicated by lymphopenia or decreased response to mitogen stimulation may be dependent upon sampling time post-vaccination. our investigations were conducted in order to examine the difference in the immune response to traditional vs. aggressive vaccination protocols and to determine if aggressive vaccination is beneficial in terms of immune function. throughout the study, leukocyte and lymphocyte counts remained within normal reference ranges (data not shown) and the ability of peripheral blood lymphocytes to respond normally to mitogens was not diminished as a result of multiple vaccine administration. the maximum vaccination group exhibited a greater response to stimulation by con a than did the minimum vaccination group. this effect could be due to the more frequent stimulation of the immune system by the maximum vaccination schedule resulting in the proliferation of immature t-lymphocyte subpopulations. or, as miyamoto et al. ( ) suggested, vaccination may act in an immunomodulatory fashion in puppies resulting in an increased blastogenic response. the maximum vaccination group did not exhibit a greater response than the minimum vaccination group to stimulation by pha. con a has been shown to be a strict t-cell mitogen for the dog. pha is capable of causing both t-lymphocyte and b-lymphocyte differentiation (krakowka and ringler, ) . if immature t-lymphocytes comprise a greater percentage of the peripheral blood population in the maximum vaccination group, these immature t-lymphocytes would be more responsive to con a than to pha. while lymphocyte phenotyping has been performed for many years in humans and mice, relatively few reagents exist for phenotyping in other animal species, in particular the dog. owing to a lack of commercially available specific canine reagents, cross-reactive anti-feline cd and cd markers were used. these antibodies bind to mutually exclusive populations of canine peripheral blood lymphocytes in proportions similar to monoclonals described by gebhard and carter ( ) and are co-expressed on approximately % of thymocytes from beagle pups. this is in agreement with the proportion of double positive lymphocyte expression in the thymus of all species where monoclonals have been defined (tompkins et al., ) . anti-feline cd antibody additionally binds to canine peripheral blood granulocytes and immunoprecipitates reduced peptides in the range of - kda. this is comparable to that reported for canine specific cd antibody (gebhard and carter, ) . reported normal values of these lymphocytes subpopulations for adult dogs and cats are similar with % cd t-and % cd -t lymphocytes in the dog and % cd + and % cd + lymphocytes in the cat (dean, et al., ; gebhard and carter, ) . age, antigenic load, and environmental conditions, however, may greatly influence lymphocyte subpopulations (joling et al., ) . multiple vaccine administration did not significantly alter the frequency distribution of cd and igg labeled lymphocytes. a significant treatment effect and a treatment by time interaction existed for cd labeled lymphocytes and for lymphocytes expressing surface igg. the average weekly means for the minimum vaccination groups were higher than the maximum vaccination groups from weeks of age until the completion of the study (figs. and ) . this difference, however, was not significant at any one point in time when the least squares means were compared. consequently, the difference in treatment appears to depend on the week or on the sampling time post vaccination and not on the specific treatment. the significant treatment by time interaction observed in igm expressing cells indicated that the minimum vaccination groups had a significantly higher percentage of peripheral blood lymphocytes expressing surface igm at and weeks of age compared to the maximum vaccination groups (fig ) . this could be the result of different sampling times post vaccination in the two treatment groups. the minimum vaccination groups received a modified live vaccine week prior to both of these sampling times. the maximum vaccination groups received a killed vaccine at weeks of age and a modified live vaccine at weeks of age. the higher percentage of igm expressing lymphocytes may be a reflection of seroconversion in the minimum vaccination groups. a similar proliferation could have occurred in the maximum vaccination groups after the, week modified live vaccination but due to a difference in sampling time post vaccination this response was not detected. in addition, no overall significant treatment effect was detected for igm expressing lymphocytes. consequently, this does not likely represent a deficiency in the immune response of the maximum vaccination groups. the administration of extensive vaccination schedules as described here is a common practice in the racing greyhound industry. these extensive vaccination protocols are used in an attempt to provide early and complete protection against the common viral pathogens and to prevent extensive financial losses due to disease outbreaks. the cost of supporting the extensive vaccination protocols in the greyhound industry in one county alone in kansas is estimated to be $ - year-'. experimental evidence presented in this report indicates that the use of multiple vaccination protocols in racing greyhounds raised in laboratory conditions does not increase the ability of their humoral immune system to respond to viral antigens. although this practice does not appear to be detrimental to the immune system, the cost vs. benefit of implementing such extensive vaccination schedules is questionable. it is important to note, however, that most racing greyhounds in kennel situations are exposed to environmental conditions that were not present in the laboratory experiments described here. therefore, further evaluation of the influence of multiple vaccination schedules on the immune system of racing greyhounds raised in kennel situations and exposed to environmental stress is currently being conducted in this laboratory. a microneutralization test for canine distemper virus canine and feline immunization guidelines host defense in the newborn animal care of the racing greyhound: a guide for trainers, breeders and veterinarians hemagglutination by canine parvovirus: serologic studies and diagnostic applications flow cytometric analysis of t-lymphocyte subsets in cats new technologies for making vaccines lymphocyte proliferation identification of canine t-lymphocyte subsets with monoclonal antibodies distribution of lymphocyte subpopulations in thymus, spleen, and peripheral blood of specific pathogen free pigs from to weeks of age combined mlv canine parvovirus vaccine: immunosuppression with infective shedding activation specificity of commonly employed mitogens for canine band t-lymphocytes immunosuppression by canine distemper virus: modulation of in vitro immunoglobulin synthesis, interleukin release and prostaglandin ez production repeated suppression of lymphocyte blastogenesis following vaccinations of cpv-immune dogs with modified-live cpv vaccines changes in blastogenic responses of lymphocytes and delayed type hypersensitivity responses after vaccination in dogs failure of vaccine or virulent strains of canine parvovirus to induce immunosuppressive effects on the immune system of the dog effects of vaccines on the canine immune system maternally derived immunity to canine parvovirus infection: transfer. decline, and interference with vaccination distemper vaccination of dogs: factors which could cause vaccine failure theoretical and practical aspects of an immunization program for dogs and cats assays of cellular immunity characterization of monoclonal antibodies to feline t lymphocytes and their use in the analysis of lymphocyte tissue distribution in the cat distemper vaccination response in greyhounds: breed variation this work was supported by the kansas racing commission. the authors would like to thank m. dalby and w. schumann for their technical assistance. this paper is contribution no. - of the kansas agricultural experimental station, kansas state university, manhattan. key: cord- -mo mvwch authors: huang, jiechen; wang, juan; xia, chengyi title: role of vaccine efficacy in the vaccination behavior under myopic update rule on complex networks date: - - journal: chaos solitons fractals doi: . /j.chaos. . sha: doc_id: cord_uid: mo mvwch how to effectively prevent the diffusion of infectious disease has become an intriguing topic in the field of public hygienics. to be noted that, for the non-periodic infectious diseases, many people hope to obtain the vaccine of epidemics in time to be inoculated, rather than at the end of the epidemic. however, the vaccine may fail as a result of invalid storage, transportation and usage, and then vaccinated individuals may become re-susceptible and be infected again during the outbreak. to this end, we build a new framework that considers the imperfect vaccination during the one cycle of infectious disease within the spatially structured and heterogeneous population. meanwhile, we propose a new vaccination update rule: myopic update rule, which is only based on one focal player’s own perception regarding the disease outbreak, and one susceptible individual makes a decision to adopt the vaccine just by comparing the perceived payoffs vaccination with the perceived ones of being infected. extensive monte-carlo simulations are performed to demonstrate the imperfect vaccination behavior under the myopic update rule in the spatially structured and heterogeneous population. the results indicate that healthy individuals are often willing to inoculate the vaccine under the myopic update rule, which can stop the infectious disease from being spread, in particular, it is found that the vaccine efficacy influences the fraction of vaccinated individuals much more than the relative cost of vaccination on the regular lattice, meanwhile, vaccine efficacy is more sensitive on the heterogeneous scale-free network. current results are helpful to further analyze and model the choice of vaccination strategy during the disease outbreaks. over the past two decades, the outbreak of infectious diseases has been threatening the safety of human lives and properties, such as the severe acute respiratory syndrome sars [ ] , h n [ ] , ebola [ ] and so on. thus, how to prevent the extensive outbreaks of epidemics has become a challenging topic in the field of public health [ ] [ ] [ ] . meanwhile, the difference of population distribution, religious belief and regional differences may greatly affect the spread of infectious diseases, for example, refs. [ ] [ ] [ ] [ ] explore the impact of various topological structures within the population on the infectious diseases spread, and it is convincingly found that heterogeneous networks may quicken the disease spreading within the population, even lead to the absence of epidemic threshold [ ] . meanwhile, the individual reactions to infectious diseases may also substantially influence the diffusion processes of epidemics. one of the most striking cases regarding the outbreaks was h n pandemic in [ ] , which induced around , deaths. during the outbreaks of h n , the suppression of epidemic processes can not only be attributed to the public measures, but also through personal and uncoordinated responses, that is, the human behavior has noticeably interfered with the epidemic spreading. in the long run, human behavior has been intricately correlated with the contagion of infectious diseases. in medieval ages, the deadly bubonic plague rendered many people to avoid and flee away from the sick and their close contacts so that their own immunity can be secured [ ] . similarly, the villagers of yorkshire in eyam tried to voluntarily quarantine themselves to stop the spread of the plague from that village [ ] . in , during the outbreak of sars, many citizens spontaneously wear the face masks, some schools are temporarily closed and the students are imperatively required to stay at home so as to avoid the further epidemic infection as much as possible [ ] . in addition, protective behavior when confronting the epidemics has also been observed in many other contexts, such as measles-mumps-rubella(mmr) [ ] , tuberculosis(tb) [ ] and hiv [ ] etc. while the impact of human behaviors on the epidemic spreading process has often been mentioned anecdotally, the accurate modeling or quantitative models are relatively fewer regarding their nature, property, or the effect they may have on the spread of the disease. at present, mathematical models have been put forward to study the role of human behavior in the context of social population, such as escape panic [ ] , pedestrian trails [ ] , but effort s to quantitatively explore the role of human behavior in the large-scale epidemics generally focus on assessing the effectiveness of various public health measures including the social distancing, school closure etc. in the recent years, there are many fields and methods to help us to study infectious disease [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , however, there is an increasing attention about the effect of spontaneous individual action or response strategy on the progression of an infectious disease, in which this kind of spontaneous actions may highly restrain from the further diffusion of epidemics and even change the fate of outbreaks. thus, it is of great significance to fully understand the interacting mechanisms between the human behavior and disease dynamics within the specified population. it is worth mentioning that funk et al. [ ] systematically summarized the related works and provided a taxonomy framework of behavior-disease models. on the one hand, they classify these models according to source and type of information that individuals base their neighbors on, in which source of information may be local or global and the type of information that individuals change their behaviors are prevalence-based or belief-based; on the other hand, they classify the previous works based on the impact of individual behavior changes on the disease dynamics, which include the following three aspects: (i) the disease state; (ii) model parameters (infection or recovering rate); and (iii) the network contact structure relevant for the spread of epidemics. in particular, for some preventable infectious diseases with the help of vaccines, the epidemic outbreaks are intricately linked with the individual vaccination behavior since the vaccines can help the vaccinators not to be infected by a specific disease. meanwhile, these vaccinators may indirectly protect their nearest neighbors with whom they contact, and then these neighbors may choose not to vaccinate again (that is, free-ride the vaccinators) so as to avoid the necessary vaccine fees or other potential risk and side effects. henceforth, the vaccination behavior may dominate the evolutionary process of vaccine preventable diseases. among them, bauch and earn [ ] seminally utilized the game theory to model the dilemmatic situation for an individual facing with the epidemics, and they proposed a class of vaccination game to denote the individual decision making and found that, for the well-mixed population, the nash equilibrium is never to vaccinate if the vaccination cost is higher than that of being infected; but there exists a nash equilibrium yielding a suboptimal vaccinated fraction if the vaccine cost is lower than that of being infected. as a further step, complex networks, beyond the well-mixed topology, provide a unified platform to characterize the topology of real-world populations, where the nodes represent individuals and links mimic the contacts among them [ ] . thus, under framework of game theory, many works are devoted to exploring the interplay between contact patterns, behavioral responses and disease dynamics. as an example, fu et al. [ ] found that heterogeneous networks, such as scale-free ones, can induce a broad range of vaccinating actions of many individuals since highdegree hubs with many neighbors become voluntary vaccinators more probably in order to reduce the risk of being infected. after that, zhang et al. [ ] demonstrated that the hubs may largely inhibit the outbreaks of infectious diseases under the voluntary vaccination policy. in the meantime, various subsidy policies on controlling the epidemic spreading have been determined from the socioeconomic perspectives within the well-mixed and networked population [ ] [ ] [ ] [ ] [ ] [ ] . furthermore, most previous works [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] often assume that the vaccine has a perfect efficacy, which will endow the complete immunity for the inoculated individuals, but an interesting topic is on how the epidemic spreads when the vaccine is not fully effective for the disease (i.e., % efficacy)? besides, in the vaccination game, whether an individual decides to vaccinate the vaccine or not will be often determined by the estimated payoff, and the vaccinating decision may be transferred from one player to another one inside the population according to a specific role model during the outbreaks. nevertheless, under some real-world scenarios, some individuals are not willing to imitate the behaviors of others as a result of special belief, religion, opinion and even awareness of a disease. according to the above description, in the real world, when a new epidemic starts to outbreak, people want to take some measures to protect themselves immediately. generally, inoculating the vaccine is considered as an effective measure, but the vaccine may fail as result of invalid storage, transportation and usage, and then rendered that the vaccinated individuals may confront the risk of being infected. henceforth, some individuals make a decision to vaccinate just judge by themselves and don't consider their neighbors. thus, in order to deeply analyze the role of vaccine efficacy and spontaneous individual decision mechanism in the outbreak of vaccine preventable diseases, we propose a vaccination game model to explore the impact of imperfect vaccine efficacy and myopic update rule in the spatially structure and heterogeneous populations. the rest of this paper is structured as follows. firstly, we depict the new vaccination game model in section in detail. then, section provides extensive numerical simulation results, which are obtained in the regular lattice and heterogeneous scalefree networks, respectively. lastly, in section , we end this paper with some conclusions and point out the potential works in the future. as mentioned above, we consider the vaccination game for a class of emerging epidemics within the structured population, where the vaccine can be obtained after the epidemic spreads. thus, in the current model, all individuals have no chances to vaccinate at the initial time step ( t = ). after that, each time step ( t ≥ ) is divided into two elementary sub-steps: one step is for the decision of inoculating the vaccine; the other one is used to model the process of epidemic spreading. among them, for the epidemic sub-steps including t = , we leverage the frequently used susceptible-infective-recovery (sir) compartment model to characterize the evolution of epidemics, where each individual may lie in the susceptible (s), infective (i) or recovery (r) state. during the vaccination decision sub-steps, each susceptible individual needs to assess the risk of being infected, and then make the decision whether he will vaccinate or not. regarding the sir model, any susceptible individual may be infected through the contact with infective neighbors and the transmission rate along each infective link is assumed to be β. meanwhile, the infected individual can be cured with the recovering rate μ, and the recovered one will not be infected again or infect any other healthy ones. hence, the probability that the susceptible player i without inoculating the vaccine will be infected by all possible infective neighbors can be written as follows, where k i in f denotes the total number of infected neighbors of the focal player i . the epidemic continues until there are no more newly infected individuals. as for the individual vaccination decision, each susceptible one will evaluate the risk of being infected and compare the difference between the vaccine cost ( c v ) and the potential expenses once he has been infected. without loss of generality, we fix the infection cost c i = , while the vaccine cost is usually lower than c i and then its relative cost can be re-scaled as < c = c v /c i < . in order to quantitatively perform the decision, by borrowing from the terms in game theory, we assume that the decision process is based on the comparison between the perceived payoffs of vacci-nation i v and the perceived payoffs of being infected i nv if he is not vaccinated, which can be expressed as follows, respectively, where λ i denotes the potential infection probability that can be calculated according to eq. ( ) . then, the susceptible agent i will independently decide to inoculate the vaccine with the following fermi-like probability, where k represents the impact of the noise or its reverse / k means the strength of strategy selection, which reflects the uncertainty of vaccination strategy adoption. here, we term this vaccination decision as the myopic update rule just based on one player's own perception, which is different from imitating the vaccination strategy of others in many previous works [ , , [ ] [ ] [ ] [ ] [ ] . when k → , agent i is totally rational and whether he will vaccinate or not is fully determined by comparing i v and i nv , on the contrary, when k → ∞ , agent i will randomly perform the vaccination choice. in addition, we consider the imperfect vaccination program, that is, the vaccine efficacy is not % and the vaccination may fail as a result of incorrect transportation, storage, and usage of vaccine. thus, we introduce an independent parameter θ to characterize the vaccine failure rate, which implies that the susceptible individual to choose the vaccination is still kept in the susceptible state with the probability θ , while the probability changing from s into v ( s → v ) state is set to be ( − θ ). once the healthy individual decides to vaccinate, he will have a chance to enter into the vaccinated ( v ) state, the sir epidemic dynamics will evolve into the sirv model as illustrated in fig. , in which the successfully vaccinated individual will be equivalent to the r-type one at the next time step, that is, the successfully vaccinated (v-type) agent does not get the infection or infect others, either. we do not know when does vaccine fails, so that at each propagating time step, inoculation individuals are judged whether the vaccine is fails or not. to be noted, the vaccinated healthy individuals will not be vaccinated again during this epidemics even if the vaccine lost its effect. in order to further explore the impact of network topology on the evolutionary process under the imperfect vaccination, we simulate the current mechanism on l × l regular lattices and scale-free networks with n = l nodes, respectively. initially, we stochastically choose i = individuals as the infective seeds within the population, and other ( n − i ) individuals are kept in the susceptible state, and thus there have no vaccinators. at t = step, the system starts the evolution according to the sir model. after that, from t = , each susceptible agent has the opportunity to receive the vaccination and then the system carries out the evolution of epidemics based on the above-mentioned two elementary steps. the system continuously evolves until there are no infective individuals. in addition, the current results are averaged over independent runs so that the large fluctuations can be removed. in all the numerical simulations, the population size is fixed to be n = . in the homogenous topology, we use the regular lattice satisfying the periodic boundary with the size l = as the underlying networks, and each individual has nearest neighbors (that is, the von-neumann neighborhood). as for the heterogeneous topology, we generate the scale-free network by using the configuration model, in which the average degree is fixed to be < k > = and the power exponent is set to be γ = . in this section, we conduct extensive numerical simulations to demonstrate the vaccination behavior on the regular lattices and scale-free networks, respectively. among them, we mainly discuss the influence of vaccine cost c and failure rate θ on the collective vaccination level within the population. without loss of generality, we set the value of parameters in the sir model as β = . and γ = / , which are identical with those in ref. [ ] . first, we investigate the equilibrium fraction of both vaccinated ( ρ v ) and recovered ( ρ r ) state individual size for different values of relative cost of vaccination c and vaccine failure rate θ . fig. plots . (yellow triangle), respectively. on the one hand, for a specific vaccine failure rate θ , ρ v declines with the increase of the relative vaccination cost c , while ρ r increases as c augments, which means that the vaccination cost will markedly affect the willingness of individuals to inoculate the vaccine. as an example, when c ≤ . , ρ v and ρ r can almost keep the similar vaccination level as c increases; however, c > . leads to the substantial reduction of ρ v and the continuous rising of ρ r since the vaccination cost is comparable to the infection cost; in particular, ρ v will be dramatically reduced when c is up to . , even tends to zero as the vaccination cost is too high, especially for c = . . on the other hand, under the same vaccination cost c, ρ v decreases as the vaccine failure rate becomes higher, for instance, the fraction of adopting the vaccination strategy under c = . is much less than that with c = . , which implies that the vaccinated fraction within the whole population will be a little more sensitive to the vaccine failure rate. then, we discuss the influence of the noise factor k on the vaccination behavior within the population in fig. , where we set σ = k , termed as the strength of selection ( < σ < ∞ ), as and . , which are slightly different from that in fig. . likewise, it can be clearly shown that ρ v declines and ρ r increases slowly when the relative cost of vaccination c lies between and . . afterwards, when the relative cost of vaccination c is more than . , the greater the noise selection strength, the more rapidly the varying trend of ρ v and ρ r . in fact, as the strength of selection increases, individuals become much more rational and will not tend to take the vaccination strategy since they will take their own economic cost and the related interests, say, free-riding behavior, into account. in particular, the relative cost c is beyond . , or the vaccine loss rate is higher (i.e., θ = . ), the un-vaccination behavior of rational individuals become much more prominent, and thus it is unable to prevent the outbreaks of epidemics, which can be observed from the larger ρ r as c > . or θ = . . next, in order to fully check the impact of relative vaccination cost c and the vaccine failure rate θ on the vaccination behavior, fig. illustrates the evolution of ρ v and ρ r within the broader ranges of c and θ . it is clearly indicated that at the lower vaccine failure rates (say, θ < . ), the fraction of vaccinated individuals is often more than half of the total population, even if relative cost of vaccination c is large (e.g., . ); meanwhile, a plethora of vacci- thus, creating the high quality vaccine is significant, which greatly determines the individual vaccination inclination. furthermore, to deeply understand individual state change in the lattice as sirv model evolves, we record the evolutionary snapshots of individual states at various time steps for θ = . , c = . and θ = . , c = . in fig. . among them, the upper eight panels denote the snapshots under θ = . and c = . , while the lower eight panels represent the ones for θ = . and c = . . at time step t = , there are no vaccinated individuals on the lattice and only i = randomly infected seeds, and then the epidemic starts to propagate at this time. after that ( t ≥ ), the susceptible individuals have the opportunity to determine whether they will inoculate the vaccine or not. it is clearly observed that most individuals choose to vaccinate under these two cases when epidemic begins to spread. however, when θ = . is lower, there is fewer vaccinated individuals to become susceptible, and then most of vaccinated individuals are immunized, in which the epidemic is hard to spread and finally tends to be extinct. reversely, for the higher vaccine failure rate (i.e., θ = . ), the vaccine is easy to be invalid, many vaccinated individuals become susceptible due to the loss of vaccine efficacy. therefore, the epidemic can be pandemic and then most of individuals enter the recovered state in the end. all these results again demonstrate that the vaccine efficacy plays the significant role in the evolution of vaccination behavior of epidemic outbreaks within the structured population. in the real world, many networks are often heterogeneous, and thus it is necessary to understand the mechanics of myopic update rule better on heterogeneous topology. to this end, we formulated the game of taking the vaccine on the scale-free network. here, we generate the scale-free network with , node under the configuration model, where the average degree of the whole network is equal to and the power exponent . after the fundamental networks are created, the system evolves according to the sirv model, which is identical with the iteration procedure on regular lattices, and the epidemic continues until there are no more newly infected individuals. first of all, we plot the time courses of fraction of susceptible, vaccinated and recovered individuals for different the relative cost of vaccination c and vaccine failure rate θ in fig. . in all panels, the red, blue and yellow lines denote the evolution of susceptible, recovered and vaccinated individuals, respectively. it can be found that the vaccinated individuals increase rapidly in a very short time, and then reach a peak. vaccinated individuals are rarely become susceptible because of the vaccine failure θ is lower (as shown in fig. a,c) so that the number of recovered ones increases a little and arrives at the equilibrium quickly, which states clearly that the epidemic is eliminated and has not become pandemic. due to the vaccine failure rate, the fraction of vaccinated individuals goes down and then tends to be zero after reaching the peak. however, when the value of vaccine failure rate θ is raised (as shown in fig. b,d) , even though the vaccinated individuals increase rapidly, they become susceptible quickly due to the high vaccine failure rate θ , it can't prevent the epidemic spread so that the number of recovered individuals increases. additionally, we found that for the value of vaccine failure rate θ = . , whatever the values of relative cost of vaccination c , the number of recovered agents is the same as that at the equilibrium. generally, when the epidemic starts to spread, many susceptibles take the vaccine in the population at a short due to the perception of infection risk. also, this vaccination behavior is almost widespread regardless of the values of relative cost of vaccination c and vaccine failure rate θ . at the lower vaccine failure rate, vaccinated individuals are hard to become susceptible, which leads to the disease propagates difficultly and be eliminated as soon as possible. these results are also consistent with the work of zhang et al. [ ] , since the hub nodes are often vaccinated immediately after the disease starts to spread. but for the higher vaccine failure rate, the vaccinated individuals become susceptible quickly, the disease can outbreak. we also consider the equilibrium fraction of both vaccinated ( ρ v ) and recovered ( ρ r ) state individual size for different values of it can be found that in the figs. and , whatever the ways of vaccination, the epidemic can outbreak and vaccinated individuals are more sensitive to the vaccine failure rate. therefore, except β = . , we consider the epidemic evolution of sirv model under the lower transmission rate β = . . meanwhile, we set the i = initial infective seeds as the top largest degree nodes, which is here termed as the hub infection scheme. correspondingly, we call the randomly selecting one for the generous case as the random infection. in summary, based on the sir epidemic dynamics, we investigate the imperfect vaccine immunity under the myopic update rule in different foundation topology including the regular lattice and scale-free networks, where the focal player makes the vaccination decision just according to his own judgement about the epidemic situation. extensive numerical simulations show that most unvaccinated susceptible individuals are willing to inoculate the vaccine under the myopic update rule, whatever the type of network is, in particular for the lower vaccine cost ( c ≤ . ) and failure rate ( θ ≤ . ). after the epidemic starts to propagate, and most of individuals change their strategies to adopt the vaccine in a short time since the individual can estimate the infection risk at the early stage, which leads the epidemics to be hard to spread within the population. however, due to the failure of vaccine or the free-riding behavior of susceptible individuals, vaccinated individuals become susceptible again and then confront the risk of being infected, which creates the potential epidemics situation. to be of great interest, we find that the impact of vaccine failure rate on the vaccination coverage becomes much higher, when compared to the role of the relative cost of vaccine. for example, the value of vaccine failure rate θ is usually assumed to be no more than %, or else most vaccinated individuals become re-susceptible again. at a fixed θ , the fraction of vaccinated individuals almost keep unchanged when the relative vaccine cost is not beyond c = . , but this value will become lower and lower after c is more than . , which is basically consistent with the reality of vaccine usage. on the contrary, on the scale-free networks, the number of vaccinated individuals is more sensitive to the effect on vaccine failure rate θ . hub nodes have a stronger inclination to adopt the vaccine under the myopic update rule, which can effectively prevent the diffusion of epidemics. hence, the disease will be eliminated quickly in heterogeneous topology. however, when the values of vaccine failure rate increase a little bit, hub nodes become susceptible and cannot prevent the epidemic spread, which leads to the epidemic outbreak. meanwhile, when the relative cost of vaccination c increases, unvaccinated susceptible individuals are not willing to choose the vaccination strategy, which can not stop the outbreak of infectious diseases. when the vaccine failure rate further increases, such as . , the number of vaccinated individuals decays to zero before the epidemic is eliminated, which is almost equivalent with the classic sir model. anyway, current results are conducive to better understanding the individual vaccination behaviors when confronting the real epidemics. the authors declare that they do not have any financial or nonfinancial conflict of interests. transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions novel influenza a (h n ) pregnancy working group. h n influenza virus infection during pregnancy in the usa an outbreak of ebola in uganda infectious diseases of humans: dynamics and control evolving public perceptions and stability in vaccine uptake vaccination greatly reduces disease, disability, death and inequity worldwide modelling disease outbreaks in realistic urban social networks dynamic social networks and the implications for the spread of infectious disease when individual behavior matters: homogeneous and network models in epidemiology a high-resolution human contact network for infectious disease transmission capturing human behaviour early assessment of anxiety and behavioral response to novel swine-origin influenza a(h n ) plagues and peoples biology of plagues: evidence from historical populations sars-related perceptions in hong kong institute of medicine (us) immunization safety review committee. immunization safety review: measles-mumps-rubella vaccine and autism immunology of tuberculosis the responsiveness of the demand for condoms to the local prevalence of aids simulating dynamical features of escape panic modelling the evolution of human trail systems dynamic cluster formation game for attributed graph clustering fast and accurate mining the community structure: integrating center locating and membership optimization detecting prosumer-community groups in smart grids from the multiagent perspective enhance the performance of network computation by a tunable weighting strategy blockchain-based medical records secure storage and medical service framework diabetic complication prediction using a similarity-enhanced latent dirichlet allocation model smart electronic gastroscope system using a cloud-edge collaborative framework social and juristic challenges of artificial intelligence the impact of awareness diffusion on sirlike epidemics in multiplex networks a new coupled disease-awareness spreading model with mass media on multiplex networks improved centrality indicators to characterize the nodal spreading capability in complex networks interplay between sir-based disease spreading and awareness diffusion on multiplex networks modelling the influence of human behavior on the spread of infectious diseases: a review vaccination and the theory of games epidemic dynamics on complex networks imitation dynamics of vaccination behavior on social networks hub nodes inhibit the outbreak of epidemic under voluntary vaccination policy evaluation for the subsidy for influenza vaccination in elderly does subsidy work? price elasticity of demand for influenza vaccination among the elderly in japan impacts of subsidy policies on vaccination decisions in contact networks simulation analysis of vaccination subsidy with abm approach preferential imitation can invalidate targeted subsidy policies on seasonal-influenza diseases subsidy strategy based on history information can stimulate voluntary vaccination behaviors on seasonal diseases effects of behavioral response and vaccination policy on epidemic spreading -an approach based on evolutionary-game dynamics a susceptible-infected epidemic model with voluntary vaccinations group interest versus self-interest in smallpox vaccination policy imitation dynamics predict vaccinating behavior impact of committed individuals on vaccination behavior the impact of imitation on vaccination behavior in social contact networks the influence of social norms on the dynamics of vaccinating behavior for paediatric infectious diseases risk assessment for infectious disease and its impact on voluntary vaccination behavior in social networks can influenza epidemics be prevented by voluntary vaccination? this project is financially supported by the national natural science foundation of china (nsfc) (grant nos. and ). key: cord- -rjud iz authors: horzinek, marian c. title: vaccine use and disease prevalence in dogs and cats date: - - journal: veterinary microbiology doi: . /j.vetmic. . . sha: doc_id: cord_uid: rjud iz abstract a yearly revaccination of adult pets against distemper, the adenoviral and parvoviral diseases is scientifically unwarranted, professionally obsolete and ethically questionable; other vaccinal antigens, however, may need yearly or even more frequent injections. base immunisation is redefined: it is complete only after the multivalent booster in the second year of life. a yearly revaccination interview, not necessarily an injection, should become the new standard. this interview is a professional service that must be taught, expertly performed and invoiced. adult animals should be “vaccinated to measure”, taking age, breed, lifestyle, the epidemiologic situation, etc. into account. post-vaccination serology should become a guide in revaccination decisions. for a solid herd immunity, more animals of the population must be vaccinated. the profession should issue regular updates of the ‘code of vaccination practice’. to counteract vaccination antagonism, a concerted action of academia, the veterinary profession and industry is required. when lecturing about pet vaccination and vaccine use in the last decade, i used to confront veterinary audiences with the following scenario: 'a pediatrician client presents her cat to a vet and asks: ''doctor, why do i need to pay you a yearly visit for revaccination of my cat? i see my children patients no more than twice in their lifetimes!'' what do you suggest as an answer? can you perhaps be more creative than . . . this is what we always did. . . . this is in the product documentation. . . . this is what most clients want. . . . this is what representatives of our profession want us to do. . . . this does not hurt. . . . this is because the immunity conferred by veterinary vaccines is short-lived. . . . this is scientifically correct . . .'. the ensuing hilarity was somewhat laboured. the difference between the medical approach and the veterinary lore of immunisation against infectious diseases is striking. this is the current schedule for routine childhood vaccination in the netherlands: www.elsevier.com/locate/vetmic veterinary microbiology ( ) - Â ( of which in the first year)-diphtheria, tetanus and polio (all inactivated). Â ( of which in the first year)-pertussis, haemophilus influenzae b. Â-mumps, measles, rubella: at months and years (all live). Â-meningococcus c: at months. due to the different living and hygienic conditions, human babies can take their first live virus immunisations relatively late in life, at months, when they are immunologically mature and maternal antibody interference is no longer a concern. while about one-half of -month-old infants still have detectable levels of maternal antibodies to measles virus, none of the -month-olds show this. among those without passive immunity to measles, only about one-third of the -month-olds mustered enough antibodies upon vaccination to resist an infection, compared with % of the -and -month-olds. consequently, the human immune system continues to develop postnatally, acquiring key abilities past the age of months. the development of the canine immune system shares many similarities with that of the human. in both species immune competence, also of the mucosal immune system, is fully developed before birth although further maturation of the responses may continue into the postnatal period (felsburg, ) . thus, in man, a single booster at years of age is accepted as being sufficient for lifelong protection. this practice is based on epidemiologic evidence only, since challenge based duration of immunity (doi) studies are out of the question. amongst the live virus vaccines are those against measles-the human counterpart of canine distemper. dogs, however, may be treated to a dozen or more boosters during their lifetimes. the question arises whether this is rational. why has veterinary medicine adopted a practice that causes raised eyebrows in the biomedical environment, e.g. when talking to immunologists? the reason is largely historic: in the first years of vaccine development, the objective of maximum protection was thought to be achieved by maximum antigenic stimulation. at the time this seemed to be the right thing to do, with the newly developed, attenuated distemper and canine infectious hepatitis virus preparations. it became common practice in subsequent vaccine developments, including the parvovirus preparations, without asking why. in recent decades, however, the frequency of vaccination has become a matter of debate-first in the usa, more recently in europe. the scenario in germany ( ) turned grim, when a well-informed journalist issued a declaration of war in a nation-wide newspaper. the lay public was activated, the foe included vets and the biologicals industry. in england ( ), a similar initiative of several newspapers based on information contained in a letter from more than british vets, contained quotes like: ''unnecessary, potentially dangerous, fraud by misrepresentation, fraud by silence, theft by deception, complete overkill'' and the like. the scenario world-wide, including the medical scene is not different, and websites abound advertising pamphlets with titles like ''vaccination, social violence and criminality'', ''the hidden truth'', ''vaccines represent a medical assault on the immune system'', ''what doctors don't tell you'', to quote a few. whereas yearly revaccination is a veterinary specialty, indiscriminate vaccination antagonism with traits of paranoia, persecution mania and all kinds of conspiracy theories is not-it is also prominent in the medical environment. actually, the first cartoons depicting a ''vaccination monster', appeared in the th century, short after edward jenner's seminal discovery. from the immunologist's viewpoint, the veterinary profession should weigh the perceived risks of side effects due to overvaccination together with vaccination failures against the true risks of a decreased herd immunity with the re-emergence of epidemics as a consequence. statistically, these are minor problems, when weighing the significance of the sporadic cases of immune-mediated pathology with that of sweeping epidemics. the real and serious threat to veterinary medicine (and of course to the canine and feline populations) is the vaccination antagonism in the public with its aggressive undertones. the professional organizations should be even more concerned about their loss of credibility. the term 'overvaccination' is suggestive in that it evokes the picture of an organism swamped with antigens, its immune system paralysed by too many components in one shot. this is an erroneous conception, in view of the fact that any organism is bombarded with antigenic molecules during its lifetime. in both veterinary and human medicine, this issue has received much attention, also from manufacturers, and the consensus is that carefully selected, tested and registered combinations are neither inferior in immunogenicity nor in safety. in veterinary medicine, overvaccination rather refers to vaccinating with excessive frequency, which has been controversial for more that a decade (''are we vaccinating too much?'' (smith, ) . after a period of indifference, the profession is now faced with organised militant campaigning combined with scaremonging. the reported side effects fulfill the criteria of selective observations, and although some have achieved prominence in the scientific literaturelike the injection site fibrosarcoma in cats -they are comparatively rare. however, also some infections have become rare, and it must be anticipated that vaccination will be discontinued when the disease to protect against is no longer around. the scenario is similar to that during the final phase of smallpox vaccination, when the rare side effects (less than in a million vaccinees) exceeded the number of natural disease cases. in line with the romantic idea that natural infections are superior to vaccines, ''infection parties'' (measles and parvo) are being organized, e.g. in germany. this is both irrational and irresponsible. infections with wild viruses are always more serious than those with their attenuated laboratory counterparts -this is why field strains were attenuated in the first place. voltaire said: ''people who believe in absurdities will inevitably commit atrocities.'' the scientific arguments in favour of less frequent revaccinations are traditionally based on antibody titers. protection against most viral diseases is indeed antibody-mediated, and antibodies are easily measured. in dogs these have been found to persist for more than years, the study did not look later. the high prevalence of adequate antibody responses (cpv, . %; cdv, . %) in a large population (> animals) ''suggests that annual revaccinations against cpvand cdv may not be necessary'' was the authors' conclusion (twark and dodds, ) . in the cat, antibodies to fpv, fcv and fhv were detected for more than four years (mouzin et al., ) . the question whether the titers found are protective or not against a field virus challenge is irrelevant for this discussion. it is not the residual serum antibody that determines survival to challenge but the population of memory cells that can quickly expand. the question about the longevity of memory cells has now been answered experimentally; the question was not, if lifelong immunity exists (which is common knowledge), but whether its mechanism relies on a lifelong presence of the antigen in the animal's organism or of the cells' longevity. the latter was not found to be the case ''memory b-cell persistence is independent of persisting immunising antigen''; (maruyama et al., ) . however, it is not an individual memory b-cell, rather a population of slowly dividing clones that persists during the life of the organism. like in neurobiology, a paradigm has been shattered: neurons and memory cells can indeed divide. finally, duration of immunity (doi) experiments in dogs have now proven beyond reasonable doubt that years protection is achieved against challenge with distemper, adenovirus- and parvovirus (gore et al., ) . while this is a timely -though by no means surprising -finding, it has been achieved at a considerable cost. it is this financial aspect (statistically sufficiently large group sizes, isolation facilities, quarantine conditions) that will preclude any further study of doi, i am afraid. underpinned by the conservatism of the veterinary profession this study will become a monument in veterinary vaccinology and determine the periodicity of revaccination. few will dare to do otherwise, i.e. to vaccinate even less frequently. though it has been the financial mainstay of many a companion animal practice, vaccination is not exciting. an injection is technically not as demanding as repairing a fracture, and the client does not see much -if she does, it is the failures: the side effects and vaccination breaks. neither can the vet impress her client -she vaccinates, but cannot (and for time reasons does not want to) explain the basic principles of immunology and epidemiology to the client. nor can any effect of the immunisation be shown. what is commonplace in surgery and internal medicine is lacking here: vaccination is probably the only veterinary measure without a follow-up. it is what i called the ''shoot-and-trust principle''. post-vaccination serology (pvs) would introduce evidence, and serve the industry and the profession alike, but it meets with considerable opposition. a yearly vaccination interview, sensibly part of a yearly health check, but not necessarily followed by an injection, should become the standard. why yearly, why an interview, what should it be about, how should it be performed-these are the obvious questions. why yearly? because many owners are used to that routine, to contact their vets for the yearly shot, for a dental appointment or other health reasons. decisions about holiday travels are taken on a yearly basis, with possible vaccinological consequences (stay in a boarding kennel, cattery, visit to foreign countries with new pathogens). the vet can schedule these visits, to entertain the relationship with the client and show responsibility for the animal family member. why an interview? because it provides the practitioner with informations necessary to take vaccinological decisions and to explain them to the client. if she fails to do this, the client will obtain them from sources of doubtful reliability. however, a conversation not only informs about the measures to be taken, it also prepares, encourages, warns, reassures and comforts. its first purpose is to build a vet-client relationship of trust, which needs to be established and developed. ''customer loyalty'' is the term in commercial publications, and a practice is a business enterprise after all. this relationship is in need of improvement -only about % of the clientele return for follow-up vaccinations; the last visit to the vet obviously did not leave a lasting impression. this is hardly unexpected: an injection given in passing, to minimise the time investment, cannot achieve customer loyalty. this myopia has done much damage to the profession. after all, the client has prepared her visit to the veterinary clinic, comes with expectations, opinions (and prejudices), which need to be taken seriously. to reject the client's views as an irrelevant lay opinion is no basis for a dialogue. emotional and social intelligence will eventually be decisive factors for forging a lasting relationship with the owner. the vaccination interview will be different for each year, and a catalogue of questions and answers must be developed. for the first year it might look as follows: the owner is informed about the preventable diseases. the advantages of vaccination versus treatment. possible side effects and complications. possible lack of protection. risk/benefit considerations. how to handle the vaccinee after the shot. the basic vaccination program (with the boosters in the second year). the onset and duration of protection. the origin of the animal. the responsibilities within the family. other animals in the household. vacations and travel plans (abroad). medical (vaccination) history, previous treatments, etc. the interested dialogue is of paramount importance (professionals like to hold monologues); questions for self-assessment include: did i practice active listening? did i show empathy? did i choose the right place, time, situation, climate? did i feel pressed for time? did i take in all messages? did i use the correct query technique? did i stimulate the client to ask questions? did i properly structure the interview (introduction, aim, course, conclusion)? did i respect the listener's need for pauses? did i use killer phrases? did i use diversion strategies (stray, digress, evade, deviate, disparage, patronize, condescend)? did i ask too much from the client? did i ignore (or even induce) worries in the client? was my client's reality the same as mine? the vet is the authoritative source of healthrelevant information and sells her knowledge (exper-tise) to the client. as long as this context is ignored, the prestige of the profession remains at stake. the interview with its considerations of the patient history, of explanations of risks and contra-indications, of the reaching of agreements, and of an informed consent, will be followed by a clinical examination: only healthy animals are vaccinated. whereas the ''one-size-fits-all'' shot has been practiced as a routine in the past, ''vaccination to measure'' will have to come in its place in the future. any ad hoc vaccination must address the individual risk of infection and disease of the vaccinee-a pampered devon rex has a lifestyle different from a stray cat, when considering the risk of exposure; the former may leave the home only for a visit to the vet. customtailored vaccination schedules will differ the client's companion is not just a dog or cat -it is a dear family member, has been given a name, is an individual and requires individual attention. neither is the client just a time-consuming nuisance -she is a partner in a conversation and deserves interest, sometimes empathy. vaccines protect against infectious disease, and a precondition for their use is a risk of infection. in most cases this hazard is an assumption, an impression not based on epidemiological data. the prevalence of e.g. distemper virus in europe amongst domestic dogs and in feral carnivores is unknown. from yearly endemics amongst unvaccinated pups, however, it can be inferred that the virus is still around. infectious canine hepatitis, on the other hand, has been seen here by clinicians and pathologist only rarely, nor has it been evidenced by pcr analysis in dogs with respiratory signs in the uk (erles et al., ) , in contrast to e.g. the usa, canada, mexico and australia. it is present in wild carnivores though. parvovirus, however, is ubiquitous, both its canine and feline varieties. herpes-, calici-and coronaviruses abound amongst cats, with high prevalences in crowded communities. felv infections are phasing out in several countries in western europe, thanks to testing and vaccination, while the prevalence of fiv has hardly changed. this is an oversimplified global view of canine and feline viral epidemiology-the vaccinating veterinarian must positively know about the local situation in her area. there is no dedicated information service available, and contacts with the regional veterinary schools and diagnostic institutions will be left to personal initiatives. promed-mail -the program for monitoring emerging diseases -is an internet-based reporting system dedicated to rapid global dissemination of information on outbreaks of infectious diseases and can be queried (http://www.promedmail.org). the veterinarian is the designated expert to provide competent advice to the client concerning epidemic risk factors and their vaccinological consequences. as stated above, vaccination is about the only veterinary measure whose result is not routinely evaluated. post-vaccinal serology, however, is not new to companion animal medicine: evidence of antibodies to rabies virus decides whether a dog may travel. an assessment of the animal's immune status would provide the vet with information about the success rate of her measures, and reassure the client. the proposal is to assess the result of vaccination by asking the question: did the vaccinee's immune system recognise the antigen? no assertion of protection, only a probability can be given -similar to the results of many assays in clinical chemistry. the first serum samples should be tested in the rd year of life, to see whether the pup vaccination (first year) plus boost (second year) have resulted in immunological memory; later tests can be done if so desired by the client, e.g. before the -yearly interval, as an aid in the decision about revaccination. when the vaccination history of an animal is unknown, a prime-boost regime will usually be preferred, unless requested otherwise by the client. interpretation of the serology data will be an element of the vaccination interview. the purpose of pvs should be to show antibody against the core vaccine components distemper, hepatitis and parvovirus (dog and cat). if antibody is present, the animal has been immunised (which is not synonymous with immune or protected). forget about titers (titres) -the bad experience with fip serology is still on everybody's mind. titer values have been attributed a biological significance they intrinsically lack, and high coronavirus antibody titers have been the veterinary death sentence for many a healthy cat. there are many reasons for rejecting titers: values differ per laboratory, because of technical variations in the tests, '' '' and '' '' are not different titers ('' : '' and '' : '' are no titers at all but the serum dilutions tested), the difference is just two-fold. virologists start to think about specificity when the titer difference is four-fold. only yes/no-data should be communicated by the laboratory -which leave no room for doubt (no uncertainly of interpretation). ideally, the vaccine industry should be involved in pvs, which could corroborate their claims of the potent antigenicity of their products. in a nutshell: the laboratory (or an in-practice test) should give a robust yes/no answer with a threshold value safely in the positive range. if the potential vaccinee tests negative (false or true) vaccination is recommended. a false-negative test will result in vaccination (in spite of antibodies) -which is similar to the present situation in many cases. if an animal tests positive (false or true) vaccination is not recommended. a false-positive test is unlikely in view of the high prevalence of antibodies in the population. . we vaccinate the same animal too often, but too few animals of the population . . . most animals in an area, a province, a country should be vaccinated-rather than revaccinating the same dog or cat time and again, which neither improves its own immune status nor contributes to herd immunity. herd immunity is defined as the indirect protection of susceptible members of a population brought about by the presence of immune individuals. to prevent serious losses from epidemics (like during the distemper epidemic in finland finland - where > dogs were infected, of which $ % succumbed; (ek-kommonen et al., ) , active campaigning for vaccination should be targeted at achieving about % immune coverage. this figure has been obtained by mathematical modelling of epidemics and confirmed by observations from natural outbreaks (like the finnish epidemic), but may not be universal, i.e. for all infectious agents. in such a situation, the effective reproduction rate r would be reduced to < , which means that there will be less than one new case per infected individual, and (if r continues to be < ) the infection will locally die out. these considerations play a role in the eradication strategy for measles. distemper cannot be eradicated because of spill-over infections from feral carnivore reservoirs and re-introduction of the agent into the domestic populations, but the spread of infection can be contained. a milkmaid's calculation can show that we are far from that % goal. thus, in germany ( ) there are $ mio. registered dogs; there are $ . mio. vaccine doses reaching the market (shppilt & shplt); there are $ . mio. purebred dogs (most of which will be immunised); the remaining . mio. vaccine doses thus are applied to . mio. dogs = % (data kindly provided by dr. uwe schultheiss, nice/france; source: gfk nürnberg). estimates made by intuitive assessments vary widely and may reflect selective observation or wishful thinking. it is of course more arduous to solicit new clients than to summon old ones, but it needs to be done. this opening article of a special issue dedicated entirely to pet vaccination is intended to set the scene for the various aspects of immunisation of the dog and cat. the discussions to follow will hopefully result in a new degree of awareness amongst veterinary practitioners. if the profession wants to play a leading role in the public discussion, if the vet (and not the internet) is to stay the animal health authority for pet owners -if microbiological, immunological and vaccinological knowledge is to be conveyed to (and rewarded by) the clientele, the profession must change its attitude. vaccinological knowledge must be acquired, entertained and kept current, which should start at the university and be perpetuated by continued education. without further discussion, and as food for thought, these are my ten commandments of pet vaccinology: . the puppy schedule should be extended to include a vaccination at week of age. . base immunisation is complete only after the booster in the second year of life. . the routine of yearly revaccinations from the third year onward is questionable. . a yearly revaccination interview, not necessarily an injection, should become the standard. . the yearly revaccination interview is a professional service that must be taught, expertly performed and invoiced. . adult animals should be ''vaccinated to measure'', taking age, breed, lifestyle, the epidemiologic situation, etc., into account. . post-vaccination serology should become a guide in revaccination decisions. . for a solid herd immunity, more animals of the population must be vaccinated. . the profession should issue regular updates of the 'code of vaccination practice'. . to counteract vaccinophobia, a concerted action of academia, the veterinary profession and industry is of paramount importance. outbreak off canine distemper in vaccinated dogs in finland longitudinal study of viruses associated with canine infectious respiratory disease overview of immune system development in the dog: comparison with humans three-year duration of immunity in dogs following vaccination against canine adenovirus type- , canine parvovirus, and canine distemper virus memory b-cell persistence is independent of persisting immunising antigen duration of serologic response to three viral antigens in cats are we vaccinating too much? clinical use of serum parvovirus and distemper virus antibody titers for determining revaccination strategies in healthy dogs key: cord- -qkykubnh authors: bhugra, priyanka; mszar, reed; valero-elizondo, javier; grandhi, gowtham r; virani, salim s; cainzos-achirica, miguel; vahidy, farhaan s; omer, saad; nasir, khurram title: prevalence of and sociodemographic disparities in influenza vaccination among adults with diabetes in the united states date: - - journal: j endocr soc doi: . /jendso/bvaa sha: doc_id: cord_uid: qkykubnh national estimates describing the overall prevalence of and disparities in influenza vaccination among patients with diabetes mellitus (dm) in united states are not well described. therefore, we analyzed the prevalence of influenza vaccination among adults with dm, overall and by sociodemographic characteristics, using the medical expenditure panel survey database from to . associations between sociodemographic factors and lack of vaccination were examined using adjusted logistic regression. among adults with dm, % lacked influenza vaccination. independent predictors of lacking influenza vaccination included age to years (odds ratio [or] . ; % confidence interval [ci], . - . ), black race/ethnicity (or . ; % ci, . - . ), uninsured status (or . ; % ci, . - . ), and no usual source of care (or . ; % ci, . - . ). nearly % individuals with ≥ higher-risk sociodemographic characteristics lacked influenza vaccination (or . ; % ci . - . ). one-third of adults with dm in the united states lack influenza vaccination, with younger age, black race, and lower socioeconomic status serving as strong predictors. these findings highlight the continued need for focused public health interventions to increase vaccine coverage and utilization among disadvantaged communities. % individuals with ≥ higher-risk sociodemographic characteristics lacked influenza vaccination (or . ; % ci . - . ). one-third of adults with dm in the united states lack influenza vaccination, with younger age, black race, and lower socioeconomic status serving as strong predictors. these findings highlight the continued need for focused public health interventions to increase vaccine coverage and utilization among disadvantaged communities. key words: diabetes, disparities, influenza, prevention, vaccination the centers for disease control and prevention (cdc) has estimated that hospitalizations and deaths from influenza infection occurred in the united states during the - season [ ] . there is substantial evidence that those with diabetes mellitus (dm) face serious adverse consequences from influenza infection, including increased likelihood of hospital admission for acute cardiovascular and respiratory diseases and all-cause mortality [ ] [ ] [ ] [ ] . therefore, the advisory committee on immunization practices (acip) and american diabetes association recommend seasonal influenza vaccination for patients with dm irrespective of age [ ] . to date, national estimates of influenza vaccination among individuals with dm in the united states are not well described. in the current study, among a nationally representative sample of adults with dm, we report estimates of influenza vaccination, characterizing sociodemographic groups, both individually and in combination, who were at particularly high risk of lacking vaccination. we included adults ≥ years with dm using pooled medical expenditure panel survey (meps) data from - . meps is administered by the agency for healthcare research and quality and provides comprehensive national data on health care utilization, expenditures, and insurance coverage for the us civilian noninstitutionalized population [ ] . a new panel of households, consisting of rounds of surveys spanning years, are enrolled on a continual basis every year. they represent a subsample of households that participated in the national health interview survey (nhis) months to year earlier. for nhis participant recruitment, the sampling design follows an area probability framework that enables representative sampling of households and noninstitutional group quarters where clusters of addresses are defined within each state. since meps data are de-identified and publicly available, it was exempt from purview of the institutional review board committee. adults with dm were identified using self-reported and/or icd- / diagnosis codes of diabetes mellitus, both type and . individuals were ascertained to have had influenza vaccination if they answered yes to having received the vaccination in the months prior to survey completion. other covariates in the study included age ( - , - , and ≥ years), sex, ethnicity (non-hispanic white, non-hispanic black, non-hispanic asian, and hispanic), family income (as a proportion of federal poverty limit; high/middleincome [≥ %] and low-income [< %]), insurance status (insured and uninsured), education level (≥ some college education and ≤ high school), and presence/absence of usual source of care. we used the person-level sampling weights which were obtained after adjusting for nonresponse, age, sex, and ethnicity (based on population estimates from the us census bureau) to obtain nationally representative results. we compared the surveyweighted proportions of influenza vaccination across different sociodemographic characteristics using rao-scott χ analysis. we assessed the association of sociodemographic characteristics with influenza vaccination using multivariable surveyspecific logistic regression adjusting for covariates and known confounders (listed in table as footnote) and reported the adjusted odds ratios (or) with % confidence intervals (ci). to analyze the cumulative associations between these characteristics and influenza vaccination, we developed a composite model of increasing number of high-risk sociodemographic characteristics including the following variables: (i) to years of age, (ii) non-hispanic black race/ethnicity, (iii) uninsured status, (iv) lack of usual source of care, (v) low-income level, and (vi) low education level (i.e., ≤high school). all analyses were performed using stata version . (statacorp, college station, tx). nearly % of adults in meps (n = ) had dm, corresponding to . million us adults annually. overall, . % ( % ci, . %- . %) of total patients with dm, representing about . million adults, did not receive influenza vaccination in the previous months. in adjusted analyses, the odds of missing influenza vaccination were highest in adults of age to years (or . ; % ci, . - . ), non-hispanic black population (or . ; % ci, . - . ), adults lacking insurance coverage (or . ; % ci, . - . ), those with no usual source of care (or . ; % ci, . - . ), adults with a low income (or . ; % ci, . - . ), and those with a completed level of education equal to or less than high school diploma (or . ; % ci, . - . ). there was no difference in receipt of vaccination based on gender or geographic location (table ) . on further analysis of the association of these characteristics (referred to here as high-risk characteristics) with influenza vaccination, when compared with the reference group without any high-risk characteristic (non-hispanic white individuals, of ≥ years of age, with middle to high family income, with health insurance, with usual source of care, and higher education level), those with ( %), ( %), ( %), and ≥ ( %) high-risk characteristics had a stepwise increase in the prevalence of lacking influenza vaccination (fig. ) . adjusting for sex, geographic region, cardiovascular risk factors, and comorbidities, we found that adults with ≥ results reported as % ( % confidence interval). abbreviations: ascvd, atherosclerotic cardiovascular disease; crf, cardiovascular risk factor; ged, general equivalency diploma; hs, high school; us, united states. * model adjusted for age, sex, race/ethnicity, family income, insurance status, education, geographic region, usual source of care, cardiovascular risk factors, and comorbidities high-risk characteristics had . -fold higher odds (or . ; % ci, . - . ) of lacking vaccination when compared with individuals without any high-risk characteristic (fig. ). we assessed differences in influenza vaccination in various sociodemographic groups in a nationally representative sample of us adults with dm. more than one-third of adults with dm aged ≥ years did not receive influenza vaccination in the prior months, translating to nearly million individuals. furthermore, vaccination rates were significantly lower in certain groups including younger adults ( - years), non-hispanic black adults, individuals without insurance, those from low-income families, and individuals lacking access to usual care, vaccination disparities similar to those reported in the general population [ , ] . adults with a greater number of the above-mentioned characteristics were found to have lower rates of influenza vaccination, with nearly two-thirds ( %) of those with or more of these sociodemographic characteristics lacking influenza vaccination. these insights will be critical for health systems and policy makers to develop targeted interventions for these missed opportunities to promote timely vaccination. these findings are particularly relevant in the current covid- pandemic, given the risk of adverse outcomes in patients with comorbid dm and/or co-infection with influenza. limitations of our study include the cross-sectional nature of the meps data, which limits the determination of causal relationships and the potential recall bias associated with self-reported influenza vaccination information in this database, which may underestimate or overestimate the true prevalence of influenza vaccination. however, the overall high quality of the meps data, its representativeness of the us population, the comprehensive adjustment for potential confounders conducted in the regression analyses, and the large sample size lend credibility to our report and make these results valuable for economic and health-policy making. in conclusion, nearly one-third of u.s. adults with dm lacked influenza vaccination, with disproportionately higher rates among vulnerable sociodemographic groups. these results underscore the importance of focused public health interventions to address these underlying factors to improve influenza vaccination rates and limit downstream preventable adverse outcomes in patients with dm. figure . national estimates and odds ratios of lacking influenza vaccination among adults with diabetes and high-risk sociodemographic characteristics. * high-risk sociodemographic characteristics include younger age, non-hispanic black race/ethnicity, lack of insurance coverage, no usual source of care, low-income, and lower level of completed education. update: influenza activity in the united states during the - season and composition of the - influenza vaccine populations at risk for severe or complicated influenza illness: systematic review and meta-analysis diabetes and the severity of pandemic influenza a (h n ) infection. diabetes care relationship between annual influenza vaccination and winter mortality in diabetic people over years clinical effectiveness of first and repeat influenza vaccination in adult and elderly diabetic patients centers for disease control and prevention (cdc). prevention and control of influenza with vaccines: recommendations of the advisory committee on immunization practices (acip) racial/ethnic differences in influenza vaccination coverage in high-risk adults influenza and pneumococcal vaccination of adults aged > or = : racial/ethnic differences author contributions: p.b., r.m., j.v.e, and k.n. and designed the current study. j.v.e. performed the statistical analysis, interpreted the data, and wrote the initial draft. r.m., g.r.g., s.s.v., m.g.a., f.s.v., s.o., and k.n. supervised and contributed support for data analyses, interpretation of findings, and critical revision of the article.all authors reviewed and approved the final version of the article submitted for publication. k.n. initiated the study.k.n. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. disclosure summary: none to report. data availability: all data generated or analyzed during this study are included in this published article or in the data repositories listed in references. key: cord- -xc jaw authors: lembo, tiziana; hampson, katie; kaare, magai t.; ernest, eblate; knobel, darryn; kazwala, rudovick r.; haydon, daniel t.; cleaveland, sarah title: the feasibility of canine rabies elimination in africa: dispelling doubts with data date: - - journal: plos negl trop dis doi: . /journal.pntd. sha: doc_id: cord_uid: xc jaw background: canine rabies causes many thousands of human deaths every year in africa, and continues to increase throughout much of the continent. methodology/principal findings: this paper identifies four common reasons given for the lack of effective canine rabies control in africa: (a) a low priority given for disease control as a result of lack of awareness of the rabies burden; (b) epidemiological constraints such as uncertainties about the required levels of vaccination coverage and the possibility of sustained cycles of infection in wildlife; (c) operational constraints including accessibility of dogs for vaccination and insufficient knowledge of dog population sizes for planning of vaccination campaigns; and (d) limited resources for implementation of rabies surveillance and control. we address each of these issues in turn, presenting data from field studies and modelling approaches used in tanzania, including burden of disease evaluations, detailed epidemiological studies, operational data from vaccination campaigns in different demographic and ecological settings, and economic analyses of the cost-effectiveness of dog vaccination for human rabies prevention. conclusions/significance: we conclude that there are no insurmountable problems to canine rabies control in most of africa; that elimination of canine rabies is epidemiologically and practically feasible through mass vaccination of domestic dogs; and that domestic dog vaccination provides a cost-effective approach to the prevention and elimination of human rabies deaths. rabies is a viral zoonosis caused by negative-stranded rna viruses from the lyssavirus genus. genetic variants of the genotype lyssavirus (the cause of classical rabies) are maintained in different parts of the world by different reservoir hosts within 'host-adaptive landscapes' [ ] . although rabies can infect and be transmitted by a wide range of mammals, reservoirs comprise only mammalian species within the orders carnivora (e.g. dogs, raccoons, skunks, foxes, jackals) and chiroptera (bats). from the perspective of human rabies, the vast majority of human cases (. %) result from the bites of rabid domestic dogs [ ] and occur in regions where domestic dogs are the principal maintenance host [ ] . over the past three decades, there have been marked differences in efforts to control canine rabies. recent successes have been demonstrated in many parts of central and south america, where canine rabies has been brought under control through large-scale, synchronized mass dog vaccination campaigns [ ] . as a result, not only has dog rabies declined, but human rabies deaths have also been eliminated, or cases remain highly localized [ ] . the contrast with the situation in africa and asia is striking; here, the incidence of dog rabies and human rabies deaths continue to escalate, and new outbreaks have been occurring in areas previously free of the disease (e.g. the islands of flores and bali in indonesia - [ ] ; http://wwwn.cdc.gov/travel/ contentrabiesbaliindonesia .aspx). in this paper, we identify four major reasons commonly given for the lack of effective domestic dog rabies control including ( ) low prioritisation, ( ) epidemiological constraints, ( ) operational constraints and ( ) lack of resources (table ) , focussing on the situation in africa. we address each of these issues in turn, using outputs from modelling approaches and data from field studies to demonstrate that there are no insurmountable logistic, practical, epidemiological, ecological or economic obstacles. as a result, we conclude that the elimination of canine rabies is a feasible objective for much of africa and there should be no reasons for further delay in preventing the unnecessary tragedy of human rabies deaths. this paper compiles previously published data (see references below) and additional analyses of those data, but we present a brief summary of the data collection methods below. hospital records of animal-bite injuries compiled from northwest tanzania were used as primary data sources. these data informed a probability decision tree model for a national disease burden evaluation [ ] , which has since been adapted for global estimates of human rabies deaths and disability-adjusted life years (dalys) lost due to rabies [ ] , a standardized measure for assessing disease burden [ , ] . hospital records were also used to initiate contact tracing studies [ ] [ ] [ ] , whereby bite-victims were interviewed to obtain more detail on the source and severity of exposure and actions taken, allowing subsequent interviews with other affected individuals (not documented in hospital records) including owners of implicated animals. statistical techniques applied to these data for estimating epidemiological parameters and inferring transmission links are described elsewhere [ , ] . rabies monitoring operations including passive and active surveillance involving veterinarians, village livestock field officers, paravets, rangers and scientists were used to collect samples from carcasses (domestic dogs and wildlife whenever found), which were subsequently tested and viral isolates were sequenced [ , [ ] [ ] [ ] [ ] , with results being used to inform estimates of rabies-recognition probabilities [ ] and for phylogenetic analyses [ , ] . operational research on domestic dog vaccination strategies was carried out in a variety of settings [ , ] . household interviews were also used for socio-economic surveys and to evaluate human:domestic elimination of canine rabies has been achieved in some parts of the world, but the disease still kills many thousands of people each year in africa. here we counter common arguments given for the lack of effective canine rabies control in africa presenting detailed data from a range of settings. we conclude that ( ) rabies substantially affects public and animal health sectors, hence regional and national priorities for control ought to be higher, ( ) for practical purposes domestic dogs are the sole maintenance hosts and main source of infection for humans throughout most of africa and asia and sufficient levels of vaccination coverage in domestic dog populations should lead to elimination of canine rabies in most areas, ( ) the vast majority of domestic dog populations across sub-saharan africa are accessible for vaccination with community sensitization being of paramount importance for the success of these programs, ( ) improved local capacity in rabies surveillance and diagnostics will help evaluate the impact of control and elimination efforts, and ( ) sustainable resources for effective dog vaccination campaigns are likely to be available through the development of intersectoral financing schemes involving both medical and veterinary sectors. dog ratios, levels of vaccination coverage achieved and reasons for not bringing animals to vaccination stations [ , ] . the study was approved by the tanzania commission for science and technology with ethical review from the national institute for medical research (nimr). this retrospective study involved collection of interview data only, without clinical intervention or sampling, therefore we considered that informed verbal consent was appropriate and this was approved by nimr. permission to conduct interviews was obtained from district officials, village and sub-village leaders in all study locations. at each household visited, the head of the household was informed about the purpose of the study and interviews were conducted with verbal consent from both the head of the household and the bite victim (documented in a spreadsheet). approval for animal work was obtained from the institutional animal care and use committee (iacuc permit # a ). (a) there is not enough evidence to define rabies control as a priority a principal factor contributing to a low prioritization of rabies control has been the lack of information about the burden and impact of the disease [ , ] . data on human rabies deaths, submitted from ministries of health to the world health organization (who), are published in the annual world surveys of rabies and through the who rabnet site (www.who.int/ rabies/rabnet/en). for the who african region (afro) comprising countries, these surveys report an average of human deaths per year between and . it is therefore unsurprising that for national and international policy-makers, rabies pails into insignificance in comparison with other major disease problems. this perceived lack of significance of human rabies is reflected in the absence of any mention of rabies in either of the two published global burden of disease surveys [ , ] , which assessed more than major diseases. these surveys adopted the metric of the daly which is widely used as the principal tool for providing consistent, comparative information on disease burden for policy-making. until recently no estimates of the daly burden were available for rabies. official data on human rabies deaths submitted to who from africa are widely recognized to greatly under-estimate the true incidence of disease. the reasons for this are manifold: ( ) rabies victims are often too ill to travel to hospital or die before arrival, ( ) families recognize the futility of medical treatment for rabies, ( ) patients are considered to be the victims of bewitchment rather than disease, ( ) clinically recognized cases at hospitals may go unreported to central authorities, and ( ) misdiagnosis is not uncommon. the problems of misdiagnosis were highlighted by a study of childhood encephalitis in malawi, in which / ( . %) cases initially diagnosed as cerebral malaria were confirmed as rabies through post-mortem tests [ ] . several recent studies have contributed information that consistently demonstrates that the burden of canine rabies is not insubstantial. human rabies deaths. estimates of human rabies cases from modeling approaches, using the incidence of dog-bite injuries and availability of rabies post-exposure prophylaxis (pep), indicate that incidence in africa is about times higher than officially reported, with , , deaths in africa each year [ , ] . consistent figures have subsequently been generated from detailed contact-tracing data: in rural tanzanian communities with sporadic availability of pep (a typical scenario in developing countries), human rabies deaths occur at an incidence of , - cases/ , /year (equivalent to - , deaths per year for tanzania) [ ] . similarly, a multi-centric study from india reported , human rabies deaths per year [ ] , consistent with model outputs of , deaths for india [ ] . a crude comparison of annual human deaths for a range of zoonotic diseases is shown in figure (top). while diseases such as severe acute respiratory syndrome (sars), rift valley fever and highly pathogenic avian influenza cause major concerns as a result of pandemic potential and economic losses, these figures provide a salutary reminder of the recurrent annual mortality of rabies and other neglected zoonoses, such as leishmaniasis and human african trypanosomiasis (hat). decision-tree models applied to data from east africa and globally indicate that the daly burden for rabies exceeds that of most other neglected zoonotic diseases (figure -bottom) [ , , ] . human animal-bite injuries and morbidity. most of the rabies daly burden is attributed to deaths, rather than morbidity because of the short duration of clinical disease. the daly burden for rabies is particularly high, because most deaths occur in children and therefore a greater number of years of life are lost [ , ] . daly estimates incorporate non-rabies mortality and morbidity in terms of adverse reactions to nerve-tissue vaccines (ntvs) [ ] , which are still widely used in some developing countries such as ethiopia, however rabies also causes substantial 'morbidity' as a direct result of injuries inflicted by rabid animals, and this is not included in daly estimates. contact-tracing studies suggest an incidence as high as / , bites by suspected rabid animals in rural communities of tanzania [ ] . thus, for every human rabies death there are typically more than ten other rabid animal-bite victims who do not develop signs of rabies, because they obtain pep (figure bottom) or are simply fortunate to remain healthy. the severity of wounds has not yet been quantified, but case-history interviews suggest that injuries often involve multiple, penetrating wounds that require medical treatment. economic burden. the major component of the economic burden of rabies relates to high costs of pep, which impacts both government and household budgets. with the phasing out of ntvs, many countries spend millions of dollars importing supplies of tissue-culture vaccine (,$ million usd pa [ ] ). at the household level, costs of pep arise directly from anti-rabies vaccines and from high indirect (patient-borne) costs associated with travel (particularly given the requirement of multiple hospital visits), medical fees and income loss [ , ] . indirect losses, represent . % of total costs ( figure ). total costs have been estimated conservatively at $ us per treatment in africa and $ us in asia accounting respectively for . % and . % of annual per capita gross national income [ ] . poor households face difficulties raising funds which results in considerable financial hardship and substantial delays in pep delivery [ , ] . shortages of pep, which are frequent in much of africa, further increase costs as bite victims are forced to travel to multiple centres to obtain treatment, also resulting in risky delays [ ] . additional economic losses relate to livestock losses derived from an incidence of deaths/ , cattle estimated to cost $ . million annually in africa and asia [ ] . however, substantially higher incidence has been recorded in tanzania, with - cases/ , cattle reported annually in rural communities (hampson, unpublished) . canine rabies introduced from sympatric domestic dog populations is also recognized as a major threat to endangered african wild dogs (lycaon pictus) and ethiopian wolves (canis simensis) [ ] [ ] [ ] [ ] . potential losses of tourism revenue may be substantial; african wild dogs are a major attraction in south africa national parks with the value of a single pack estimated at $ , per year [ ] and ethiopian wolves are a flagship species for the bale mountains national park. psychological impact. an important, but often underappreciated component of disease burden is the psychological impact on bite-victims and their families. in rural tanzania, . % of households with dog bite victims feared a bite from a suspected rabid animal more than malaria [ ] because malaria can be treated whereas clinical rabies is invariably fatal and malaria treatment is generally affordable and available locally in comparison to pep. when human rabies cases occur, the horrifying symptoms and invariably fatal outcome result in substantial trauma for families, communities and health care workers [ ] . increasing incidence of rabies in africa has prompted concerns that the epidemiology of the disease may be more complex, involving abundant wildlife carnivores that may sustain infection cycles [ , [ ] [ ] [ ] [ ] . there is also uncertainty about the level of vaccination coverage needed to control rabies particularly in rapidly growing domestic dog populations [ , ] . to eliminate infection, disease control efforts need to be targeted at the maintenance population [ ] . this is clearly demonstrated for fox rabies in western europe, whereby control of rabies in foxes (through mass oral vaccination) has led to the disappearance of rabies from all other 'spill-over' hosts [ ] . despite the predominance of domestic dog rabies in africa, the role of wildlife as independent maintenance hosts has been debated, and many perceive the abundance of wildlife as a barrier to elimination of canine rabies on the continent. it has also been argued that the predominance of dog rabies is an artefact of poor surveillance and under-reporting in wildlife populations [ ] . in the wildlife-rich serengeti ecosystem in tanzania, evidence suggests that domestic dogs are the only population essential for maintenance [ , , ] : ( ) phylogenetic data showed only a single southern africa canid-associated variant (africa b) circulating among different hosts [ ] ; ( ) transmission networks suggested that, for wildlife hosts, within-species transmission cannot be sustained [ ] ; and ( ) statistical inference indicated that cross-species transmission events from domestic dogs resulted in only relatively short-lived chains of transmission in wildlife with no evidence for persistence [ ] . the conclusion that domestic dogs are the only maintenance population in such a species-rich community suggests that elimination of canine rabies through domestic dog vaccination is a realistic possibility, and provides grounds for optimism for wider-scale elimination efforts in africa. in other parts of central and west africa, transmission of rabies appears to be driven by domestic dogs [ ] . an outstanding question relates to southern africa. earlier and recent evidence indicate that jackal species (canis mesomelas and c. adustus) and bat-eared foxes (otocyon megalotis) may maintain the canid variant in specific geographic loci in south africa and zimbabwe [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , but it is still not clear whether these cycles can be sustained over large spatial and temporal scales in the absence of dog rabies [ , , ] . independent wildlife cycles may preclude continent-wide elimination of this variant through dog vaccination alone and wildlife rabies control strategies, in conjunction with dog vaccination, may need to be considered in specific locations [ ] . a critical proportion of the population must be protected (p crit ) to eliminate infection and this threshold can be calculated from the basic reproductive number (r , defined as the average number of secondary infections caused by an infected individual in a susceptible population) [ ] . vaccinating a large enough proportion of the population to exceed p crit will not only protect the vaccinated individuals but will reduce transmission such that, on average, less than one secondary infection will result from each primary case (effective reproductive number, r e , ), which can ultimately lead to elimination. vaccination has eliminated canine rabies in many countries demonstrating the success of this concept [ ] . however, theory suggests that r increases with population density [ ] and thus higher coverage will be needed in higher density populations. however, evaluation of historical outbreak data from around the world and recent data from tanzania indicate that r in domestic dog populations is consistently low (between . and . ) [ ] , confirming the feasibility of rabies elimination through vaccination in african domestic dog populations. an important conclusion of this study was that in populations with rapid turnover (such as those in many african countries) at least % of the population must be vaccinated during annual campaigns to prevent coverage falling below p crit between campaigns. data from africa clearly show that very few control efforts have reached these levels of coverage [ table ], which is why rabies remains a persistent problem [ ] . although emergence of new variants maintained in wildlife also remains a possibility, as shown in the usa, where wildlife rabies now dominates since elimination of canine rabies [ ] . for africa, these questions are likely only to be resolved with large-scale intervention involving mass vaccination of dogs. several arguments are given for why mass vaccination campaigns have failed to achieve the high levels of coverage that are necessary to interrupt rabies transmission. we counter these arguments below: a perception of many inaccessible stray/ownerless dogs. a common claim is that the majority of dogs in africa are unowned 'stray' animals, and therefore inaccessible for parenteral vaccination. it is not hard to see why this perception has arisen -unrestrained dogs, without any apparent evidence of ownership, are commonly observed. further investigation, however, usually reveals that the vast majority are owned, and at least one household claims some responsibility, including presentation for vaccination. published studies in africa, which quantify the proportion of unowned dogs, are admittedly sparse, but all support this observation [ ] [ ] [ ] . capture-mark-recapture methodologies and household questionnaires used in african settings have all found consistently low estimates (tunisia , % [ ] , %, % and % in three sites in n'djamena, chad [ ] , and % in a peri-urban site in tanzania [ ] ). notably, the tanzanian site was selected specifically on the basis of reports of many unowned dogs. while mark-recapture methods yield reliable estimates of unowned dog numbers, their implementation and analysis is not trivial and efforts are underway to develop simpler, yet robust methodologies [ ] . certainly in traditional africa, i.e. most of sub-saharan africa, the issue of roaming dogs seems not to be one of a lack of ownership, but rather an inability or unwillingness by owners to confine their dogs. unwillingness/inability to bring dogs for vaccination. published studies tend to refute the idea that owners are often unable or unwilling to restrain their dogs for parenteral vaccination. a multi-country who-commissioned study (tunisia, sri lanka and ecuador) concluded that ''dogs which are not catchable by at least one person are rare and represent generally less than % of the dog population'' [ ] . similarly a study from nepal found that - % of dogs were accessible to parenteral vaccination [ ] . although an early study in turkey concluded that % of all free-roaming owned dogs could not be captured by their owners [ ] , more recent surveys found that most unvaccinated dogs could be handled (only % could not) and that a much larger proportion ( %) resulted from a lack of information about the campaign -a much easier problem to remedy (unpublished data). in africa, very similar figures were obtained in a multi-site study in urban and rural tanzania, where only % of vaccination failures were due to a reported inability by the owner to handle the dog, while % of cases were due to poor information dissemination [ ] . however, there may be settings in transitional africa (e.g. parts of southern africa including kwazulu natal [ ] ) where handling of dogs is more difficult due to a break-down in traditional animal husbandry and other social factors, and more intensive efforts may be required for these special cases. given that most dogs are accessible for parenteral vaccination, high coverage can be achieved with well-planned vaccination campaigns. during pilot programmes in urban and rural africa which have not charged owners for vaccination, coverages obtained have exceeded % [ , , ] . pastoral communities pose particular challenges due to remote locations and seminomadic lifestyles, but . % coverages can still be achieved through house-to-house delivery strategies or community-based animal health workers [ ] . young pups usually make up a large proportion (. %) of african dog populations [ ] and there is a widespread perception among veterinary authorities and dog owners that they should not be vaccinated, which leads to insufficient coverage [ ] . however, rabies vaccines can safely be administered to pups , months of age [ ] , and in village campaigns in tanzania, vaccines consistently induced high levels (. . iu/ml) of rabies virus neutralizing antibody [ ] . the issue of inclusion of pups can effectively be addressed through appropriate advertising before campaigns. cost-recovery, through charging dog owners for rabies vaccination, is widely promoted for sustainable programmes and to encourage responsible dog ownership. however, charging for a vaccination that represents a public rather than a private good, can be counterproductive, resulting in low turnouts and coverage (, %) with little or no impact [ ] . charging for vaccination may indeed be the principal reason why owners are unwilling to bring dogs for vaccination. ineffective campaigns that achieve , % coverage are a waste of resources and can be highly demoralising for veterinary staff and communities. when resources are spread thinly, such that only low coverage is achieved or only small pockets are well vaccinated, then large-scale failure is inevitable. a more epidemiologically sensible strategy is to focus resources into a single (preferably well-bounded) area where high coverage can be consistently achieved. uncertainty about dog population sizes and ecology for effective design and planning of vaccination campaigns. official figures used for planning frequently underestimate true population sizes. for example, gsell [ ] found that the owned dog population in a municipality in tanzania was six times larger than official records. although standard survey methodologies for estimating dogs/household or dog:human ratios [ , [ ] [ ] [ ] are not without problems (for example, double ownership of dogs), a rough estimate of owned dog populations can be derived from national (human) population censuses, and can be corrected for different demographic and ecological settings [ , ] . more detailed studies can be conducted to identify key household determinants of dog ownership (for example, religion, age and sex of household heads, household size, socio-economic level, and livestock presence/absence [ , , , ] . such determinants have been used to generate a 'dog density' map of tanzania, for assistance in planning national rabies vaccination campaigns ( figure ). the above factors are all generally described as obstacles that ultimately lead to a lack of investment into rabies control and surveillance. we suggest that investment would actually reap multiple benefits including economic ones, if appropriate strategies are implemented overcoming the constraints described. a lack of surveillance and diagnostic capacity for rabies detection. poor surveillance and diagnosis capacity means that ( ) data is insufficient to demonstrate disease burden and motivate policy-makers, and ( ) impacts of control efforts cannot be evaluated. considerable progress has been made in the development of simple and inexpensive techniques for sample preservation and rapid post-mortem diagnosis suitable for laboratories with limited storage and/or diagnostic resources with potential to increase incountry capabilities for surveillance. a new direct rapid immunohistochemical test (drit) requires only light microscopes [ ] , which are widely available. the test is simple and can be performed by a range of operators if appropriate training is provided. field evaluation studies in africa demonstrated that this assay has characteristics equivalent to those of the direct fluorescent antibody (dfa) test, the global standard for rabies diagnosis, including excellent performance on glycerolated field brain material [ , ] , the preservative of choice under field conditions [ , ] . other simple field-diagnostics that allow rapid screening, including enzyme immunoassays [ ] , dot blot enzyme immunoassays [ ] and lateral-flow immunodiagnostic test kits [ , ] are being evaluated. these tools offer hope of extending diagnostic capacity in resource-limited settings. animal-bite injury data from hospitals are an easily accessible source of epidemiological information and have been verified as reliable indicators of animal rabies incidence and human exposures [ , ] . furthermore, increasing availability of communication infrastructure through mobile phone network access in remote areas could enhance surveillance by allowing real-time reporting. costs of effective dog vaccination campaigns are beyond the budget of veterinary services. veterinary services in africa usually report very limited budgets and often have to divert resources during outbreaks of other diseases [ , ] . this is clearly the most significant constraint to effective rabies control. however, with increasing human and dog populations, dog rabies incidence, human exposures to rabies and the costs required to prevent human rabies deaths through pep will invariably continue to rise unless rabies can be controlled at the source, i.e. in domestic dog populations [ ] . many countries in asia, such as thailand, vietnam and sri lanka have greatly reduced human rabies deaths through increased pep use, but at a very high cost [ ] . in vietnam, for example, deaths fell from in to in with administration of . , pep courses per year at an estimated cost of ,$ million/year [ ] . although domestic dog populations need to be targeted for the effective control of rabies, this is usually deemed to be the responsibility of veterinary services even though many of the benefits accrue to the medical sector. in rural tanzania, dog vaccination campaigns led to a rapid and dramatic decline in demand for costly human pep [ ] . in pastoral communities, vaccination not only reduced rabies incidence, but has now resulted in a complete absence of exposures reported in local hospitals for over two years (figure ) . large-scale campaigns can therefore translate into human lives and economic savings through reduced demand for pep. costs per dog vaccinated are generally estimated to be low (rural tanzania ,$ . [ ] , philippines ,$ . - . [ ] , tunisia ,$ . [ ] , thailand ,$ . [ ] and urban chad ,$ . [ ] ) and preliminary studies suggest that including dog vaccination in human rabies prevention strategies would be a highly cost-effective intervention at ,us $ /daly averted (s. cleaveland, unpublished data; see also ) . developing joint financing schemes for rabies prevention and control across medical and veterinary sectors would provide a mechanism to use savings in human pep to sustain rabies control programs in domestic dogs. although conceptually simple, the integration of budgets across different ministries is likely to pose political and administrative challenges. however, given sufficient political will and commitment, developing sustained programmes of dog vaccination that result in canine rabies elimination should be possible. in conclusion, here we show that a substantial body of epidemiological data have now been gathered through multiple studies demonstrating that: ( ) rabies is an important disease that exerts a substantial burden on human and animal health, local and national economies and wildlife conservation, ( ) domestic dogs are the sole population responsible for rabies maintenance and main source of infection for humans throughout most of africa and asia and therefore control of dog rabies should eliminate the disease, ( ) elimination of rabies through domestic dog vaccination is epidemiologically feasible, ( ) the vast majority of domestic dog populations across sub-saharan africa are accessible for vaccination and the few remaining factors compromising coverage can be addressed by engaging communities through education and awareness programs, ( ) new diagnostic and surveillance approaches will help evaluate the impact of interventions and focus efforts towards elimination, and ( ) dog rabies control is affordable, but is likely to require intersectoral approaches for sustainable programmes that will be needed to establish rabies-free areas. appendix s appendix with additional references. can rabies be eradicated? emerging epidemic dog rabies in coastal south africa: a molecular epidemiological analysis re-evaluating the burden of rabies in africa and asia overview of rabies in the americas current status of human rabies transmitted by dogs in latin america rabies on flores island, indonesia: is eradication possible in the near future? estimating human rabies mortality in the united republic of tanzania from dog bite injuries quantifying the burden of disease: the technical basis for disability-adjusted life years estimating the ''avoidable'' burden of disease by disability adjusted life years (dalys) exploring reservoirs dynamics: a case study of rabies in the serengeti ecosystem rabies exposures, post-exposure prophylaxis and deaths in a region of endemic canine rabies transmission dynamics and prospects for the elimination of canine rabies maintenance of a microparasite infecting several host species: rabies in the serengeti a dog rabies vaccination campaign in rural africa: impact on the incidence of dog rabies and human dog-bite injuries evaluation of a direct, rapid immunohistochemical test for rabies diagnosis molecular epidemiology identifies only a single rabies virus variant circulating in complex carnivore communities of the serengeti rabies control in rural africa: evaluating strategies for effective domestic dog vaccination a cross-sectional study of factors associated with dog ownership in tanzania strategies for the control and elimination of rabies in asia canine and human rabies in cameroon the global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in and projected to the world health report : reducing risks, promoting healthy life rabies encephalitis in malaria-endemic area assessing the burden of human rabies in india: results of a national multi-center epidemiological survey estimating the public health impact of rabies the epidemiology of animal bite injuries in uganda and projections of the burden of rabies an important public health problem: rabies suspected bites and post-exposure prophylaxis in a health district in turkey rabies control in rural tanzania: optimising the design and implementation of domestic dog mass vaccination programmes rabies in african wild dogs (lycaon pictus) in the serengeti region rabies and mortality in ethiopian wolves (canis simensis) integrating epidemiology into population viability analysis: managing the risk posed by rabies and canine distemper to the ethiopian wolf the cost efficiency of wild dog (lycaon pictus) conservation in south africa rabies and other lyssavirus diseases infectious diseases of livestock with special reference to southern africa canine rabies ecology in southern africa molecular epidemiology of rabies in bat-eared foxes (otocyon megalotis) in south africa molecular epidemiology of rabies: focus on domestic dogs (canis familiaris) and black-backed jackals (canis mesomelas) from northern south africa immunization coverage required to prevent outbreaks of dog rabies comparison of vaccination strategies for the control of dog rabies in machakos district identifying reservoirs of infection: a conceptual and practical challenge rabies in europe -epidemiological cycles and impact of oral vaccination of foxes rabies in southern africa dog population structure and cases of rabies among dog bite victims in urban and rural areas of borno state molecular epidemiology of rabies virus in south africa rabies in bat-eared foxes in south-africa molecular epidemiology of rabies virus in south africa: evidence for two distinct virus groups molecular epidemiology of canid rabies in zimbabwe and south africa mongoose rabies in southern africa: a re-evaluation based on molecular epidemiology the epidemiology of rabies in zimbabwe. . rabies in jackals (canis adustus and canis mesomelas) rabies in zimbabwe: reservoir dogs and the implications for disease control the epidemiology of rabies in zimbabwe. . rabies in dogs (canis familiaris) infectious diseases of humans: dynamics and control synchronous cycles of domestic dog rabies in sub-saharan africa and the impact of control efforts enzootic rabies elimination from dogs and reemergence in wild terrestrial carnivores, united states coverage of pilot parenteral vaccination campaign against canine rabies in n'djaména report of a who consultation on dog ecology studies related to rabies control. geneva: world health organization (who/rab demographic, spatial and behavioural heterogeneities in an urban dog (canis familiaris) population, relevant in planning rabies control in iringa surveying roaming dog populations: guidelines on methodology accessibility of dog populations for rabies control in kathmandu valley report of the rd consultation on oral immunization of dogs against rabies. geneva: world health organization (who/rab dog rabies and its control is it possible to vaccinate young canids against rabies and to protect them? proceedings of the sixth southern and eastern african rabies group/world health organization meeting welfare and health assessment of tanzanian dogs and its relationship to immunological response to rabies vaccination owner valuation of rabies vaccination of dogs a dog ecology study in urban and semi-rural area of zambia the epidemiology and control of domestic dog rabies ecological and epidemiological data requirements for the planning of dog rabies control colombo humane dog population and rabies management project aspects of dog ownership and canine rabies control in africa and asia dog ecology and demography information to support the planning of rabies control in machakos district standard operating procedure for the direct rapid immunohistochemistry test for the detection of rabies virus antigen. national laboratory training network course. atlanta: us department of health and human services rabies diagnosis for developing countries simplified technique for the collection, storage and shipment of brain specimens for rabies diagnosis. who/rab.res/ simple technique for the collection and shipment of brain specimens for rabies diagnosis development and evaluation of an enzyme immunoassay for rapid diagnosis of rabies in humans and animals rapid diagnosis of rabies in humans and animals by a dot blot enzyme immunoassay evaluation of a rapid immunodiagnostic test kit for rabies virus a simple and rapid immunochromatographic test kit for rabies diagnosis proceedings of the sixth southern and eastern african rabies group/world health organization meeting proceedings of the seventh southern and eastern african rabies group/world health organization meeting transmission dynamics and economics of rabies control in dogs and humans in an african city preventing the incurable: asian rabies experts advocate rabies control report to the world health organization. dog rabies elimination demonstration project rabies control in the republic of the philippines: benefits and costs of elimination economics of human and canine rabies eliminationguidelines for programme orientation costdescription of a pilot parenteral vaccination campaign against rabies in dogs in n'djaména, chad we are indebted to the ministries of livestock development and fisheries and of public health and social welfare, tanzania national parks, tanzania wildlife research institute, ngorongoro conservation area authority, tanzania commission for science and technology, and national institute for medical research for permission and collaboration; the frankfurt zoological society and the mwanza and arusha veterinary key: cord- -p qbxi authors: kitching, r. p.; salt, j. s. title: the interference by maternally-derived antibody with active immunization of farm animals against foot-and-mouth disease date: - - journal: british veterinary journal doi: . /s - ( ) - sha: doc_id: cord_uid: p qbxi summary foot-and-mouth disease (fmd) is a highly contagious disease affectingruminants and pigs. in countries in which control of fmd relies predominantly on vaccination, young stock ingest specific anti-fmd virus antibodies in the colostrum. this maternally-derived antibody (mda) provides immediate protection against infection with fmd virus, but also interferes with the development of active immunity following vaccination. however, susceptibility to infection precedes the ability to respond to vaccination in the presence of mda. currently available vaccines cannot overcome this inhibitory effect of mda, and protection of young stock can only be provided by their- isolation from fmd virus. neonates of all species are born into a hostile environment of physical and biological dangers. the obligate parasites in particular require to infect new susceptible individuals in order to ensure their own survival. the immune system has developed to respond to the various strategies employed by these pathogens to take advantage of their intended host, and consists of a number of different components which reflect the varied and diverse methods of enuy and establishment that have evolved. however, not only are the different species of farm animal born with their immune system at different levels of maturity, the different parts of the complete system do not become functional simultaneously. at birth, the calf can immunologically respond to bluetongue virus (maclachlan el al., ) and foot-and-mouth disease (fmd) virus (nicholls et al., ) by producing neutralizing antibody, but can only partially respond to infection with parainfluenza- virus (thorsen et al., ) . experimental infection of the foetal calf has been used to show how the developing immune system - / / - /$ . / © bailli~re tindall responds to different antigens during its ontogeny (see review by osburn, ). the immune system of the pig is less mature at birth; it can respond to hog cholera vaccination at week of age (precausta et al., ) but not effectively to fmd vaccination until weeks after birth (francis & black, ) . however, despite the development of a functionally competent immune system, there is inevitably a lag period between immunization and the development of active immunity. it is during this period that prevalent viruses can establish themselves in young animals. irnmediate immunity in the newborn pig or ruminant is provided in the colostrum of the dana. all classes of antibody are present, in concentrations greater than those present in the parental blood, together with immunologically active cells. the specificity of this antibody reflects the vaccination and disease history of the dana, and therefore, by boosting the antibody levels to those pathogens associated with neonatal mortality through vaccination, the newborn animal can receive from its mother high levels of specific protection. however, this maternally derived antibody (mda) is equally effective in preventing the response to active vaccination in the young animal as it is in providing protection against disease. unlike the situation in primates, transfer of immunoglobulins across the epitheliochorial placenta of farm animals during pregnancy is not possible. early passive immunity in these species is transferred to the offspring posl-partum by the absorption of colostrum through the gut mucosa. in the calf and piglet an indiscriminate uptake by the gut epithelium of macromolecules and immunocompetent cells in colostrum is possible for the first - h of life (logan el al, ) . the process is non-selective and is responsible for the rapid increase of iga, igg and igm in the circulation of the suckling neonate, with peak titres occurring at - h postpartum. the persistent detection of mda in the serum and secretions of the offspring is dependent upon the initial colostral uptake, which is determined by the immune status of the mother, and the half-life of antibody in the offspring, which is different for each isotype. mda specific for fmd virus has been found to persist for up to months in calves and months in piglets (mll & wittman, ) . estimations of the half-lives of individual mda isotypes vary. one set of values for the calf gives figures of . days for iga, . days for igm and days for igg (banks, ) . the corresponding figures for pigs are . - . days for iga, . - . days for igm and . - days for igg (curtis & bourne, ) . variability in these results is due to the range of methods used for naeasurement, and whether allowance has been made for the production of antibody by the neonatal immune system and the dilution effect of increasing blood volume during growth. indeed, francis and black ( ) concluded that the decay of serum neutralizing igg titres during the first days of life in the pig was largely a result of expanding blood volume and not catabolism of the antibody. there is ample evidence that in addition to the protective potential of mda, it is also responsible for marked antigen-specific immunosuppression in young ani-mals for periods that exceed the period of protection (francis & black, ) . this is demonstrated in vivo by interference with the serum antibody response to vaccination, and in vitro by a reduction in the reactivity of lymphocytes upon stimulation with antigen. in this way mda may interfere with the active immunization of young animals in a reversible fashion. in cattle and pigs, this phenomenon has been demonstrated for several infectious diseases including fmd. it has long been appreciated that the active immunization of vertebrates early in life is not as effective as in the mature individual. immaturity of the immune system at birth is partly responsible for this observation, although it has been shown in the domesticated species that good vaccination responses can be generated from the nd week of life (ahl & wittman, ) . the greatest suppressive influence on vaccination response in the neonate is mda. immediately after birth, there is a short period of generalized suppression of b and t lymphocyte responsiveness, which could be due to the transfer of immunosuppressive factors in colostrum such as cortisol, histamine and cytokines (clover & zarkower, ) . however, it has been clearly shown that the presence of mda in the offspring correlates with the antigen-specific suppression of antibody responses, an effect that can be mimicked by the passive administration of monoclonal antibodies to neonatal mice (xiang & ertl, ) . the mechanism by which mda causes this effect is not completely determined for any species. the current hypotheses build upon the proposed mechanisms for regulation of the immune response in adults. initially it was thought that mda interfered with the generation of an antibody response following vaccination of young animals purely by the enhanced removal of inactivated vaccine antigens or by neutralization of attenuated live vaccines. in both instances it was thought that vaccine antigen would be prevented from encountering the immunocompetent cells of the neonatal immune system by the effective 'antigen blockade' provided by mda to the specific microorganism. more recent evidence suggests that mda has a direct suppressive effect upon immunocompetent cells via a similar negative feedback system to the one that is thought to regulate the antibody response in mature animals (katz, ) . by the cross-linking of membrane-bound immunoglobulin fc-receptors with surface immunoglobulin, immune complexes comprised of mda and vaccinal antigen may deliver a negative signal to the b cell. this suppressive signal is antigenspecific and has the potential to be limited to particular mda isotypes (uhr & mohler, ) . mda could thus act directly on b lymphocytes to down-regulate the proliferation and differentiation required for antibody production. alternatively mda complexed with vaccinal antigen may act through a regulatory network to either suppress antigen-specific th cells or actively up-regulate the production of an antigen-specific t suppressor cell population (harte & playfair, ) . a third theoly of mda-related immunosuppression makes use of the 'idiotype-anti-idiotype' immunoregulatory network proposed by jerne ( ) . in this antigen-free system mda would induce antibody in the offspring which recognized its own antigen-binding site, or idiotype. the internal image antibody molecules, or anti-idiotypes, thus created could then interact with antigen receptors on the surface of b and t lymphocytes due to their similarity to the initiating antigen. this leaves the fc portion of the antibody molecule free to deliver a negative signal to the cell through the fc receptors. in reality the results of vaccination trials in young animals do not decisively confirm or refute any one of these theories. suppression of the antibody response to rabies virus vaccination in both the dog (aghomo et al, ) and the mouse (xiang & erfl, ) has been shown to occur for considerable periods after mda has fallen below detectable levels. in the mouse system the suppression of in vitro t lymphoproliferation responses was more prolonged than the effect on the antibody response. the authors concluded that in this experimental system mda-induced t suppressor cells were responsible for vaccination failure in these neonatal mice rather than a simple reduction in antigenic load. in addition to the mda-mediated effects on neonatal immunocompetence in the mouse, fujii and yamaguchi ( ) reported that immunization of pregnant mice induced cd + t lymphocytes which were capable of either producing a suppressive factor themselves or stimulating a population of t suppressor cells to secrete such a factor that could cross the placenta and induce specific humoral and cellular immunosuppression in the neonate. one of the authors has also previously reported the induction in mice of suppressor t cells in offspring following maternal immunization (koshimo et al., ) . imnaunocompetent cells and various factors are absorbed by the gut during the first h of life in the domesticated species and, therefore, it is possible that these may have a regulato~ t effect on the immature immune system in these species similar to the transplacental factors in mice (palmerly & beer, ) . in the case of fmd vaccination in pigs, francis and black ( ) concluded that the complete immunological unresponsiveness seen in the first weeks of life was due to immaturity of the immune system and antigen blockade by high titre mda, and as this titre declined an active suppression of t and/or b cells occurred to variable degrees. the degree of inhibition of the antibody response in these piglets was directly proportional to the mda titre at the time of vaccination. this was reflected in the outcome of the challenge experiment which showed that whereas partial protection was achieved by vaccination at weeks old, earlier vaccination conferred no protection to fmdv challenge after months. in this same study it was possible to elicit a primary antibody response, consisting of igm, at an age when iga and igg responses were totally suppressed. this observation supports the view that a period of t lymphocyte immunosuppression follows the initial state of unresponsiveness, and that this interferes with the generation of secondary antibody responses. in this case the suppression acts after the initial stage of antigenprocessing and recognition by b cells, and affects the regulation of the evolution of the antibody response by interference with clonal expansion and antibody isotype-switching, both of which are necessary for a secondary response and the generation of 'immunological memory', and thus long-term protection. similar results have been reported from studies on the effects of mda on vaccination of calves against several viral diseases (marshall & frank, ; kimman et al., ) . vaccination of calves with high mda titres at -week-old inhibited the active production of antibody to bovine coronavirus (heckert et al., ) . again the igm response was least susceptible to the suppressive effects of mda in these calves, whereas both the serum igg~ and secretory iga responses were markedly depressed. however, it is notable that the degree of suppression to the different coronavirus proteins was not uniform, and the attthors suggest that the more immunogenic viral proteins may be able to elicit antibody responses at mda titres that inhibit the response to other proteins. the reported success of oil-emulsion vaccines in the face of high mda titres may also be due to improved immunogenicity (morgan & mckercher, ) . this suggests that the duration of the interference of mda with antibody responses to vaccines may be specific to individual protein sub-units or even epitopes (van maanen et al., ) , which emphasizes the importance of vaccine potency in a situation where high mda titres are present. in support of this hypothesis that interference by mda could be specific to particular antigens are the results of kit et al. ( ) who were able to partially overcome the mda to pseudorabies with a live glycoprotein glii-deleted marker vaccine. ill many of the fmd endemic regions of the world cattle, and sometimes also pigs, are vaccinated between one and four times a year, against the prevalent serotypes of fmd virus. the half-life of mda to fmd virus in the calf is approximately days (nicholls et al., ) and days in the pig (francis & black, ) , although in the pig the decline in concentration was considered to be due more to the increase in body weight than degradation or excretion of the mda. the initial blood level of mda and its subsequent persistence relates directly to its level in the colostrum and the efficiency with which it is adsorbed. heifers tend to have lower levels of specific anti-fmd virus antibody in their colostrum than adult cows, and consequently their calves receive lower quantities of specific antibody than the calves of second or third lactation cows. this can result in an earlier susceptibility to fmd infection in endemic situations, and makes it more difficult to formulate vaccination schedules. in south america, nicholls el al. ( ) showed that mda against fmd was likely to persist for - months, and that calves with mda vaccinated against fmd not only failed to respond, but that vaccination depressed the serum titre of specific fmd virus antibody in these animals. they recommended that calves receive their prima w vaccination at - months of age. a similar situation exists in the large dairy herds in the middle east (kitching, unpublished observations). high yielding dairy cows have been imported from europe and north america into a hostile climate and an environment in which previously unencountered disease such as fmd and rinderpest are endemic. clinical fmd is kept under control by three or four times a year vaccination, but frequently it is the - month age group which develops disease in spite of this vaccination regime. many farm managers had become frustrated by the apparent ineffectiveness of the fmd vaccine, whereby they had been using a variety of calfhood vaccination protocols, almost all of which initiated vaccination before months of age, and in some instances as early as day old. the reason for the vac-cine failure was tile same as had been shown in south america a decade earlier, except in the middle east the cows were being vaccinated far more frequently and efficiently and the mda in their calves was at a very high level. the calves were reaching the age of or months, by which time they had received at least two ineffective vaccinations because of the mda, and were then becoming susceptible to infection with fmd virus. to compound the problem, if the calves developed clinical fmd, the environmental shedding of virus from these calves was frequently sufficient to overcome the immunity of other animals on the farm, resulting in a major outbreak and loss of production from the milking herd. a study was undertaken in which a number of the larger dairy herds participated, to examine different calfllood vaccination programlnes. the results of this previously unpublished study support many of the conclusions reached by nicholls et al, ( nicholls et al, ( , , but in addition addressed some of the problems more relevant to the middle east situation. assuming the level of management was sufficient to ensure that all calves received adequate colostrum, preferably pooled colostrum to include colosu'um from older cows, vaccination at day old or month of age, even if it was followed by a booster vaccination at days old or months of age, respectively, was ineffective. it could not be shown, however, that vaccination at these ages reduced the level of circulating antibody against fmd virus in calves, as there was no statistically significant difference between antibody levels in the vaccinated groups and unvaccinated control groups. when calves which had previously failed to respond to vaccination because of mda were revaccinated at an age at which mda no longer interfered with the response (i.e. at or months of age), there was no evidence that these calves had been primed by the first vaccination. they showed a similar response to vaccination as totally naive calves. this is contrary to the results of nicholls et al. ( ) , although it is acknowledged that comparisons between free ranging south american cattle and zero-grazed intensively-reared dairy animals in the middle east may not apply. calves with waning mda could become clinically infected with fmd virus prior to being able to respond to fmd vaccination. calves with antibody titres below : , measured using the liquid phase enzyme-linked imnmnosorbent assay (hamblin et al., ) , became susceptible to infection, depending on the level of fmd virus challenge. however, calves with titres greater than : failed to respond to vaccination. this situation accounted for the persistence of fmd on one large farm, where the -month-old age group would become infected, maintain infection in the group for approximately month and then pass infection to the next, month younger group with which it was in contact and which was just developing susceptibility to infection, in spite of this younger group receiving vaccination. at all times during the study the strain of fmd virus causing the outbreaks was monitored for changes in antigenic characteristics which could modify the interpretation of the results. surprisingly, the virus remained antigenically stable over the -year period of the study, even though the pressure to mutate in order to evade vaccinal immunity was very great. the conclusion of the study was that together with a number of management recommendations, the most effective vaccination programme for calves of well vaccinated dams, was vaccination of all calves at , and months of age, to ensure that all calves had good levels of protection. vaccination of pigs against fmd is less widely practised due to the rapid turnover in the pig population. in addition, the immaturity of the immune response of the young pig makes vaccination of the sow during pregnancy a more effective method by which to protect the litter. some response to vaccination in -week-old pigs in the presence of mda was shown by francis and black ( ) . however, it was the recommendation of francis that vaccination of pigs from immune sows be delayed until - weeks of age, although additional vaccination at - weeks of age could be justified in order to protect those piglets which had received insufficient mda (francis, ) . francis and black ( ) found no evidence in the pig that vaccination in the presence of mda depressed the specific antibody to fmd virus. the vaccines used in cattle outside of south america against fmd use a saponin and aluminium hydroxide adjuvant. these vaccines are less effective in pigs, and an oil adjuvant is used in pig fmd vaccines. however, in south america, oil adjuranted fmd vaccines are used in cattle, and it is claimed that these vaccines overcome the depressive effects of mda (sadir et al., ) . experimental results showed that calves over days of age, but still with mda, responded as well as adult cattle to the oil-emulsified fmd vaccine. however, there was a - day delayed response in mda free calves under days of age vaccinated with this vaccine, which was suggested to be due to high levels of cortical hormones (sadir et al., ) . in summal t, it has been shown for several of the domesticated species that mda can have a marked antigen-specific suppressive effect upon active antibody production in the young, the degree and duration of which is directly related to mda titres shortly after birth. there is a gradual recovery of immune function in which the individual can become partially responsive prior to the acquisition of full immunoconlpetence. the precise point or points in the immune system of the offspring at which maternally-derived factors interfere is not defined. some authors have described generalized cellular responsiveness (clover & zarkower, ) , and others describe antigen-specific reduction in both primary and secondary antibody responses (husband & lascelles, ) . however, it appears that individual lymphocyte subsets may be more or less susceptible to the effects of mda. wittman and ohlinger ( ) found that mda titres which interfered with the cytolytic t lymphocyte response to aujeszky's disease vaccination in piglets did not prevent the sensitization of lymphocytes for antibody production. interestingly, it has also been shown that high titres of mda in piglets suppressed the generation of 'memory cells' following vaccination against aujeszky's disease (kuiper et al., ) whereas lower mda titres that still suppressed the formation of antibody permitted the generation of immunological memory, which was apparent from the production of a secondary-type antibody response upon subsequent virus challenge (van oirschot & de leeuw, ) . it is also possible that anatomical compartments within the immune system are affected variously by mda, as has been shown to be the case for the mucosal immune response to respiratory syncytial virus vaccination in calves (kimman et al., ) . this study showed that a protec-tive mucosal antibody response could be effectively primed by the local application of attenuated virus in the face of mda titres that inhibited all primal-y antibody responses and the generation of systemic antibody memo w. thus, by taking advantage of these observed qualitative and quantitative variations in the degree of immunosuppression induced by mda, it may be possible to design vaccination su'ategies that offer better protection against infectious diseases of young livestock. control of fmd by vaccination has benefitted little fl'om the recent advances in vaccine technology (see review by kitching, ) . iinprovements in antigen production and concentration techniques have not resulted in significantly better vaccines, and fmd remains a disease that cannot be controlled by vaccination alone. the interference by mda in tile active immunization of young stock merely makes control of the disease even more difficult. cah,es with declining mda become susceptible to infection with live virus before they are able to respond to an inactivated vaccine. this observation suggests that the), would also respond to a live vaccine at a higher serum level of mda than they would using a dead vaccine. however, previous attempts to develop a live attenuated fmd vaccine were unsuccessful as the virus quickly reverted to virulence. the genome sequences associated with virulence of fmd virus are not known, but stocks of the original attenuated vaccine still exist. if it was possible to fix the mutations responsible for attenuation of fmd virus, vaccination with live virus could again become an option, although the reputation that live fmd vaccines have acquired may exclude their use under any circumstances. if a live vaccine can partially overcome interference by mda, an alternative approach might be to insert fmd virus genes into a live vector. the glycoprotein gene of rabies virus has been placed in the vaccinia virus genome (pastoret el al., ) and the f and h genes of rinderpest virus have been placed in the genomes ofvaccinia virus (yihna el al, ) and capripoxvirus (romero et al, ) to produce effective live vaccines against rabies and rinderpest, respectively. these recombinant vaccines will replicate in the presence of mda to rabies or rinderpest as there ufill be no inhibition of the pox virus vector. initial attempts to do the same for fmd xdrus have so far been unsuccessful. similarly, peptide vaccines have not replaced conventional fmd vaccines in spite of considerable research effort. this has in part been blamed on their failure to stimulate appropriate b and t cell populations. if, as has been suggested, mda selectively suppresses antigen-specific responses, there would be little potential for peptide vaccines to overcome mda. however, lipford et al. ( ) have recently reported the development of immunostimulating complexes (iscoms) containing lipids and the saponin quil a, which induce antigen-specific cytolytic t cells. the incorporation of fmd xdrus antigens into an iscom could improve peptide immunogenicity. there is at present no completely effective strategy to protect young stock against fmd by vaccination in situations in which fmd is endemic. only by isolating them completely from challenge with field virus until their mda has declined sufficiently for them to respond to conventional vaccines can disease be prevented, but such an approach in many countries may be too expensive to contemplate. the serological response of young dogs to the flul t lep strain of rabies virus vaccine. veterina o protection of young animals against foot and mouth disease host defence in the newborn animal immnnologic responses in colostrum-fed and colostrum-deprived calves half-lives of immunoglobulins igg, iga and igm in the sermn of new-born pigs. hnmunolo~ the immoral immune response of young animals to foot-and-mouth disease vaccination. foot-and-mouth disease bulletin effect of the sow vaccination regimen on the decay rate of maternally derived foot and mouth disease antibodies in piglets response of young pigs to fmd oil emulsion vaccination in the presence and absence of maternally derived neutralising antibodies maternal t cells of immunised pregnant mice induce imnmne suppression in their offspring enzylne-linked immunosorbent assay (elisa) for the detection of antibodies against foot-and-month disease virus. iii. evaluation of antibodies after infection. epidemiolo~, a~td h~fection failure of malaria vaccination in mice born to immtme mothers. ii. induction of specific suppressor cells by maternal igg mucosal and systemic antibody responses to bovine coronavirus structural proteins in experimentally challengeexposed calves fed low or high amonnts of colostral antibodies antibody response to neonatal vaccination in calves towards a nenvork theory of the immune system adaptive differentiation of lymphocytes: theoretical implications for mechanisms of cell-cell recognition and regulation of imnmne responses printing for local and systemic antibody memory responses to bovine respirato w syncitial virus: effect of amotmt of virus, virus replication, route of administration and maternal antibodies circumvention of maternal antibody of newborn pigs with glycoprotein giii-deleted marker vaccine tile application of biotechnology to the conu-ol of foot-and-mouth disease virus maternal antigenic stimulation actively produces suppressor activity in offspring sensitisation studies with the intranasal (i.n.) vaccine (s~vax ,n) against aujeszky's disease based on the bartha strain vaccination with inamunodonfinant peptides encapsulated in quil a-containing liposomes induces peptide-specific primary cd + cytotoxic t cells changes in the serum immtmoglobulin levels of colostrum-fed calves during the first weeks post-partum anti-xdral responses of bluetongue virus-inoculated bovine foetuses and their dams clinical and immunologic responses of calves with colostrally acquired maternal antibody against parainfluenza- virus to homologous viral infection hnmune response of neonatal swine to inactivated fmdv vaccine with oil adjuvant. i. influence of colostral antibody the effect of maternally derived antibodies on the response of calves to vaccination against foot-and-mouth disease effect of age on response of cattle to vaccination against foot-and-mouth disease ontogeny of inmaune responses in cattle colostral cell-mediated immulfity and the concept of a common secretol-y inamune system a recombinant vaccinia-rabies virus for oral vaccination of wildlife against rabies single capripoxvirus recombinant vaccine for the protection of cattle against rinderpest and lumpy skin disease response to foot-and-mouth disease vaccines in newborn calves. influence of age, colostral antibodies and adjuvants bovine parainfluenza- vaccine studies regulatory effect of antibody on the intmtme response interference of maternal antibodies with the immnne response of foals after vaccination against equine influenza intranasal vaccination of pigs against aujeszky's disease. comparison with one or two doses of an inactivated vaccine in pigs with moderate maternal antibody titres aujeszky's disease vaccination and infection of pigs with maternal immunity: effects on cell-and antibody-mediated immunity transfer of maternal antibodies results in inhibition of specific immune responses in the offspring protection of cattle against rinderpest with infectious vaccine virus recombinant expressing the ha or f gene key: cord- -br qk xb authors: cha, sung-ho title: the history of vaccination and current vaccination policies in korea date: - - journal: clin exp vaccine res doi: . /cevr. . . . sha: doc_id: cord_uid: br qk xb there may be many reasons for the significant decrease in the incidence of the pediatric infectious diseases in modern korea; this could be due to the improvement of sanitary facilities, significant growth of korean economy, improvement of nutrition, development and dissemination of antibiotics and implantation of vaccination, and overall improvement of medical technology. the development of vaccination has been highlighted as a striking achievement of the modern medical sciences with new technologies in many fields of medicine. since , the method for vaccination has opened its new era by suk-young jee, known as the jenner in korea who wrote a book about smallpox vaccination, and it led an opportunity to propagate the needs for the vaccination in korea. there was a time when pediatric wards were full of patients with parasitic diseases and many vaccine-preventable diseases such as diphtheria, pertussis, japanese b encephalitis, and poliomyelitis in s- s. we do not see those infectious diseases that often any more in recent years. however, we still have patients with water-borne diseases and other communicable diseases related to increasing international travels. we just experienced the first pandemic influenza of the st century in and avian influenza is still a threat to humans in other parts of the world with an unpredictable potential of pandemicity. in addition, we have tough battles with emerging antibiotic resistance in many strains of bacteria and increased opportunistic infections due to improvement of medical technology involving more aggressive treatment modality and use of medical devices. researches in many areas are under way and we hope that some of them may be preventable and decreased with a development of new vaccines in the future. there may be many reasons for the significant decrease in the incidence of the pediatric infectious diseases in modern korea; this could be due to the improvement of sanitary facilities, significant growth of korean economy, improvement of nutrition, development and dissemination of antibiotics and implantation of vaccination, and overall improvement of medical technology. the development of vaccination has been highlighted as a striking achievement of the modern medical sciences with new technologies in many fields of medicine. since , the method for vaccination has opened its new era by suk-young jee, known as the jenner in korea who wrote a book about smallpox vaccination, and it led an opportunity to propagate the needs for the vaccination in korea. there was a time when pediatric wards were full of patients with parasitic diseases and many vaccine-preventable diseases such as diphtheria, pertussis, japanese b encephalitis, and poliomyelitis in s- s. we do not see those infectious diseases that often any more in recent years. however, we still have patients with water-borne diseases and other communicable diseases related to increasing international travels. we just experienced the first pandemic influenza of the st century in and avian influenza is still a threat to humans in other parts of the world with an unpredictable potential of pandemicity. in addition, we have tough battles with emerging antibiotic resistance in many strains of bacteria and increased opportunistic infections due to improvement of medical technology involving more aggressive treatment modality and use of medical devices. researches in many areas are under way and we hope that some of them may be preventable and decreased with a development of new vaccines in the future. joseon dynasty and cover vaccination-related works in korea in modern history and review the objectives and directions of current vaccination policies in south korea. according to the literature, the history of vaccination can be traced back to as early as the th century when the monks in india tried to immunize themselves by drinking snake venom. the first vaccination was inoculation with human smallpox, a practice widely carried out in ancient india, arabia, and china. this method of vaccination consisted of collecting pus from a patient suffering from mild form of smallpox virus infection and inoculating the sample to a healthy human, which later led to a minor infection [ , ] . this method was first introduced in england by a greek named e. timoni. however, this method had a risk of spreading smallpox in the community and even worsening the health condition of the person who received the inoculation [ ] . while the use of human smallpox vaccine was controversial, e. jenner came up with bovine smallpox vaccine in ; this new method also faced controversy, but continued to be universalized. smallpox became a preventable disease by injecting pus extracted from a human infected with cowpox virus. jenner named the substance "vaccine" after the latin word "vacca" which means "cow, " and thus the process of giving vaccine became "vaccination" [ , ] . some people claim that the joseon dynasty is called "the dynasty of communicable infectious diseases" because many infectious diseases were rampant at that time. infectious diseases were rampant not only in joseon but all over the world. measles and smallpox were prevalent in our neighborhood country china; as a result, effort was put into controlling contagious diseases in this country [ , ] . in china, rudimentary inoculation of duibub (wearing clothes of a patient) and bimeobbub (spraying something to a patient's nostril) was invented in the middle of the th century. these kinds of skills were accumulated by late th century and even russians came to china to learn these methods [ ] . many people across the country died from smallpox and measles in . about nine hundred persons were reported dead in "kyoungsung" (old name of seoul) but indeed incalculable. during the reign of "jeongjo" ( - ), one of king of the joseon dynasty, times of plague had occurred ( times including his childhood). especially in the th year of his reign, measles significantly spread widely causing serious damage to entire population. measles were more common in children mainly and some infected children were abandoned by the parents who were afraid of being infected [ ] . in , the death toll due to measles contagious diseases with fever reached tens of thousands in seoul and throughout the country. in during king yeongjo's reign, it was recorded that the fourth princess died of measles and one of king's physicians, sang-kyung cho, advised the prince to be away in another palace for protection and the king agreed to his advice [ ] . in , yak-yong chung ( - ), one of the famous scholars in the field of the realist school of confucianism, introduced vaccination for the first time in korea during the joseon dynasty. in his book, magawhetong, he introduced jenner's vaccination in supplement section, under the subtitle, jongduyoji. also he found inoculating methods using collecting pus from a patient with smallpox from kangheejajeon in beijing, china. he got a copy of book, called junsijongdubang, and introduced to korea from beijing in [ ] . the practice has been successfully done by je-ga park ( - ) after he was appointed as a mayor of youngpyung city (now pocheon, northern part of seoul), and the practice was passed on to jong-in lee, a doctor in pocheon. jong-in lee started to vaccinate people, especially those in the wealthy class, who lived in pocheon city. the method for vaccination has met its new era by suk-young jee ( - ), known as a korean jenner since the opening of the port in . in , he learned to methods of vaccination from japanese, wrote a book called woodooshinsul to propagate the needs for the vaccination. as the effect of the vaccination has started to be seen, in september , the first cowpox vaccination clinic was built in castle of jeonju, followed by the second cowpox vaccination clinic built in gongju in . the vaccination recommendation was proposed in . according to the recommendation, "all children are required to be vaccinated between days and a year after the birth. " in , the jonggyso, the cowpox vaccination office, has been built to produce vaccines and to carry out vaccination. in , the hansung (old name of seoul) vaccination recommendation was been established and distributed. the small pox vaccination efforts had historical significance because ability to control the infectious disease was achieved and the vaccination saved many lives by preventing smallpox during http://www.ecevr.org/ http://dx.doi.org/ . /cevr. . . . this period [ , ] . in , with the establishment of the department of bacteriology in the japanese governor-general of korea, the production of vaccine had been continued. in , the vaccine for cholera had started to be produced in the department of bacteriology. there was neither regulation for the test of the vaccination nor the authority for the facility inspection. rather, only production and vaccination had been performed. for the people, it was probably hard to understand the concept of classic vaccination in that it was done by injecting the bad substances such as pus obtained by small pox patients or cows which were processed specifically to healthy people. however, unlike the western world, people considered the vaccination as mandatory due to the curiosity for the vaccination and the belief for the goodness of the vaccination, which was done forcefully in the japanese era. the vaccinations for cholera, typhoid fever, typhus, scarlet fever, diphtheria, and others had been performed in the japanese era. in , . % of people had anti-typhoid vaccine while maximum . % of people had in . the vaccination for cholera was distributed only when cholera was prevailing throughout the country. vaccination for the other diseases except cholera and typhoid fever cost a lot of money and its effectiveness was only being examined as an academic review and approach, therefore, they were not enough to use widely. in , korea's first anthrax vaccination (kidasado institute, japan) was tried in changyoung, gyeongsangnamdo in korea, and in , the first production of vaccines and immune serum was prepared in the ministry of agriculture and the forestry rinderpest serum manufactory. in , cholera, smallpox vaccine were produced in the kidasado institute in japan. in , korea's first rinderpest (cattle plague) vaccination (the ministry of agriculture and the forestry serum manufactory) test was performed to , people, and in , eight vaccines include anthrax, rinderpest were produced in the general of korea serum manufactory of the japanese governor-general of korea. in , the name of vaccine producing organization was changed to the korea veterinary service laboratory of the japanese governor-general of korea [ ] . in august , after world war ii, under the rule of the us army, it renamed as the joseon quarantine laboratory, expanded the organizations, and produced cholera vaccine in the same year. for the prevention of epidemics of cholera which was widespread throughout the country, the vaccine was produced enough to prevent for , , people. in , bacillus calmette-guérin (bcg) vaccine was produced and inoculated, and in , the central quarantine laboratory produced anti-serum and performed vaccination against preventable diseases [ ] . in , the infectious disease prevention act was established and routine vaccination was specified. smallpox, diphtheria, whooping cough, typhoid fever, typhus, paratyphoid fever, and tuberculosis vaccination were given. diphtheriatetanus-pertussis (whooping cough) (dtp) vaccine in , killed polio vaccine in , and inactivated vaccine for typhoid fever in were used. in august , in accordance with article amendment of decree of the state council, it was proclaimed as the national quarantine laboratory, and they produced vaccines including cholera and tested them with a self-calibration me thod. in december , according to decree no. , the korea national institute of health organization was proclaimed. after that, "biological agents based on interdisciplinary" was enacted for strict quality control included the immune effects of preventive medicine, prevention of side effects in september . polio vaccine in , cholera vaccine in , measles vaccine inoculation and the time table of vaccination were made in . the pediatric vaccination schedule has been revised times since [ ] . in , the advisory committee on immunization practice was organized, and it consisted of sub-committees. in , the recommended childhood immunization schedule for contagious diseases was developed, and in , so unified national vaccination service seemed to be possible [ , ] . also in november , the enforcement regulations of the communicable diseases preventive measure was proclaimed, and in august , the enforcement ordinance of the communicable diseases preventive measure was proclaimed. according to the communicable diseases preventive measure, infectious diseases were classified as class , class , and class . and it is advised on regulations concerning about obligations of registration and report, medical examinations, immunizations, and preventive measures. in order to know the evolution of the modern vaccination in this country, we need to know the restructuring process and the establishment of the korea center for diseases control and prevention. the origin of the korea centers for disease control and prevention at the present time can be found at the health administration installed by the edict of king gojong in . the institutes of health and the training center for medicare in , was renamed as the josun quarantine laboratory and the national chemistry laboratory in , respectively [ ] . as the independent organizations that were established as the national quarantine institute, the national chemical laboratory, the national institute of health, the national herbal laboratory were integrated into one in december , then, the national institutes of health was launched. [ ] in , the severe acute respiratory syndrome (sars) in southern china spread around the world and resulted in a lot of casualties and economic loss. the systematic national disease management system was urgently needed after the sars epidemic, in order to protect life and property from the new and reemergence infectious diseases, the korea centers for disease control and prevention which was integrated with a unified inspection and quarantine work and research capabilities by expanding and reorganizing the national institutes of health in january , [ ] . in , the life science research team, the biological safety assessment team, the bio-science and information team were newly established. the national institutes of health was reorganized as the korea centers for disease control and prevention which consists of the national public health institute and branches of the national quarantine station [ ] . december, to management of infectious disease. also aspect of users, the korea centers for disease control and prevention improved the national infectious disease surveillance system and infectious disease web statics system to provide high-quality information based on scientific data and to keep pace with the rapid changes in medical health care not only in domestics but also in all over the world. additionally it has published the public health weekly report since april, . the surveillance annual report included annual infectious disease outbreak and report materials [ ] . the health budget and management would be made by publishing a white book or a government report in . the purposes of project for the national immunization program are to immunize more people against more diseases which finally influence to the national health, to establish policies based on the evidence, to enhance the national expanded vaccination program, to make confidence for vaccination, to expand routine immunization coverage reaching more children with newly available vaccines, and to integrate other critical health interventions with immunization. on these purposes the government confirmed the national immunization program and here is an overview of the main detailed facts [ ] . the advisory committee on immunization practice was founded on january and is comprised of or less members including government officials, health care providers, lawyers and people who are recommended by consumer organization. it specifies coverage of vaccination, quality and standard methods of vaccination, detailed policies and eradication of preventable infectious diseases, which were holding conferences a year. the practice of the national immunization program was based on evidence [ ] . fourteen infectious diseases are belong to the national immunization program which includes tuberculosis, hepatitis b, diphtheria/tetanus/pertussis, measles/mumps/rubella, poliomyelitis, varicella, japanese encephalitis, influenza, typhoid, and hemorrhagic fever with renal syndrome for routine vaccination according to communicable diseases preventive measures, enforcement [ ] . when there are rapid http://www.ecevr.org/ http://dx. doi.org/ . /cevr. . . . increased number of infectious diseases or occurring new emerging infectious disease in the community, temporary vaccination would be given based on the article (e.g., nationwide measles vaccination in ) [ ] . also private health medicare recommended kinds of vaccination including haemophilus influenzare type b, hepatitis a, pneumococcus, human papillomavirus, and rotavirus. the criteria for selection of the national immunization program is effectiveness, stability, cost-benefit, convenient application, financial resources, storage and social-cultural standards. for management of immunization practice, they published the "epidemiology and management" which included the basic concept of vaccination, methods and practice in vaccination, and management of side effects on [ ] . evaluated immunity against vaccine preventable diseases, immunity (antibodies) against human papillomavirus in korean women, policies for managing hepatitis b, development of policies for vaccination against japanese encephalitis were carried out in [ ] . the national expanded vaccination program was developed to increase vaccination rate in korea. the current status of the doses of vaccination including hospitals and public health care center are , , doses but estimated to be near , , doses considering the low report rate of private clinics and hospitals. the proportion of vaccination rate is % for public health centers and % for private sector, respectively [ ] . in an effort to achieve the vaccination rate for eradication of the infectious diseases, every children who enter the primary school should have submitted a sheet of conformation of measles vaccination. the national expanded vaccination program was under taken [ ] . the current national immunization program is limited to public health centers, and visitors of private medical facilities (clinics and hospitals) spent up to , won (about usd) until age due to get the financial burden by themselves. the necessity for the expanded program is emphasized due to inaccessibility to public health center, equity issues in vaccine between public health center and hospitals, which were being a problem in enhancing the vaccination rate [ ] . the trial of the expanded vaccination program which was implemented in daegu city and gunpo city in july to december , and it enhanced the vaccination rate by % compared to last year. the proportion ratio dropped in public health centers by %, whereas the rate rose by % in private clinics and hospitals. another same trial program took place in other cities from january to december . then, % of the participants answered "satisfactory" in a survey about the trial program, % answered "very satisfactory. " the computerized registration and report rate jumped up to . % from . %. the trial program had taken up the legal backgrounds and securing budget for the expanded program [ ] . the vaccination rate was around % for several months from late to early due to consecutive cases with severe adverse events including deaths after vaccination which facilitated the public fear for vaccination. as a result, the adverse events following immunization surveillance system and the national vaccine injury compensation program were developed [ ] . there was total of , cases for years period from to . pandemic influenza was , ( . %), bcg was , ( . %), diphtheria-tetanus-acellular pertussis (dtap) was ( . %), influenza was ( . %), measles-rubella (mr) was ( . %), japanese b encephalitis was ( . %), hepatitis b was ( . %). the number of bcg side effects was increased to tenfold in - due to changed strain [ ] . the korea centers for disease control and prevention developed computerized and standardized vaccination registration and management program for the management of the personal vaccination records from to [ ] . while the rate of measles vaccination was under % (complete eradication rate), breakouts occurred in every - years and a major breakout which took place in - affected , patients between - years old with mortality cases. in an effort to maintain over % vaccination rate, a nationwide measles vaccination program took place in on , , students (elementary nd grade to high school st grade) and announced eradication of this disease based on who standards in november [ ] . about , people received national support ( , won per person; about usd) for immunoglobulin administrahttp://www.ecevr.org/ http://dx. doi.org/ . /cevr. . . . tion, antigen and antibody tests for hepatitis b to prevent vertical infection from infected mothers. the participation rate was % in , % in , % in , % in , and % in [ ] . the goal for managing influenza is decreasing morbidity and mortality rate to achieve reduced disease burden. the vaccination program selected the high risk groups for vaccination with priority. the influenza surveillance system operated and monitored daily and weekly surveillance for influenza and influenza like illness altogether with laboratory surveillance [ ] . the growing interest of public health related to vaccination reflects that they are well aware of preventable diseases and safety issues of vaccines unlike in the past. it seems that public began to see new vaccine development not only as a treatment for a disease but as a public health problem. as of the year , public health authorities in korea presented computerized vaccination registration and policies for infectious disease-i.e., the fight against tuberculosis, prevention of vertical transmission of hepatitis b program, measles elimination, and influenza management-and continued to maintain it since then. with spontaneous introductions of new vaccines, the selection of vaccines to be produced and to be used must be determined based on local disease epidemiology and disease burden of each and every applied region. in order to do so, it requires the interests of public health authorities in practical and economical aspects-i.e., budget. a much higher standard is required in regards to the criteria of vaccine safety and biochemical characteristics of vaccines compared to those in the past years, and yet is still continued to be revised. finally, i hope that this review paper would be valuable to understand our past history of vaccine and vaccine policies in our country. a short history of vaccination the medical history of china. seoul: iljong publisher academy of korean studies. the korean encyclopedia s role in the introduction of smallpox vaccine the health history of western. seoul: shinkwang publisher korean society of infectious diseases. the history of infectious diseases in korea cultural heritage administration. the annals of the joseon dynasty variolation" and vaccination in late imperial china, ca - the medical policies in the reign of jeong-jo. the hankookhakbo. seoul: iljeesa the medical history of korea. seoul: tamgusa daejeon: the national archives of korea cheongwon: the korea center of diseases control and prevention key: cord- -s yx u authors: tizard, ian r. title: adverse consequences of vaccination date: - - journal: vaccines for veterinarians doi: . /b - - - - . - sha: doc_id: cord_uid: s yx u the importance of adverse effects from vaccination must not be overstated. vaccine benefits greatly exceed any risks from the procedure. neither must they be minimized. unnecessary vaccination must be discouraged. hypersensitivity reactions to vaccine components are real and must be guarded against. residual virulence, although a concern tends to be more a hypothetical than a real problem. progressive improvements in animal vaccines have significantly reduced the chances of adverse effects occurring, although some issues persist. one such example is injection-site sarcomas in cats. another issue is the influence of animal size on the prevalence of adverse events in dogs. vaccination is the only safe, reliable, and effective way of protecting animals against the major infectious diseases. society does not remember the devastating toll taken by infectious diseases before the development of modern vaccines. exaggerated fear of negative side effects has discouraged owners from having their pets (and themselves) from being vaccinated. the rise of the internet and the development of social media have enabled those who oppose vaccination to spread their opinions. those who resist vaccination for themselves or their children are unlikely to be enthusiastic about vaccinating their pets. much of this resistance is a result of adverse events and controversy regarding effectiveness associated with the earliest vaccines. in spite of the fact that these problems have long been solved, it takes a considerable time before confidence is restored. there is a lack of awareness of the rigorous safety tests that modern vaccines must undergo before they are marketed. good manufacturing practices and the quality control procedures used by the biologics industry, together with rigorous regulatory controls, serve to minimize the occurrence of these events. past issues have been corrected and vaccine safety has steadily improved. modern vaccines are safe to use and overwhelmingly beneficial. adverse events associated with vaccination that might compromise the health of an animal are usually rare, mild, and transient. hypothetical, speculative, or historical adverse effects sometimes dominate perceptions. nevertheless, it has been truly said, "the most dangerous vaccine is the one not given." in reading this chapter the reader should be aware that the events described here are rare, somewhat historical, and relatively unimportant when compared with the benefits of vaccination. drivers of vaccine usage differ significantly between companion animals and commercial livestock. owners of companion animals are concerned for the health and well-being of their pets and are intolerant of any adverse events that cause discomfort, pain, or sickness. livestock producers in contrast vaccinate to maintain livestock health, prevent disease spread, maximize economic return, and to minimize zoonotic disease risks. vaccines that cause a drop in milk production, decreased feed conversion, increased time to market, or a decline in carcass quality may have significant economic consequences and will not be used. in determining whether a vaccine causes an adverse effect, the following three principles should apply. first, is the effect consistent? the clinical responses should be the same if the vaccine is given to a different group of animals, by different investigators, and irrespective of the method of investigation. second, is the effect specific? the association should be distinctive and the adverse event linked specifically to the vaccine concerned. it is important to remember that an adverse event may be caused by vaccine adjuvants and components other than the major antigens. finally, there must be a temporal relationship. administration of the vaccine should precede the earliest manifestations of the event or a clear exacerbation of a continuing condition. the us centers for disease control and prevention (cdc) has classified adverse events as follows: . vaccine-induced events: these are events that would not occur in the absence of vaccination and are therefore attributed to the vaccine. an example would be an allergic response to a vaccine component such as egg protein. vaccine potentiated reactions: these are events that might have occurred anyway but may have been precipitated by the vaccine. one possible example is purpura hemorrhagica in horses. . programmatic error: events that occur in response to technical errors in vaccine storage, preparation, handling, and administration. . coincidental events: these are simply events that happen by chance or result from some underlying illness. the use of vaccines is not free of risk, and an owner has reason to be upset if their healthy animal is sickened by the administration of a vaccine. residual virulence and toxicity, allergic responses, disease in immunodeficient hosts, neurological complications, and harmful effects on the fetus are potential risks associated with the use of vaccines (table . ). veterinarians should use only licensed vaccines, and the manufacturer's recommendations must be carefully followed. before using a vaccine, the veterinarian should consider the likelihood that an adverse event will happen, and also the possible consequences or severity of this event. these factors must be weighed against the benefits to the animal. a common but mild complication requires a very different consideration than a rare, severe complication (table . ). the issue of the risk associated with vaccination remains in large part a philosophical one because the advantages of vaccination are well documented and extensive, whereas the risk for adverse effects is poorly documented, and in many cases, largely speculative. nevertheless, established facts should be recognized, unsubstantiated allegations rebutted by sound data, and uncertainties acknowledged. for example, there is absolutely no evidence that vaccination itself leads to ill health. although difficult to prove, a negative, competent statistical analysis has consistently failed to demonstrate any general adverse effect of vaccination. identification of an adverse event is based on the clinical judgment of the attending veterinarian and is therefore subject to bias. standard case definitions of a vaccine-associated adverse event are not yet available. it still is often difficult to distinguish association from causality (box . ). traditionally, adverse events resulting from vaccine administration have been reported by veterinarians to manufacturers or government agencies. the resulting numbers have been difficult to analyze satisfactorily for two major reasons. first, reporting is voluntary, so significant underreporting occurs. adverse events are often regarded as insignificant, or it may be inconvenient to report them. second, very little data has been available on the number of animals vaccinated. although manufacturers know the number of doses of vaccine sold, they are unable to measure the number of animals vaccinated. it has, however, proved possible by examining the electronic medical records of a very large small animal general practice, to determine the prevalence of vaccine-associated adverse events in over a million dogs. the use of a standardized reporting system within a very large population has permitted objective analysis of the prevalence of adverse events occurring within three days of vaccine administration. out of , , dogs receiving , , vaccine doses, adverse events were recorded ( . / , dogs); . % of these events occurred on the same day the vaccine was administered, . % were considered to be allergic reactions, . % were classified as anaphylaxis, and . % were considered "vaccine reactions" and were likely caused by innate immune responses. three dogs died. the lowest rate of such events was associated with bordetella more than in animals showing adverse reactions (. %) common greater than but less than animals per animals vaccinated ( %- %) uncommon more than but less than animals per animals vaccinated ( . %- %) rare more than but less than animals per , animals vaccinated ( . %- . %) very rare less than animal in , reported (, . %) autism spectrum disorder is a chronic developmental disorder in children. its causes are largely unknown. it usually becomes apparent in young children over one year of age at around the same time they receive their initial vaccinations. in a paper published in , a physician studied children with autism. he asked the parents if the children had been vaccinated, with the measles, mumps, and rubella vaccine, within the previous two weeks. eight said yes, so the author went on to assert in his paper that this vaccine caused autism. he postulated that autism resulted from measles infection. the paper was eventually retracted and the author lost his medical license. subsequent population-based studies have failed to demonstrate any link between vaccination and autism. thousands of children are vaccinated every year and large amounts of data are available for analysis. all these show the same thing. there is no link between vaccination and autism risk. however, the word was out. the internet and twitter spread the word. additionally, pet owners began to claim that their dog's behavior had changed after vaccinationcanine autism. the british veterinary association felt obliged to issue a statement regarding these claims. "there is currently no reliable scientific evidence to indicate autism in dogs or a link between vaccination and autism. vaccinations save lives and are an important tool in keeping our pets healthy. all medicines have potential side-effects but in the case of vaccines, these are rare and the benefits of vaccination in protecting against disease far outweigh the potential for an adverse reaction." vaccination and the highest rate with lyme disease vaccine. additional analysis indicated that the risk of adverse events was significantly greater for small dogs than for large dogs ( fig. . ); for neutered than for sexually intact dogs; and for dogs that received multiple vaccines on one occasion. each additional vaccine dose administered increased the risk of an adverse event occurring by % in dogs under kg and by % in dogs heavier than kg ( fig. . ). highrisk breeds included dachshunds, pugs, boston terriers, miniature pinschers, and chihuahuas. overall, the increased prevalence of adverse events in young adult, small-breed, neutered dogs and their relationship to multiple dosing suggests that veterinarians should look carefully at the practice of giving the same vaccine dose to all dogs irrespective of their size. in another report, from japan dogs showed an adverse event out of , vaccinated ( . / , doses). (vaccines used included canine parvovirus, canine distemper, canine adenovirus , canine coronavirus, and leptospirosis.) of these dogs, died, had anaphylaxis, developed dermatological signs, and showed gastrointestinal signs. about half the anaphylaxis events occurred within minutes of vaccination. additional analysis of these anaphylaxis cases reported % collapse, % cyanosis, and both collapse and cyanosis in % of affected dogs. breeds affected included miniature dachshunds ( %; these accounted for about % of all the anaphylaxis cases), chihuahuas ( %), mixed breeds ( %), and toy poodles ( %). miniature schnauzers also appeared to be unusually prone to anaphylaxis. the highest frequency of adverse reactions occurred in dogs under kg. most adverse events were observed within hours after vaccination. the adverse event rate in japan as reported here ( . / , doses) is much higher than in the united kingdom ( . / , doses), or in the united states ( . / , dogs). vaccines may elicit mild transient injection site reactions as a result of inflammation. these inflammatory responses may manifest themselves within two to three days. as pointed out in chapter , some degree of inflammation is required for the efficient induction of protection. this may cause pain or pruritus. the sting produced by some vaccines may present problems, not only to the animal being vaccinated, but also to the vaccinator, if the animal reacts violently. lethargy, anorexia, soreness, minor behavioral changes, and tenderness at the vaccine site are normal postvaccinal responses and should resolve within to hours. swellings may develop at the reaction site less commonly. these may be firm or edematous and may be warm to the touch. they appear within hours and can last for about a week. unless an injection-site abscess develops, these swellings leave little trace. vaccines containing killed gram-negative bacteria may be intrinsically toxic owing to the presence of pathogen-associated molecular patterns such as endotoxins, lipids, muramyl peptides, and porins that can bind to pattern recognition receptors and provoke cytokine release. in extreme cases this may lead to anorexia, and fever. although such reactions are usually only a temporary inconvenience to male animals, they may be sufficient to provoke early embryonic deaths in pregnant females. it may be prudent to avoid vaccinating pregnant animals unless the risks of not giving the vaccine are considered to be too great. vaccination with either immunestimulating complex (iscom) vaccines or live recombinant vectored vaccines against influenza and tetanus may induce an acute-phase response in horses. innate immune responses may reduce an animal's growth rate and diminish its feed efficiency. this growth suppression can be mimicked by injection of interleukin (il)- and tumor necrosis factor (tnf)-a. these cytokines act on the brain to reduce appetite while at the same time, causing degradation of skeletal muscle. intranasal vaccines such as those containing bordetella bronchiseptica and some viruses may cause transient cough or sneezing. this simply reflects the mild innate response triggered as the vaccine organisms invade the upper respiratory tract. vaccines have the potential to cause rare but serious allergic reactions (type i hypersensitivity). for example, allergic responses may occur when an animal produces immunoglobulin (ig)e in response, not only to the immunizing antigen, but also to other components in vaccines. the most significant allergens are often vaccine excipients. for example, reactions are most likely to occur after injection of vaccines that contain trace amounts of fetal calf serum (specifically bovine serum albumin), egg proteins (ovalbumin), or gelatin. (gelatin and serum albumin are added to vaccines as stabilizers to protect the vaccine antigens during the freeze-drying process.) some vaccines may also contain antibiotics such as neomycin to which an animal may be sensitized. severe allergic responses have been associated with the use of killed foot-and-mouth disease, rabies, and contagious bovine pleuropneumonia vaccines in cattle. signs include angioedema, affecting mainly the head and ears, urticaria, pruritus, acute-onset diarrhea, vomiting, dyspnea, and collapse. all forms of hypersensitivity are more commonly associated with multiple injections of antigens and therefore tend to be associated with the use of killed vaccines. it is important to emphasize that a type i hypersensitivity reaction is an immediate response to an antigen and occurs within a few minutes after exposure to an antigen ( fig. . ). it is good practice to keep an animal in the clinic for to minutes after vaccination to ensure that any immediate problems can be promptly recognized and treated (box . ). reactions occurring more than two or three hours after administration of a vaccine are likely not type i hypersensitivity reactions. in type ii hypersensitivity reactions, antibodies directed against an animal's own cells act together with complement to cause cell lysis. these antibodies are usually induced by the presence of animal cells in the vaccine. natural hemolytic disease of the newborn (hdn) in calves is very rare, but it has resulted from vaccination against anaplasmosis or babesiosis. these vaccines contain pooled red cells from infected calves. in the case of anaplasma vaccines, for example, the blood from infected donors is pooled, freeze-dried, and mixed with adjuvant before being administered to cattle. the vaccine against babesiosis consists of fresh, infected calf blood. both vaccines cause infection, and consequently, the development of immunity in recipients. they also stimulate the production of antibodies against the injected red cells. if cows sensitized by these vaccines are then mated with bulls carrying the same blood groups, they can transmit these antibodies to their calves through colostrum. the calves that drink this colostrum may then develop hemolytic disease. hdn in piglets had a similar pathogenesis when sows were immunized with a hog cholera vaccine containing pig blood. beginning in , multiple outbreaks of an unexplained hemorrhagic disease in newborn beef calves were reported from many countries in western europe. affected calves showed sudden onset bleeding including nasal hemorrhage, petechiation on mucus membranes, and excessive bleeding from minor wounds such as injection, or ear-tag sites. the disease appeared to days after birth and affected calves could die within hours. it is now called bovine neonatal pancytopenia (bnp). investigation showed an early drop in platelets, monocytes, and neutrophils was followed by drops in erythrocyte and lymphocyte numbers. the net result was a profound pancytopenia. the bone marrow could be completely aplastic. mortality was as high as % in severely affected calves, but there were also many subclinical cases. because this disease only occurred in suckled calves and developed within hours of first suckling, it appeared to result from the consumption of colostrum. further investigations showed that the colostrum from these cows contained antibodies directed against the major histocompatibility complex (mhc) class i molecules expressed on neonatal leukocytes and bone marrow stem cells. cells of the thrombocyte, lymphocyte and monocyte lineages, and precursors of neutrophil, erythrocyte, and eosinophil lineages were affected. further investigations showed that the disease was triggered by administration of a specific vaccine against bovine virus diarrhea (bvd). this vaccine-pregshure-contained inactivated bovine viral diarrhea virus (bvdv) grown in bovine kidney cells. a potent, oil-in-water emulsion adjuvant containing quil a, cholesterol, and mineral oil was then added. immunization with this anaphylaxis is a life-threatening medical emergency. deterioration can occur very rapidly and time is of the essence. initiate treatment immediately. if an animal is undergoing acute anaphylaxis take the following steps: . stop administering the vaccine. in the case of dogs and cats, administer epinephrine : at . mg/kg intramuscularly. repeat every - minutes if necessary. if very severe and shock has developed, place an intravenous catheter and administer . mg/kg of : , epinephrine by slow intravenous infusion and monitor blood pressure and perfusion. alternative routes of administration include intracardiac or intratracheal. avoid subcutaneous administration because epinephrine is a potent vasoconstrictor and absorption is delayed. in the case of foals administer epinephrine : at . to . mg/kg ( . - ml for a kg foal) given slowly intravenously or intramuscularly. in adult horses administer epinephrine at . mg/kg ( - ml for a kg horse) slowly intravenously. if the condition is mild, this dose may be administered intramuscularly. repeat every - minutes if necessary. . secure the airway, intubate if necessary, and administer oxygen to animals showing respiratory symptoms. . provide isotonic shock crystalloid fluids (normal saline or lactated ringer solution) intravenously to help restore adequate blood pressure in hypotensive animals. the volume required depends on the animal's response, but may be as high as ml/kg for dogs and ml/kg for cats. administer an h -antihistamine such as diphenhydramine every - hours if necessary. . once the animal is stabilized consider administering a fast acting glucocorticosteroid by the slow intravenous route to prevent late-phase responses. vaccine induced antibodies against the bovine kidney cells in some cows. these antibodies, when transferred to calves via colostrum, bound to their leukocytes and bone marrow stem cells, killed them, and so induced pancytopenia (fig. . ) . not all calves born from cows that received this specific vaccine developed clinical disease. the quantity and specificity of their antibody response determined the risk to their calves. antibody levels remained high in some cows for many years and were boosted by each pregnancy. as a result, bnp cases occurred for many years after pregshure was removed from the market in . type iii hypersensitivity reactions (immune-complex-mediated) may be induced by vaccination. the deposition of immune-complexes in tissues may cause local inflammation or cause a generalized vasculitis such as purpura. some rabies vaccines may also induce a local complementmediated vasculitis in the skin resulting in ischemic dermatitis and local alopecia. this may occur at the injection site or at remote locations such as the ear tips, footpad, tail, or scrotum. this vasculitis is most often seen in small dogs such as dachshunds, miniature poodles, bichon frises, and terriers. in dogs infected with canine adenovirus- (cav- , infectious canine hepatitis), an immunecomplex-mediated uveitis and a focal glomerulonephritis both develop. the uveitis, commonly called "blue-eye," is seen both in dogs with natural infections and in those vaccinated with live attenuated cav- vaccine (fig. . ). the uveitis results from the formation of virus-antibody complexes in the anterior chamber of the eye and in the cornea with complement activation and consequent neutrophil accumulation. the neutrophils release enzymes and oxidants that damage corneal epithelial cells, leading to edema and opacity. the condition resolves spontaneously in about % of affected dogs. replacing cav- with cav- in vaccines has largely eliminated this problem. see chapter . type iv hypersensitivity (delayed) reactions are t-cell-mediated inflammatory responses. they may occur at the injection site in response to vaccination, but a more common reaction is local granuloma formation. this may be in response to persistent adjuvants containing alum or oil. vaccines containing a water-in-oil adjuvant produce larger and more persistent lesions at injection sites than vaccines containing alum or aluminum hydroxide. these lesions may develop into sterile abscesses and if the injection site is dirty, these abscesses may become infected. injection site lesions are of major concern in the meat industries. modified live vaccines must be able to establish themselves transiently in a vaccinated animal yet at the same time not cause disease. they must be safe in animals and their human companions. they must be as stable as possible to enable long-term storage. they must be environmentally safe. it may be possible to achieve minimal virulence with maximal immunogenicity, but this may be unattainable in animals with any defects in their immune function. the normal distribution of immunological competence in an outbred population is such that some animals will inevitably be susceptible to an otherwise avirulent organism. this immunosuppression may result from minor stresses, but equally important some common viral infections such as canine distemper, feline pancytopenia, or feline leukemia also cause immunosuppression to a degree that an animal may become susceptible to otherwise avirulent vaccinal agents. it is also appropriate to point out that modified live vaccines are attenuated for a specific target species for administration by a specified route. if administered to the wrong species or in the wrong way residual virulence may cause disease. thus some modified live vaccines may retain the ability to cause disease. a good example is brucella abortus strain . although highly immunogenic in cattle, s can cause severe reactions in vaccinated cows. swelling, fever, anorexia, depression, and a drop in milk yield have been reported. s can also cause abortion in pregnant cows and orchitis in bulls and humans. safer attenuated brucella vaccines are now available. similar residual virulence hazards are associated with the soremouth vaccine and the sheep toxoplasmosis vaccine. some modified live herpes vaccines or calicivirus vaccines given intranasally may spread to the oropharynx and result in persistent infection. in these cases, the vaccine virus may infect (and protect) other animals in contact. because live vaccine strains may be released into the environment, safety issues involving not only the animal but also its environment must be addressed. are there changes in the tissue tropism of the virus? are there changes in the carrier through the incorporation of new foreign genes? is there reversion to virulence through the incorporation of complementation genes? is there exchange of genetic information with other wild type or vaccine strains of the carrier? will the carrier spread unwanted genes such as antibiotic resistance into the environment? these questions are highly relevant in the aquaculture industry where modified live vaccine viruses may escape into the aquatic environment (chapter ). postvaccinal canine distemper encephalitis is a rare complication that may develop in dogs and ferrets after administration of modified live canine distemper vaccines. affected animals may show neurologic signs such as aggression, incoordination, and seizures, or die suddenly. the pathogenesis of this condition is unclear. it may be the result of residual virulence, increased susceptibility, or triggering of a latent paramyxovirus by the vaccine. vaccination during pregnancy carries uncertain risks, especially when live vaccines are used. the fetal immune system may not have developed sufficiently to defend itself against the vaccine strain of the virus. mlv bluetongue virus vaccine has been reported to cause malformations in the offspring of ewes vaccinated while pregnant. the severity of the lesions depends upon the stage of pregnancy at vaccination. for example, mlv bluetongue administered to ewes between and days of gestation has caused hydranencephaly and retinal dysplasia in lambs. live erysipelothrix rhusiopathiae vaccines have been reported to cause abortions in sows. the stress from this type of vaccination may also be sufficient to reactivate latent infections; for example, reactivation of equine herpesviruses has been triggered by vaccination against african horse sickness. a modified live virus (mlv) parvovirus vaccine administered during pregnancy has been reported to cause hydranencephaly and cerebellar hypoplasia in kittens. many viruses promote their own survival by suppressing their host's immune system. although immunosuppression is greatest in virulent strains, some mlvs may remain somewhat immunosuppressive. for example, some mlv canine parvovirus strains may depress t cell responses to mitogens in puppies for two to five weeks following administration, or even cause a lymphopenia. similarly, mlv canine distemper may cause immunosuppression and thrombocytopenia. in view of this it may be best to avoid performing elective surgery on dogs for at least one week postvaccination. mlv bovine viral diarrhea (mlv-bcd) vaccines may suppress neutrophil functions and lymphocyte blastogenesis in vaccinated calves. as a result, they may potentiate intercurrent infections. mlv-bvd may also induce mucosal disease to days after vaccination. vaccination with an mlv-bhv vaccine has been shown to exacerbate the lesions of experimental moraxella-induced pinkeye (chapter ). several vaccine combinations may also result in transient immunosuppression. for example, a combination of distemper and adenovirus vaccines can reduce canine lymphocyte counts and their responsiveness to mitogens, although the individual components are not detectably immunosuppressive. this t cell suppression may be accompanied by simultaneous enhancement of b cell responses and raised immunoglobulin levels. many of these cases of "immunosuppression" attributed to vaccines may however simply reflect alterations in the th /th balance or transient alterations in lymphocyte recirculation patterns. they are rarely of clinical significance. as pointed out in an earlier chapter, older vaccine viruses were attenuated by prolonged passage in tissue culture or eggs. in some cases, it is possible to reverse the attenuation process by backpassage through their natural hosts. for example, attenuated distemper strains cannot grow in canine lung macrophages. back-passage of the canine distemper virus (cdv) rockborn strain for as few as three passages in puppies resulted in the virus regaining this ability. by four passages the virus could cause weight loss. by five passages, immunosuppression returned. the virus that had been back-passaged six to seven times had regained its virulence. the use of genetically defined, gene deleted attenuated vaccines has largely eliminated this type of problem. louis pasteur's first rabies vaccine contained dried rabbit brain tissue. when injected into patients it induced antibodies against myelin basic protein and an acute demyelinating encephalomyelitis developed in about . % of recipients. rabies vaccines have had an undeserved bad reputation ever since. in , it was proposed that a new syndrome existed that linked diverse human autoimmune diseases with the use of adjuvanted vaccines. it was called autoimmune/ autoinflammatory syndrome induced by adjuvants (asia). this syndrome has been investigated to determine whether it is an insignificant clinical term or whether there is an underlying mechanism that links adjuvants to autoimmunity. aluminum-containing adjuvants were claimed to be the "cause" of asia. however, patients receiving allergen-specific immunotherapy receive up to times more injected aluminum than regular vaccine recipients and have a lower incidence of autoimmune disease. current data does not support the causation of asia by vaccine adjuvants. there is a lack of any reproducible evidence for any link between adjuvants and autoimmunity. one obvious problem with this proposed syndrome is that vaccination is so commonplace whereas autoimmunity remains uncommon. after all, huge numbers of people receive influenza vaccines annually without untoward effect. there is a single animal study that appears to show that a link might exist between vaccination and the development of autoimmunity. a retrospective analysis of the history of dogs presenting with immune-mediated hemolytic anemia (imha) showed that of ( %) dogs with imha had been vaccinated within the previous month, compared with a randomly selected control group of dogs in which % had been vaccinated. dogs with imha that developed within a month of vaccination differed in some clinical features from dogs with imha unassociated with prior vaccination. some studies using very large databases have tended to confirm this effect, in that they showed an approximately three-fold increase in diagnoses of autoimmune thrombocytopenia, and a two-fold increase in diagnoses of imha in dogs in the days following vaccination, compared with other time periods. other studies have failed to show any association between vaccination and imha. the overall prevalence of these diseases remains low, and they can be diagnosed at times not temporally associated with vaccination. vaccination may therefore serve as a trigger for these diseases in some dogs-a vaccine potentiated reaction. contaminating thyroglobulin found in some vaccines (usually from the presence of fetal bovine serum) may lead to the production of antithyroid antibodies in vaccinated dogs. lymphocytic thyroiditis has been found in % of beagles on necropsy, but there was no association detected between vaccination and the development of this thyroiditis. in the s, a swine influenza vaccine induced guillain-barré syndrome (an autoimmune polyradiculoneuritis) in about case per , human recipients. (current influenza vaccines have a risk of about : million. it appears that the older influenza vaccine was unique in this respect.) cases of this syndrome in dogs have been rarely reported. in some animals, the administration of potent, adjuvanted vaccines may stimulate the transient production of autoantibodies to connective tissue components such as fibronectin and laminin. vaccination of some weimaraner puppies may lead to the development of a severe hypertrophic osteodystrophy. the disease appears within days of administration of mlv canine distemper vaccine. systemic signs include anorexia, depression, fever, and gastrointestinal, nervous, and respiratory symptoms, in addition to symmetrical metaphyseal lesions with painful swollen metaphyses. radiological examination shows radiolucent zones in the metaphyses, flared diaphyses, and formation of new periosteal bone. it is possible that the condition is triggered by the vaccine in genetically susceptible animals. these dogs may have a preexisting immune dysfunction with low concentrations of one or more immunoglobulin classes, recurrent infections, and inflammatory disease. it has been suggested that weimaraners are especially susceptible to this condition and that they therefore receive only killed virus vaccines. a mild transient polyarthritis has been reported in some dogs following vaccination. the dogs show a sudden onset of lameness with swollen and painful joints within two weeks of vaccination. the dogs recover within two days. no specific breed or vaccine has been associated with this problem. vaccination against calicivirus has been associated with polyarthritis and a postvaccination limping syndrome in cats. a search of web sites regarding vaccination of pets reveals that a large number express great concern regarding the practice of overvaccination. by this is meant the use of unnecessary vaccines and by implication a significant threat to the health of pets. conversely a search of pubmed, the ncbi web site, reveals only a single scientific paper regarding this subject. the paper describes renal disease in a spaniel that received seven doses of vaccine from its owner, one vaccine per month, in the absence of any veterinary supervision. as a result, the dog developed immune-complex lesions in its kidney glomeruli. this was very likely a type iii hypersensitivity nephropathy. clearly administration of excessive and unneeded vaccines is inappropriate. there are no health benefits and each additional dose of vaccine carries with it the chances of an untoward event. as pointed out throughout this text, the risk/benefit assessment of any vaccination procedure must be a subject for discussion between a veterinarian and the pet owner. there are many reasons why a veterinarian may suggest that it may be beneficial to vaccinate an animal and it is inappropriate to blame those vets who choose to vaccinate animals more frequently than currently recommended without a full knowledge of each specific case. this is called clinical judgment. these are discussed in chapter . errors in manufacture and administration modified live vaccines cannot contain preservatives (except antibiotics in viral vaccines). as a result, occasional cases of vaccine contamination have occurred. these have been a major issue in the past when viral identification required culturing. modern identification techniques such as the polymerase chain reaction have made such contamination a thing of the past. there are numerous examples of such contamination. for example, mycoplasma contamination was a feature of many live virus veterinary vaccines. the pestivirus of border disease contaminated some soremouth and pseudorabies vaccines; bovine leukemia virus has contaminated bovine blood vaccines such as those against babesiosis and anaplasmosis. bluetongue virus has contaminated some canine vaccines. injection site selection should include consideration of potential adverse reactions in addition to the hypersensitivity reactions described earlier. for example, injection in the gluteal muscles/hip region of cattle should be discouraged because gravitational drainage along fascial planes can occur. should an abscess develop, considerable tissue damage may occur and result in eruptions in undesirable locations with lesions that require prolonged time to heal. they may result in unacceptable blemishes in meat destined for human consumption (chapter ). veterinarians and other vaccine users may be inadvertently exposed to animal vaccines as a result of unintended inoculation or spraying. some of these vaccines may cause sickness. veterinarians, their assistants, and other animal handlers should be especially careful when administering injectable vaccines to avoid needle-stick and eye injuries. if an individual is accidentally self-injected with a mineral oil-adjuvanted vaccine, seek immediate medical treatment regardless of the dose injected. with the notable exception of brucellosis, these events are rarely reported. nevertheless, accidents do occur and veterinarians should be fully aware of these risks. brucellosis is an existential hazard to veterinarians. the cdc has established a passive surveillance registry. in the two years to , individuals reported needlestick injury related exposure to the brucella vaccine strain rb , five were splashed in the eye, and one was splashed into an open wound. although most received antibiotics, reported clinical disease. approximately to million doses of brucella vaccines were administered annually in to . it is estimated these would have resulted in at least needle-stick injuries, suggesting that exposure to rb is substantially under-reported. a vaccinia recombinant rabies vaccine bait has been air-dropped across many states in the united states to vaccinate wildlife. several instances of human exposure to these baits have been reported. (the vaccine baits have toll-free numbers printed on them.) in ohio, there were reports of bait contact and of these involved contacts with the vaccine. one individual developed a severe vaccinia infection and had to be hospitalized. bordetella bronchiseptica causes respiratory disease in dogs and atrophic rhinitis in pigs. infection of humans is rare but has been documented. in at least one case a young boy was inadvertently sprayed in the face with a "kennel cough vaccine." he had been holding his dog but the dog moved. he developed a pertussis-like respiratory disease that lasted several months despite antibiotic treatment. there have been reports of clients experiencing respiratory difficulty following administration of an intranasal vaccine to their dogs. needle-stick injuries are not uncommon and many involve vaccines. a woman was inadvertently inoculated with the sterne anthrax vaccine while vaccinating her horse. she did not develop anthrax but did develop a local reaction within hours. serious inflammatory reactions are associated with injected mycobacterium paratuberculosis vaccine. self-injections appear to be a major issue in the aquaculture industry where workers have to work fast to vaccinate slippery fish. veterinarians are encouraged to report all adverse reactions to the vaccine's manufacturer and the regulatory authorities. this provides both with the critical information that is used to evaluate and monitor vaccine safety in the field. in this way vaccine safety can be progressively improved. adverse reactions should be reported to the vaccine manufacturer first. after that, they should be reported to the appropriate regulatory authorities. in the united states, adverse vaccine events should also be reported to the us department of agriculture aphis center for veterinary biologics at - - - . they have an online electronic report form. reports can also be made by fax or mail. vaccine lot and serial numbers should be noted in vaccination records because this will facilitate an investigation. the use of standardized reporting systems is encouraged. web: http://www.aphis.usda.gov/animal_health/vet_biologics/vb_adverse_event.shtml fax or mail: download the pdf form at http://www.aphis.usda.gov/animal_health/vet_ biologics/publications/adverseeventreportform.pdf and fax to ( ) - or mail to the center for veterinary biologics (cvb), dayton avenue, po box , ames, iowa , usa. telephone: ( ) - in canada, suspected adverse events (sae) should be reported to the canadian center for veterinary biologics (ccvb) in ottawa at - - - . as stipulated by the health of animals regulations, all reports that indicate "serious expected" or "serious unexpected" adverse events related to the use of a veterinary biologic, including lack of efficacy, must be reported to ccvb within days of that information becoming known to the permit or license holder. follow-up reports, including case conclusions, must be submitted to ccvb in a timely manner. all other reports should be investigated by the license/permit holder, summarized in a summary update report, and submitted to ccvb every six months. summary update reports should be submitted within days of the end of the reporting period. sae related to veterinary biologics are categorized as one of the following: adverse event (ae), serious ae, unexpected ae, and lack of efficacy. a causality assessment should also be assigned to each sae. each case should be classified as probable, possible, unlikely, or unknown. form cfia/acia , notification of suspected adverse events to veterinary biologics, may be found at http://inspection.gc.ca/english/for/pdf/c e.pdf. in the united kingdom adverse events should be reported to the veterinary medicines directorate. forms can be obtained at their website at www.vmd.defra.gov.uk or by calling their pharmacovigilance team at . the veterinary medicines directorate (vmd), an agency of the department for environment, food, and rural affairs, is responsible for the suspected adverse reaction surveillance scheme (sarss) for veterinary medicines. adverse reactions in animals in the united kingdom should be reported at http://www.vmd.defra.gov.uk/ adversereactionreporting/default.aspx. human reactions to veterinary medicines in the united kingdom should be re new zealand in new zealand adverse event reports should be made to the ministry for primary industries adverse events in humans associated with accidental exposure to the livestock brucellosis vaccine rb human illness associated with use of veterinary vaccines evaluation of the safety of vaccinating mares against equine viral arteritis during mid or late gestation or during the immediate postpartum period pharmacovigilance: suspected adverse events vaccination and ill-health in dogs: a lack of temporal association and evidence of equivalence vaccine hypersensitivity-update and overview adverse reactions to vaccination: from anaphylaxis to autoimmunity revisiting adverse reactions to vaccines: a critical appraisal of autoimmune syndrome induced by adjuvants (asia) vaccine-induced enhancement of viral infections rabies vaccine is associated with decreased all-cause mortality in dogs vaccine-associated adverse events large-scale survey of adverse reactions to canine non-rabies combined vaccines in japan adverse events after vaccine administration in cats: , cases adverse events diagnosed within three days of vaccine administration in dogs adverse vaccinal reactions in dogs and cats a space-time cluster of adverse events associated with canine rabies vaccine aa amyloidosis in vaccinated growing chickens ige reactivity to vaccine components in dogs that developed immediate-type allergic reactions after vaccination membranoproliferative glomerulonephritis possibly associated with over-vaccination in a cocker spaniel fatal adverse pulmonary reaction in calves after inadvertent intravenous vaccination anaphylaxis in dogs and cats comparative vaccine-specific and other injectable-specific risks of injection-site sarcomas in cats immune modulation following immunization with polyvalent vaccines in dogs key: cord- - jlnw e authors: sato, ana paula sayuri title: pandemic and vaccine coverage: challenges of returning to schools date: - - journal: revista de saude publica doi: . /s - . sha: doc_id: cord_uid: jlnw e since march , brazil has faced the pandemic of the coronavirus disease (covid- ), which has severely modified the way in which the population lives and uses health services. as such, face-to-face attendance has dropped dramatically, even for child vaccination, due to measures of social distancing to mitigate the transmission of the virus. several countries have recorded a substantial drop in vaccination coverage in children, especially of those under two years of age. in brazil, administrative data indicate the impact of the covid- pandemic on this downward trend, which was already an important challenge of the national immunization program in recent years. many children will be susceptible to immunopreventable diseases, which reinforces the need to assess the vaccine status of schoolchildren before returning to face-to-face classes. vaccination (along with other public policies, especially those aimed at expanding sanitation) has made possible to substantially decrease the number of deaths of children under five years of age worldwide . widespread vaccination allowed the eradication or control of immunopreventable diseases in several regions of the world, including brazil, due to successful immunization programs [ ] [ ] [ ] . in brazil, since the s, vaccine coverage in children under one year of age had rates above %, which indicated the high participation of the population in vaccination and the good performance of the national immunization program (nip) . the gradual implementation of the brazilian unified health system (sus) in the late s allowed for a high rate of vaccine coverage through the expansion and decentralization of health services, mainly due to its principle of universal and free access to vaccination [ ] [ ] . throughout its history, the nip faced several challenges. in the s, the first national surveys of vaccination coverage showed worse coverage in poorer segments of the population; this difference disappeared in the late s, indicating that equity of access to vaccination had been reached in different socioeconomic strata of brazil , , . however, according to the national survey, the country now has a lower coverage on both the richer and the extremely poor demographics . moreover, from onwards vaccine coverage rates have declined about % to % , , due to factors not yet understood. the measles epidemic that hit several states in and is an immediate consequence of the decrease in vaccine coverage . among the possible explanations for this, we have the decrease in the perception of risk of these diseases and the increased perception of risk of adverse events following immunization (aefi). this phenomenon was also recorded in other countries, due to the success of immunization programs when disease control or elimination is reached, a result of the prolonged maintenance of high vaccination coverage. thus, success itself has become a great challenge . however, it is accepted that this is not the sole reason: among other factors that influenced the drop in vaccination coverage since , the emergence of vaccine hesitancy is highlighted. this a phenomenon that has gained importance in various parts of the world and is characterized by the delay in accepting or refusal of the vaccine, regardless of its availability and access to health services , - . the political and economic crisis, the decrease in government support for the sus and the dissemination by social networks of distorted information about vaccines are also worthy of mention, all of which possibly contributed to the sharp drop in vaccine coverage in recent years [ ] [ ] [ ] . in , due to the pandemic of coronavirus disease (covid- ), face-to-face attendance in health services dropped dramatically in many countries; this included child vaccination, given the measures of social distancing to mitigate viral transmission [ ] [ ] [ ] [ ] [ ] [ ] [ ] . efforts to contain the pandemic, which involve distant medicine practices and the use of other technologies in order to continue health care at home, have affected vaccination actions, which require travels to the healthcare unit . parental concern in exposing children to sars-cov- when taking them to health services for vaccination also contributed to the decline in vaccination coverage , [ ] [ ] [ ] . a risk-benefit study in african countries showed that avoidable deaths from routine vaccination outweigh the excess risk of death from covid- associated with attendance at the healthcare unit, evidencing the need for increasing vaccination coverage at this time . child vaccination coverage has declined sharply during the pandemic in several regions of the world , . in the usa, a considerable decline in the vaccine coverage of children was found, starting in the week after the national emergency scenario was declared (march , ). higher rates were found among children under two years of age . in england, three weeks after the introduction of social distancing (march , ), there was a . % drop in doses of the measles-mumps-rubella vaccine, compared to the same period in . in michigan (usa), completeness of the vaccination schedule for five-year olds dropped from . % to . % in may . at months, it was found that measles vaccine coverage decreased from . % to . % . in indonesia, where immunization occurs in schools, a significant drop in coverage of the basic vaccination schedule was predicted after the closure of schools in march . moreover, it is known that this impact will be even more important in families with unfavorable socioeconomic conditions . the world health organization (who) estimates that at least million children will be susceptible to immunopreventable diseases such as measles, diphtheria and polio because of the decrease in vaccination coverage during the covid- pandemic . it is worth remembering that outbreaks of measles were attributed to the interruption of vaccination services during the - ebola epidemic in west africa, causing a second public health crisis [ ] [ ] . the pandemic of the new coronavirus has challenged health systems around the world in providing essential services, including immunization programs, as routine vaccination and mass vaccination campaigns could contribute to the spread of covid- . on march , , who and the pan american health organization published recommendations on vaccination during the covid- pandemic. the measures considered three scenarios of availability of health services and included the temporary suspension of mass vaccination campaigns during this period. it was recommended that routine vaccination be maintained in places where essential health services had operational capacity of human resources and supply of preserved vaccines, respecting social distancing and other measures to control transmission of sars-cov- , . in brazil there was the recommendation of suspending routine immunization during the first days of the influenza vaccination campaign, as this was a period in which older adults and health professionals were supposed to be vaccinated; although this was valid as a safety measure for the older population, it has generated concern among brazilian medical societies . the who recognizes this fragility and recommends efforts to ensure high vaccination coverage, seeking herd immunization for preventable diseases, in such way that vaccination programs should adopt innovative measures , . vaccination strategies in vehicles, at home or in specific rooms and well-separated from the locations of other clinical visits could be used, as well as the identification of absentees and recruitment for vaccination with the aid of electronic immunization registries (eir) , [ ] [ ] [ ] . eir allow greater efficiency of health services, because, in addition to providing the evaluation of vaccination coverage, they also help in routine practice and enable the convocation of absentees, thus increasing the scope of immunization , . in addition, they are important sources of information, which can be applied in the evaluation of performance indicators and in the development of epidemiological research , . in , researchers from countries such as the usa and the united kingdom evaluated in real time the decline in vaccination coverage and the number of doses applied during the covid- pandemic through eir. with this quick identification, it is possible to quickly adopt strategies in the face of this challenge , , . with the emergence of many radical groups worldwide that deny the importance of the pandemic and its associated mitigation measures, vaccine hesitancy might acquire more strength, especially considering the availability of vaccines for covid- in the near future that will have an important role in dealing with this disease . the safe resumption of day care centers and schools should be a national priority. children have lost fundamental benefits of social, educational and developmental nature. for many parents, it will not be possible to return to work if these institutions remain closed, thus exacerbating social inequities. several individual practices (use of masks, hygiene, social distancing, temperature measurement etc) as well as environmental ones (maximum capacity and layout of classrooms, cleaning etc) will be necessary to prevent the transmission of sars-cov- between schoolchildren and staff, including in transportation to schools , . however, in addition to care for covid- , the american academy of pediatrics recommended that schools, health services, and local health authorities promote child vaccination well before the beginning of the school year. it is important that children receive vaccines at the recommended age and be updated in case of vaccine delay due to the pandemic . this recommendation should be considered in other countries, including brazil. in brazil, the pandemic was an additional challenge for the return to schools due to the abovementioned immunopreventable diseases, as we recently faced a consistent drop in vaccination coverage and a wide epidemic of measles that reached several states and amounted for thousands of cases. this situation has worsened in , which until august had registered more than , confirmed cases of measles . according to data from the nip information system (is-nip), when comparing the number of first doses of the pentavalent vaccine applied in march with march , we found a decrease of % ( figure) [ ] [ ] . these data indicate that the return to classes may increase the risk not only of the expansion of measles epidemics throughout the country, but also of the reemergence of other already controlled diseases, such as diphtheria and the whooping cough. studies show that outbreaks of diphtheria occur when vaccination coverage drops due to migration and/or political instability, emphasizing that it is a disease of relevant lethality [ ] [ ] [ ] . thus, it is evident that, before the progressive return of face-to-face school activities, intensive actions to assess the vaccine situation of this population will be necessary in order to recover sufficient vaccination coverage to prevent or reduce the spread of immunopreventable diseases . innovative instruments, such as eir, can be useful for real-time assessment of vaccination coverage, as well as to warn about immunization and rescue individuals with vaccine delay , , , [ ] [ ] [ ] . to date, there are no studies on the impact of covid- on the decline in vaccine coverage. delays in child vaccination (a demographic that should have been immunized in the most intense moment of social distancing) are also yet to be studied, even in other countries. moreover, despite the universal access to child vaccination achieved by the nip in the last decade, this impact will probably be greater in children from families with unfavorable socioeconomic conditions, due to less access to health services and information. when social distancing measures are loosened, many children will be susceptible to preventable diseases, and there will be a need to assess the vaccine situation of schoolchildren before returning to school , [ ] [ ] [ ] , . the covid- pandemic recalled the importance of vaccination by showing how fast a disease can spread and cause irreparable harm in societies without this defense. when a safe and effective vaccine for sars-cov- is available, immunization programs will have an even greater challenge of strengthening and reaching those most vulnerable . world health organization. global vaccine action plan - : review and lessons learned successes and failures in the control of infectious diseases in brazil: social and environmental context, policies, interventions, and research needs the contribution of vaccination to global health: past, present and future coberturas vacinais e doenças imunopreveníveis no brasil no período - : avanços e desafios do programa nacional de imunizações the brazilian health system: history, advances, and challenges doenças infecciosas no brasil: das endemias rurais às modernas pandemias effectiveness of influenza vaccination and its impact on health inequalities desigualdades sociais e cobertura vacinal: uso de inquéritos domiciliares socioeconomic inequalities and vaccination coverage: results of an immunisation coverage survey in brazilian capitals qual a importância da hesitação vacinal na queda das coberturas vacinais no brasil? longitudinal profiling of the vaccination coverage in brazil reveals a recent change in the patterns hallmarked by differential reduction across regions trends and spatial distribution of mmr vaccine coverage in brazil during epidemiologic methods in immunization programs vaccine hesitancy: definition, scope and determinants the emergence of vaccine hesitancy among upper-class brazilians: results from four birth cohorts vaccine confidence and hesitancy in brazil os desafios atuais da luta pelo direito universal à saúde no brasil the public health crisis of underimmunisation: a global plan of action the debate on vaccines in social networks: an exploratory analysis of links with the heaviest traffic here we go again: the reemergence of anti-vaccine activism on the internet routine childhood immunisation during the covid- pandemic in africa: a benefit-risk analysis of health benefits versus excess risk of sars-cov- infection decline in child vaccination coverage during the covid- pandemic -michigan care improvement registry impact of the covid- pandemic on emergency department visits -united states early impact of the coronavirus disease (covid- ) pandemic and physical distancing measures on routine childhood vaccinations in england effects of the covid- pandemic on routine eediatric vaccine ordering and administration -united states routine vaccination during covid- pandemic response the potential impact of covid- pandemic on the immunization performance in indonesia the impact of covid- on the routine vaccinations: refletions during world immunization week at least million children under one at risk of diseases such as diphtheria, measles and polio as covid- disrupts routine vaccination efforts, warn gavi, who and unicef [news release reduced vaccination and the risk of measles and other childhood infections post-ebola the health impact of the - ebola outbreak covid- disrupts vaccine delivery guiding principles for immunization activities during the covid- pandemic. geneva: who; pan american health organization. the immunization program in the context of the covid- pandemic sociedade brasileira de pediatria sociedade brasileira de imunizações. calendário vacinal da criança e a pandemia pelo coronavírus. rio de janeiro: sbp pan american health organization. vaccination of newborns in the context of the covid- pandemic world health organization regional office for europe. guidance on routine immunization services during covid- pandemic in the who european region national immunization program: computerized system as a tool for new challenges monitoring vaccination coverage: defining the role of surveys sistemas informatizados de registro de imunização: uma revisão com enfoque na saúde infantil the vaccines act: deciphering vaccine hesitancy in the time of covid- challenges of "return to work" in an ongoing pandemic reopening primary schools during the pandemic covid- and school return: the need and necessity covid- planning considerations: guidance for school re-entry. itasca, il: aap; vigilância epidemiológica do sarampo no brasil - semanas epidemiológicas a clinical and epidemiological aspects of diphtheria: a systematic review and pooled analysis global epidemiology of diphtheria diphtheria in the former soviet union: reemergence of a pandemic disease authors' contribution: study design and planning; data collection, analysis and interpretation; preparation and review of the manuscript; approval of the final version; public responsibility for the content of the article: apss. the authors declare no conflict of interest. key: cord- -y z l ji authors: carter-pokras, o.; hutchins, s.; gaudino, j.a.; veeranki, s.p.; lurie, p.; weiser, t.; demarco, m.; khan, n.f.; cordero, j.f. title: the role of epidemiology in informing united states childhood immunization policy and practice date: - - journal: ann epidemiol doi: . /j.annepidem. . . sha: doc_id: cord_uid: y z l ji one of the ten greatest public health achievements is childhood vaccination because of its impact controlling and eliminating vaccine-preventable diseases (vpds). evidence-based immunization policies and practices are responsible for this success and are supported by epidemiology that has generated scientific evidence for informing policy and practice. the purpose of this report is to highlight the role of epidemiology in the development of immunization policy and successful intervention in public health practice that has resulted in a measurable public health impact: the control and elimination of vpds in the united states. examples in which epidemiology informed immunization policy were collected from a literature review and consultation with experts who have been working in this field for the past years. epidemiologic examples (e.g., thimerosal-containing vaccines and the alleged association between the measles, mumps, and rubella (mmr) vaccine and autism) are presented to describe challenges that epidemiologists have addressed. finally, we describe ongoing challenges to the nation’s ability to sustain high vaccination coverage, particularly with concerns about vaccine safety and effectiveness, increasing use of religious and philosophical belief exemptions to vaccination, and vaccine hesitancy. learning from past and current experiences may help epidemiologists anticipate and address current and future challenges to respond to emerging infectious diseases, such as covid- , with new vaccines and enhance public health impact of immunization programs for years to come. epidemiology is the foundation of effective immunization policy and practice in the united states . epidemiologic methods, such as surveillance of vaccine-preventable diseases (vpds) and vaccination coverage, risk factor identification for both disease and lack of vaccination, community intervention and effectiveness studies, and assessment of access to and quality of vaccination services have contributed to the historic reduction or elimination of many vpds in the united states and the americas. epidemiology has contributed to immunization policy and practice at most levels of the immunization field--from vaccine development to ensuring that vaccines reach those who need them and result in the desired public health impact, disease control, and when feasible, disease elimination. for example, surveillance and studies of childhood infectious diseases provide the basis of morbidity and mortality data used to make j o u r n a l p r e -p r o o f immunization was selected as an example for examination of epidemiology in informing public health policy and practice because childhood immunization is one of the ten greatest public health achievements in the united states--it saves lives and is cost-effective. , - a study of . million children years of age or younger born during - found that routine childhood vaccination prevented million cases of illnesses and , premature deaths from vpds, resulting in a net savings of an estimated $ billion in direct medical costs and $ . trillion in societal costs to the united states. , this paper highlights the role of epidemiology in immunization policy development and public health practice that have led to major reductions in vpds. the success of childhood immunization programs has resulted from coordinated efforts that began with a rigorous science base--including epidemiologic methods and studies--that informed decision-making, led to public health policy, and continues to guide immunization services delivery. the working definition for policy in this paper is one generally used in public health: "a law, regulation, procedure, administrative action, incentive, or voluntary practice of governments and other institutions." this definition can be further summarized as described by torjman: "those decisions that seek to achieve a desired goal that is considered to be in the best interest of all members of society." j o u r n a l p r e -p r o o f through this examination of how epidemiology contributed to the successes, we also highlight lessons learned from immunization policy and practice that may be applicable to other public health programs, particularly those priorities delineated in healthy people . the united states has a robust policy-making apparatus for immunization policy development that supports all stages, from vaccine development to immunization practice. many stakeholders in the public and private sector are engaged at each step--from the consideration of candidate vaccines to vaccination of children once the food and drug administration (fda) (figure ) license new vaccines. many groups share responsibility in program implementation at the state, local, and even the health care office level in order to ensure high vaccination coverage, and reduction and control of vpds. vaccine development requires a large and diverse research infrastructure with funding from public and private sectors that begins by identifying diseases suitable for vaccine development ( figures and ) . once a candidate vaccine is developed, rigorous testing for safety, tolerability, immunogenicity, and efficacy follows with phase i, ii and iii clinical vaccine trials ( figure ). the private sector funds most clinical trials to demonstrate the safety, tolerability, immunogenicity, and efficacy of a candidate vaccine while the public sector funds vaccine development for selected vaccines and establishes priorities for vaccine development. developing new vaccines is an expensive and high-risk proposition, estimated to cost up to $ million dollars per vaccine and is a lengthy process, often taking more than a decade to bring a vaccine from development to market. the fda in the united states plays a key role in j o u r n a l p r e -p r o o f examining a candidate vaccine for its composition and source and the methods used for, and findings from,testing the vaccine's safety, purity and potency. only after the fda reviews and accepts the evidence from these initial steps, will it further examine evidence from human clinical trials about safety, tolerability, immunogenicity, and efficacy for the candidate vaccine in humans after finding a candidate vaccine to be safe and efficacious in humans, fda can then proceed to issue a license for the manufacture and commercial distribution for the vaccine ( figure ). , once the fda approves a vaccine, advisory committees such as the advisory committee on immunization practices (acip) recommend whether a new vaccine targeted for children and adults should be included in its recommended schedules for routine immunization ( figure ). , state and local immunization programs and health care providers play major roles in ensuring that vaccine coverage of a new vaccine quickly reaches high levels, and that established vaccines maintain a high coverage level needed to reduce or control vpds. professional organizations, such as the american academy of pediatrics (aap), the american academy of family physicians (aafp), and the american college of physicians (acp), make recommendations to their members on best practices to ensure high vaccination coverage and, in collaboration with the acip, recommend a schedule of routine immunization. government programs and insurance companies have a major role in the financing of vaccine purchase, and access to those vaccines. insurance companies cover many immunizations through their health care coverage plans. government programs, such as the vaccines for children program (vfc), provide targeted funding to cover costs for all acip-recommended vaccines for uninsured and underinsured children ages years and younger. many stakeholders from federal, state and local agencies, health plans, hospitals, clinics, employers, health care providers and philanthropic organizations play key roles in the implementation and day-to-day operation of the united states j o u r n a l p r e -p r o o f immunization system. the complex infrastructure of laws, regulations, funding streams, and programs continues to be informed by a spectrum of diverse epidemiologic surveillance and studies. we now describe some key elements of the federal agencies and respective advisory committees that inform immunization policy development. the national vaccine program office (nvpo), provides strategic leadership and coordination among federal agencies and other stakeholders to help reduce the burden of preventable infectious diseases. nvpo and national vaccine advisory committee (nvac) were established to comply with section of the public health service act. , nvpo obtains advice from the national vaccine advisory committee (nvac), which recommends approaches to control and prevent human infectious diseases through vaccine development, and provides advice on prevention of adverse reactions to vaccines ( figure ). , one example of nvac's key role was during and after the time of the major measles resurgence of the s was when it issued a call for action to eliminate endemic measles in the united states by using epidemiological evidence to improve childhood vaccination along with simultaneous monitoring of burden of measles. use of scientific evidence by nvac and the advisory committee for immunization practices' (acips') is a strong example of how epidemiology has contributed to the development of evidence-based national policy and has strengthened the immunization system in the united states. , , this example is discussed later in the article. j o u r n a l p r e -p r o o f as mentioned earlier, in the united states, vaccine development is supported by a combination of public and private sector research. in the public sector, the federal government through the united states department of defense, the national institutes of health, and other agencies within the department of health and human services (hhs) funds vaccine development. vaccine manufacturers invest significantly in all phases of vaccine development. the fda is the government regulatory agency that approves vaccines for commercial use. the sponsor of a vaccine submits the required documentation on safety, efficacy, and other aspects of the candidate vaccine to the fda. following internal reviews, the proposal is presented to the vaccines and related biological products advisory committee (vrbpac) (figure ), which then makes recommendations for licensing and additional data requests based on this evidence. the fda administrator makes the decision to approve the candidate vaccine based on the recommendation of the advisory committee. if approved, a vaccine license is issued with specific indications, precautions and contraindications. the advisory committee on immunization practices (acip), provides advice and guidance to the director of the centers for disease control and prevention (cdc) regarding use of vaccines and related agents for control of vaccine-preventable diseases in the civilian population of the united states ( figure ). , once a vaccine is licensed, and following a comprehensive review of the scientific evidence, the acip recommends vaccines for routine use and provides guidance on vaccine administration schedules likely to achieve the best levels of disease protection. years. , [ ] [ ] [ ] the increased availability and recommendations for more childhood vaccines represent remarkable achievements of the maturing immunization system of the united states to prevent vaccine preventable diseases, but have contributed to growing concerns about vaccine safety acceptability. [ ] [ ] [ ] [ ] [ ] the community preventive services task force, established by hhs in , develops guidance on community-based approaches to increase vaccination coverage based on available scientific evidence. , , this taskforce has provided evidence-based guidance for effective community-based approaches to reach and sustain high vaccination coverage ( figure ). effective strategies recommended include "multi-component" efforts such as combining health care system and community interventions together, use of client reminder/recall and provider reminder systems, use of client incentives, use home visits, and implementing state or local school immunization requirements for attendance. from this point on, we use the terms, "surveillance" and "monitoring" interchangeably to refer to the ongoing, systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health in contrast to "point in time" epidemiologic studies and outbreak investigation data use. vpds and reports national summaries of notifiable diseases, a regular feature in the mmwr. , cdc also monitors sporadic, endemic, epidemic and pandemic disease incidence overall and among population sub-groups to target and improve disease prevention and control efforts, including national elimination and global eradication initiatives. the recognition that hpv and hepatitis b vaccines can prevent cancer, has led to the inclusion of cancer and more recently precancerous disease surveillance and registries as data sources for monitoring the impact of vaccines in reducing cervical and liver cancer, respectively. [ ] [ ] [ ] [ ] since the s, after the resurgence of measles, the national immunization survey (nis) has been measuring immunization coverage at national and state levels using standardized methods. the nis originally targeted children - months of age, but now includes adolescents in a module designated as nis-teen. , the nis (preschool child) and nis-teen are multi-modal telephone-based surveys of parents with provider verification of immunization records. the nis has been essential in monitoring coverage for new vaccines as they are incorporated into the recommended immunization schedule. ensuring the safety of vaccines is a key component of table, those affected can apply for compensation through a streamlined process that avoids lengthy litigation. , immunization policy, practice, and epidemiology are necessarily intertwined. epidemiology informs policy and strategies to be incorporated into immunization practice through a process j o u r n a l p r e -p r o o f that begins with the consideration of what diseases may be preventable by a vaccine and continues with the identification of evidence-based strategies to effectively ensure high immunization coverage and optimally control or eliminate vpds. the development of childhood vaccines is preceded by collection and analysis of epidemiological data on the incidence of vpd-related conditions, disease morbidity and mortality, and evidence that infection confers protection against recurrence of the disease ( figure ). a recent example of this process related to the severity of varicella disease including mortality among adults in the united states prior to development of the varicella vaccine. also, as we write during the current pandemic, we are seeing unprecedented international scientific efforts to respond to the widespread community transmission of the novel coronavirus, sars-cov- , and the resulting waves of suffering and death related to covid- . these field clinical trials provide efficacy data and additional safety data about candidate vaccines. , these clinical trials are developed using rigorous epidemiologic methods, which include identifying the targeted trial population, randomization of participants to vaccination or placebo/alternative comparator groups, surveillance of the disease targeted by the vaccine, and monitoring of adverse events following vaccine administration. there are many examples of how epidemiologic evidence from vpd surveillance systems and outbreak investigation have contributed to better understanding of vaccine effectiveness and have led to changes in recommendations of vaccine administration. following introduction of a new vaccine, it is necessary to measure its population effectiveness in reducing the incidence of the targeted condition. results from ongoing surveillance of vpds and studies of reported outbreaks also provide opportunities to investigate waning vaccine immunity, reduced vaccine effectiveness, and gaps in vaccination due to missed opportunities to vaccinate during clinical encounters and/or vaccine hesitancy. the contribution of epidemiologic studies is evident, for example, in the development of recommendations for pertussis vaccines. studies of several pertussis outbreaks provided evidence that adults and adolescents were sources of disease transmission to young children, and that previously vaccinated adolescents were responsible for school outbreaks because of waning immunity. these findings led to additional child dose recommendations and the development of a new acellular vaccine booster recommended for adolescents and adults. [ ] [ ] [ ] the evidence of both waning immunity and that vaccinated pregnant women were able to provide passive immunity to their developing fetuses, also led to recommendations for routine tetanus and influenza vaccination for pregnant women. , epidemiologic studies of measles outbreaks led to the recognition that measles vaccination before months of age was associated with lower vaccine effectiveness. this was the basis for the acip recommendation that the first measles dose be administered on or after months of age. similarly, evidence from outbreaks among college students and school children showed insufficient effectiveness of a single measles dose to provide herd immunity. this led to recommendations for two doses of measles vaccines, one at - months and a second at to years of age. , other examples include a study of pertussis risk relative to the receipt and time since vaccination of the fifth dose of diphtheria and tetanus toxoids, and acellular pertussis vaccine (dtap) during an outbreak, and the role of varicella surveillance leading to change in immunization schedule from a single varicella dose to a two-dose schedule. epidemiologic studies have been used to evaluate new, and untested outbreak control interventions, such as evaluating recommendations to health care providers to vaccinate children using cdc's minimum immunization intervals during pertussis outbreaks and to use a third vaccination, during recent upsurges in mumps outbreaks. from to , the united states experienced a major nationwide resurgence of measles, which was detected by cdc's measles surveillance. the response to these events perhaps provides the best case-study of how epidemiologic evidence has informed, refined, and redirected united states immunization policy and practice. examination of reasons for the resurgence identified two kinds of outbreaks: ( ) large outbreaks among unvaccinated preschoolaged children, mainly in large urban centers, and ( ) smaller outbreaks among vaccinated children who, we know retrospectively, needed a second dose of a measles-containing vaccine. , additional analyses showed that unvaccinated preschool-aged outbreaks affected mostly young minority children in urban areas, with african american, latino, and american indian/alaska native children who contracted measles at rates three to times higher than white children did. the nvac examined evidence that pointed to challenges in the united states immunization system that likely contributed to the measles resurgence and to low immunization coverage rates that were well below healthy people objectives for preschool children. low vaccination coverage was primarily attributed to barriers in access to vaccination services or to missed opportunities to vaccinate by health care providers. , cost of vaccine was a key risk factor for uninsured or underinsured children. studies indicated that children visiting health care providers did not always receive all the recommended vaccines they were due, suggesting that missed opportunities to vaccinate were also important risk factors. , , - nvac's report concluded that immunization services needed to be enhanced and expanded. to guide efforts to increase vaccination rates, the report recommended that a national, standardized surveillance system to track age-appropriate immunization coverage across jurisdictions was necessary. this led to the creation of the national immunization survey to track the uptake of new childhood vaccines and monitor vaccination rates among young children - months of j o u r n a l p r e -p r o o f age to guide initiatives to more completely vaccinate these children with all recommended vaccines. , [ ] [ ] [ ] [ ] [ ] the key nvac findings and recommendations were published in , in what is now considered a report of historic significance. the nvac recommendations were embraced by policy makers and resulted in the launch of the childhood immunization initiative (cii). the cii, a presidential initiative, included several key elements: ( ) improving access to immunization services, ( ) developing immunization information systems, ( ) providing free vaccines to uninsured children (the vaccines for children program), and ( ) creating the national immunization program at cdc, now within the national center for immunization and respiratory diseases. improved access to immunization services improving access required addressing missed opportunities for immunizations. at the time, there were differences in recommendations between the acip, the american academy of pediatrics (aap) and the american academy of family practice (aafp). a major accomplishment of the cii was harmonizing the childhood immunization schedule jointly endorsed by acip, aap, and aafp, revisions of which have become a well-established convention and practice standard since . [ ] [ ] [ ] to address missed opportunities, programs targeted health care providers to remind them to make every child's medical visit, including acute and chronic care visits, a vaccination visit. tools are now available to health care providers to help them assess and improve immunization practices and identify ways to eliminate missed opportunities for vaccination at their offices. immunization registries or immunization information systems (iis) before the cii, most parents did not know the immunization status of their child. use of completed immunization cards and access to scattered immunization records among child providers were very limited and there were no electronic medical records that would allow clinicians to accurately assess immunization status at every visit (something particularly difficult at emergency room visits). immunization registries were developed to assist in the immunization assessment at each health j o u r n a l p r e -p r o o f care visit. by the mid- s, provider-based and population-or community-based immunization registries, now called immunization information systems (iis), were created for use by health providers to address immunization record scatter across clinics. iis are powerful and effective tools that provide timely access to immunization status at the point of care and have reduced missed opportunities by targeting under-vaccinated children for vaccination reminders and recalls, even before the introduction of electronic health record (ehr) systems. , [ ] [ ] [ ] as new vaccines were added to the immunization schedule, the combined series have been expanded. table includes a glossary of selected measures of vaccine completeness. , the acip expansion of recommended vaccines to adolescents and adults led to upgrades of the nis to specifically measure vaccination coverage for adolescents, including tetanus-diphtheriaacellular pertussis (tdap) and meningococcal conjugate vaccine (menacwy), by creating the nis -teen module in . , , in , monitoring for human papillomavirus (hpv) vaccination was added. like the original preschool child nis, this nis adolescent module includes provider-verified receipt of vaccines rather than relying on self-reported vaccination and provides data at state and selected local levels. vaccination coverage among young children and adolescents is found in figure and tables and . the end of the th century and the subsequent decades of the st century have witnessed further declines and the control of many vpds. polio has been eliminated from the americas and most of the world and it is near eradication worldwide. diseases like diphtheria, tetanus, measles, in spite of the retraction, this article created major concerns among parents considering vaccinating their children and continues to affect vaccination coverage of the mmr vaccine. a large epidemiologic study in denmark provided strong evidence of a lack of association between mmr and autism. similarly, a study in the united kingdom did not find any association between mmr and autism. the institute of medicine in the united states examined all available evidence and concluded that there was no evidence to link mmr vaccination and autism. the consequences of the subsequently retracted wakefield article include dramatic initial declines in mmr vaccination coverage in some countries. there were numerous resulting outbreaks of measles and mumps in the united kingdom, france, and elsewhere. [ ] [ ] [ ] [ ] surveillance documented that, in , the united states experienced cases in states, the largest number of measles cases since endemic measles was eliminated in . nis has also confirmed other study findings that suggest that those who intentionally delayed vaccination are significantly more likely to have heard or read unfavorable information about vaccines than parents who did not intentionally delay. additionally, parents who intentionally delayed due to vaccine safety or efficacy concerns were significantly more likely to seek information from the internet rather than from a health care provider compared with parents who delayed because of child illness. differences by race have been documented in j o u r n a l p r e -p r o o f these analyses--the percentage of parents who intentionally delayed immunizations was highest among white, non-hispanics ( . %), american indian/alaska natives ( . %), followed by asians ( . %), hispanics ( . %), and blacks ( . %). further analyses are needed to evaluate which parental, community and other characteristics and risk factors underlie these notable differences by racial/ethnic groups in childhood vaccine delays, for example examining how differences in historical experiences with vpds and trust may influence vaccine decision making among different groups. findings about intentional delays in immunization among some -year-old children and the ability of parents to claim religious or philosophical exemptions raise questions about the influence of the ease of parent claims in some states and higher state vaccination exemption rates. one study found that states enacting stricter exemption policies tend to have lower rates of exemptions. in recent years, congress and states, such as california, vermont, utah, washington and oregon, have passed or attempted to pass laws to modify or eliminate the use of non-medical exemptions. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] these policy initiatives are being met with public controversy and opposition by nationally-organized and grassroots groups communicating vaccine safety, civil liberty, other concerns, and also anti-vaccine sentiments. [ ] [ ] [ ] [ ] [ ] the legal viability and public health effectiveness of these more restrictive strategies remain to be determined. early studies of california's non-medical exemption elimination show that, while non-medical exemptions declined, geographic clustering of these exemptions remained leaving populations of students at-risk for vpds in a number of communities. [ ] [ ] [ ] epidemiological studies clearly play a key role in monitoring changing child immunization coverage, non-medical exemptions to school immunization requirements and other measures of vaccine hesitancy trends and the impact of policy changes and the interventions to address them. another important immunization practice issue is addressing differences in vpd morbidity and disparities in vaccination coverage among special populations. epidemiological studies proved to be particularly relevant when examining the impact of haemophilus influenzae type b (hib) and hepatitis a (hepa) vaccines on the american indian/alaska native (ai/an) population. the introduction of the hib vaccine significantly reduced hib incidence in ai/an children. surveillance proved to be critical in demonstrating a greater response with the first dose of the polyribosylribitol phosphate conjugated to the meningococcal outer membrane protein (prp-omp)-containing hib vaccines for ai/an infants providing earlier protection. in fact, when alaska switched from prp-omp to non-omp vaccine during a vaccine shortage, ai/an hib incidence increased. , again, epidemiological evidence was important to guide immunization practice. besides experiencing higher hib disease incidence, ai/an children historically had more than a five-fold higher incidence of hepa virus infection and were experiencing frequent large-scale outbreaks every - years. with the implementation of routine hepa vaccination in among high-risk populations (e.g., ai/ans), disease incidence and outbreak disparities were completely eliminated. as another special population, the amish were the last group to experience a polio outbreak in the united states. in , pennsylvania noted an increase in hib disease among amish preschool children. an epidemiologic study of hib carriage showed high levels of hib carriage and low vaccination coverage among amish households. a study among amish parents who did j o u r n a l p r e -p r o o f not vaccinate their children found that only % identified personal-belief objections as a factor, % reported that vaccination was not a priority compared with other daily activities, and % would vaccinate children if offered locally. these findings encouraged the state to target hib vaccination programs to amish communities and craft specific educational messages to amish parents leading to a reduction in hib disease in this special population. these examples show how public health used epidemiologic surveillance to document increases in disease incidence and disparities in vaccination coverage in special populations in order to respond with targeted interventions to address these problems and achieve disease prevention successes. epidemiologists are improving their methods to track new vaccine uptake, especially for newer vaccines including the multi-dose human papillomavirus (hpv) vaccine to prevent cervical cancer and the tdap booster for adolescents and adults. the hpv vaccine experience epidemiologists have looked closely at the factors associated with rates of hpv vaccine initiation and completion to examine vaccine uptake and acceptance. observed differences pointed out that further research was needed to better understand population-specific barriers to completion of the hpv series. monitoring hpv uptake, first among adolescent girls and later among adolescent boys, epidemiologists focused on identifying risk factors associated with low hpv vaccination.a telephone survey of mothers of - -year-old girls found that the predominant perception was that their daughters were at low risk for hpv infections and hpv-related diseases. findings also showed that mothers and their health care providers lacked sufficient knowledge about hpv disease and hpv vaccines. many mothers also reported that they believed that their daughters were currently too young to receive the hpv vaccine although receipt might be more acceptable at later ages. also, mothers reported significant concerns about the long-term safety of these vaccines. the most commonly identified reasons for mothers accepting these vaccines for their daughters included: their perceptions that their daughters were at high risk for acquiring hpv; their beliefs that the vaccine had a favorable safety profile; their intentions to prevent cervical j o u r n a l p r e -p r o o f cancer among their daughters and protect them against cancer; their own personal experience with hpv infection or hpv-related diseases; and their recalling strong physician recommendations to vaccinate their daughters. these findings have been shaping the messages and strategies to promote hpv vaccination with a stronger focus on the cancer prevention benefit of this vaccine. as in other countries, the impact of the covid- pandemic on the united states immunization system and policies is starting to become apparent as covid- continues to rapidly spread across communities. since public health authorities across the united states have needed to urgently implement non-pharmaceutical public health disease containment measures (e.g., shelter-in-place, postponements of noncritical health care visits), early epidemiological studies are already documenting a dramatic decline in ordering and administration of childhood vaccines, vfc clinic capacity to vaccinate children, and immunization coverage rates for vpds. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] rapid development of new covid- vaccines is an imperative because of the severe consequences of covid- disease, which is disproportionately impacting people over years of age, people with heart disease, diabetes, other chronic diseases, essential service workers and populations of color. [ ] [ ] [ ] [ ] however, as new vaccines for covid- are being developed and tested, new reports also suggest the emergence of major challenges for new covid- vaccination uptake. [ ] [ ] [ ] several reports state that that up to % percent of polled respondents were hesitant about accepting new covid- vaccines when they become available. , j o u r n a l p r e -p r o o f previous epidemiological studies have shown that after vaccine supply chain disruptions and shortages have occurred, uptake of vaccine may slowly recover and could remain persistently lower than prior uptake well behind recommended target coverage rates when supplies become available. re-engaging patients for clinical preventive services and increasing vaccination among people who have previously declined or fallen behind schedule during and after the covid- crisis are critical strategies to prevent other vpd outbreaks, which could further strain our health care system, emergency response systems, and economy and, thus, slow economic and societal recovery from the pandemic. [ ] [ ] [ ] with delays in vaccinations, vaccine hesitancy and upcoming seasonal influenza transmission, during the pandemic, we face new challenges that risk losing historical achievements in individual and community health and new unknown risks of further preventable illnesses, disabilities and death. , [ ] [ ] [ ] [ ] previous epidemiologic evidence suggests that by reducing the incidence of vpds such as influenza and pneumococcal disease, we also would reduce burden on the health care facilities that are already under pressure in communities responding to the waves of covid- outbreaks and community-wide transmission. immunization policy makers, public health practitioners and health care providers must plan new immunization initiatives that include proactively and transparently gaining back the trust of an already skeptical public whose trust in public health and health care advice during this pandemic have been sorely tested. , [ ] [ ] [ ] epidemiologic surveillance, research and program evaluation will be essential nationally, regionally and within communities to guide needed interventions that successfully respond to these new public health challenges. more challenging is the ongoing need to develop new, specific vaccines for emerging diseases with high morbidity and mortality and rapid spread as real-time countermeasures, notable at the time of this writing during the covid- pandemic. [ ] [ ] [ ] [ ] , especially challenging is that currently governments are usually the sole funding source for vaccine development unless commercial manufacturers offer to help and see financial and other incentives including the potential for more routine population-wide use. [ ] [ ] [ ] [ ] [ ] [ ] [ ] to be ready to respond effectively to the eventuality of new, emergent vaccine-preventable outbreaks and community-wide biological attacks, policy makers, health officials, legislators and other stakeholders can work together to ensure that policies are in place to expedite development of new vaccines, ensure vaccine safety and efficacy, and determine appropriate resources in a timely fashion. public/private partnerships can be developed to meet the demands for research and development of new vaccines and to establish capacity for production. additional public health system capacity across all levels and communities could be enhanced and sustained in order to address mass vaccine distribution and administration by health care providers, vaccination monitoring, disease surveillance, and program and policy evaluations to meaningfully inform policy and program decisions in realtime. j o u r n a l p r e -p r o o f uniform, quick, appropriate and timely reporting of disease cases and adverse events by physician offices, hospitals, laboratories, schools or other institutions such as child-care and correctional facilities can be more firmly established. enhanced electronic reporting from electronic laboratory and health record systems, data analyses and information dissemination can be enhanced to function more rapidly in real-time. rapid surveillance using electronic data is needed to provide more timely and accurate situational status assessments, target services and improve response time to public health emergencies. epidemiologists can expand their use of methods from other public health disciplines, such as community-based participatory research, qualitative research, rapid-cycle quality improvement work and evaluation methods to better identify vaccine acceptance disparities and differences in perceptions, knowledge, attitudes, and beliefs among specific populations, including providers. interventions that overcome the barriers and address the needs of special populations can be developed, implemented, evaluated and disseminated. epidemiology remains essential for informing policy and programmatic practice decision making to prevent and respond to vpds. epidemiologic studies of the large united states measles resurgence identified major factors by further identifying determinants of low vaccination coverage. these efforts were crucial for focusing policies and programmatic strategies at national, state and local levels. surveillance and epidemiologic research have also been essential in monitoring the impact of vaccinations on infectious disease incidence and vaccine acceptance j o u r n a l p r e -p r o o f by clinicians, parents and patients. while epidemiology has positively influenced changes in immunization policy and led to historic reductions in vpds, the reduction of vpd incidence has created new challenges in our ability to help parents and providers understand why vaccines remain essential. recent developments have led to public questioning of the value and risks of vaccinations while vaccine acceptance is high. , [ ] [ ] [ ] , , , , however, the nation must be vigilant in continuously measuring vaccine use, vaccine-preventable diseases, and vaccine safety, to avoid the trap of being victims to our own success. j o u r n a l p r e -p r o o f table . vaccination coverage among adolescents ages - years, by race/ethnicity and selected vaccines and doses* -national immunization survey -teen, (nis -teen), united states, † vaccine-preventable disease table working g. historical comparisons of morbidity and mortality for vaccine-preventable diseases in the united states elimination of measles and of disparities in measles childhood vaccine coverage among racial and ethnic minority populations in the united states. the journal of infectious diseases centers for disease control and prevention. benefits from immunization during the vaccines for children program era -united states ten great public health achievements--united states ten great public health achievements--united states economic evaluation of the routine childhood immunization program in the united states office of the associate director for policy and strategy. definition of policy what is policy? ottawa, ca: caledon institute of social policy office of disease prevention and health promotion assembling a global vaccine development pipeline for infectious diseases in the developing world united states food & drug administration. blood, vaccines and other biologics the history of the united states advisory committee on immunization practices (acip) united states department of health and human services united states department of health and human services. vaccines & immunizations. national vaccine advisory committee (nvac) centers for disease control and prevention. recommendations of the advisory committee on immunization practices: programmatic strategies to increase vaccination coverage by age years--linkage of vaccination and wic services. mmwr morbidity and mortality weekly report recommendations of the advisory committee on immunization practices: programmatic strategies to increase vaccination rates--assessment and feedback of provider-based vaccination coverage information. mmwr morbidity and mortality weekly report children's hospital of philadelphia. vaccine history: developments by year vaccination and risk communication: summary of a workshop reviews of evidence regarding interventions to improve vaccination coverage in children, adolescents, and adults. the task force on community preventive services institute of medicine (us) committee on immunization finance policies and practices calling the shots: immunization finance policies and practices nonmedical exemptions from school immunization requirements: a systematic review increasing appropriate vaccination: vaccination requirements for child care updated guidelines for evaluating public health surveillance systems: recommendations from the guidelines working group national notifiable disease surveillance system (nndss). national notifiable conditions using population-based cancer registry data to assess the burden of human papillomavirus-associated cancers in the united states: overview of methods annual report to the nation on the status of cancer, - , featuring the increasing incidence of liver cancer the hpv vaccine impact monitoring project (hpv-impact): assessing early evidence of vaccination impact on hpv-associated cervical cancer precursor lesions monitoring effect of human papillomavirus vaccines in us population, emerging infections program national immunization survey: the methodology of a vaccination surveillance system national vaccination coverage among adolescents aged - years--united states, . mmwr morbidity and mortality weekly report safety monitoring in the vaccine adverse event reporting system (vaers) the vaccine safety datalink: successes and challenges monitoring vaccine safety the food and drug administration's post-licensure rapid immunization safety monitoring program: strengthening the federal vaccine safety enterprise national vaccine injury compensation program. health resources and services administration vaccine development: from concept to early clinical testing trends in varicella mortality in the united states: data from vital statistics and the national surveillance system a strategic approach to covid- vaccine r&d the road to immunity during covid- : developing & distributing a vaccine. special presentation and panel discussion from the covid- conversations webinar series sponsored by the special presentation and panel discussion webinar sponsored by the fred hutchinson cancer research center rapid covid- vaccine development tetravalent dengue vaccine reduces symptomatic and asymptomatic dengue virus infections in healthy children and adolescents aged - years in asia and latin america. the journal of infectious diseases safety overview of a recombinant live-attenuated tetravalent dengue vaccine: pooled analysis of data from clinical trials preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the advisory committee on immunization practices (acip) preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine recommendations of the advisory committee on immunization practices (acip) and recommendation of acip, supported by the health care infection control practices advisory committee (hicpac), for use of tdap among health-care personnel prevention and control of seasonal influenza with vaccines measles vaccine efficacy in children previously vaccinated at months of age mmwr morbidity and mortality weekly report acip releases supplementary report on measles prevention association of childhood pertussis with receipt of doses of pertussis vaccine by time since last vaccine dose, california prevention of varicella: recommendations of the advisory committee on immunization practices (acip) did children receive dtap vaccinations earlier after accelerated dtap immunization recommendations by local public health during pertussis outbreaks in oregon?: an evaluation of immunization practice changes among community clinicians. paper presented at: annual meeting of the council of state and territorial epidemiologists catch-up immunization schedule for persons aged months- years who start late or who are more than month behind, united states impact of a third dose of measles-mumpsrubella vaccine on a mumps outbreak adverse events following a third dose of measles, mumps, and rubella vaccine in a mumps outbreak patterns of transmission in measles outbreaks in the united states, - . the new england journal of medicine measles outbreak among unvaccinated preschool-aged children: opportunities missed by health care providers to administer measles vaccine missed opportunities for immunizations: a review of the evidence causes of low preschool immunization coverage in the united states recommended by the national vaccine advisory committee centers for disease c, prevention. county-level trends in vaccination coverage among children aged - months -united states national, state, and local area vaccination coverage among children aged - months--united states vaccination coverage among children aged - months -united states coverage among children - months by state, hhs region, and the united states vaccination coverage among u.s. children aged - months entitled by the vaccines for children program the measles epidemic. the problems, barriers, and recommendations. the national vaccine advisory committee the president's child immunization initiative--a summary of the problem and the response effectiveness of a practice-based intervention to increase vaccination rates and reduce missed opportunities ?cdc_aa_refval=https% a% f% fwww.cdc.gov% fpertussis% fout breaks% ftrends.html. accessed assessing immunization coverage in private practice infants and children (wic childhood immunization registries designed to expedite: immunization registry information systems immunization information systems to increase vaccination rates: a community guide systematic review comunity preventive services task force. recommendation for use of immunization information systems to increase vaccination rates immunization information systems use during a public health emergency in the united states vaccines for children program overview of the national health interview survey and its sample design. vital health stat vaccination coverage of -year-old children--united states vaccination coverage among children in kindergarten -united states, - school year. mmwr morbidity and mortality weekly report centers for disease control and prevention. human papillomavirus vaccination coverage among adolescent girls national, regional, state, and selected local area vaccination coverage among adolescents aged - years -united states ?cdc_aa_refval=https% a% f% fwww.cdc.gov% fvaccines% fpare nts% fdiseases% fchild% f -diseases.html. accessed changes in childhood immunization decisions in the united states: results from & national parental surveys risk factors associated with parents claiming personal-belief exemptions to school immunization requirements: community and other influences on more skeptical parents in oregon parental hesitancy about routine childhood and influenza vaccinations: a national survey understanding thimerosal, mercury, and vaccine safety ileal-lymphoid-nodular hyperplasia, nonspecific colitis, and pervasive developmental disorder in children ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children world health organization (who) an assessment of thimerosal use in childhood vaccines thimerosal in vaccines: a joint statement of the american academy of pediatrics and the public health service. mmwr morbidity and mortality weekly report immunization safety review: thimerosal-containing vaccines and neurodevelopmental disorders prevalence and characteristics of autism spectrum disorder among children aged years--autism and developmental disabilities monitoring network, sites, united states a population-based study of measles, mumps, and rubella vaccination and autism. the new england journal of medicine autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association institute of medicine (us) immunization safety review committee an outbreak of mumps in the metropolitan area of walsall, uk. international journal of infectious diseases : ijid : official publication of the international society for infectious diseases measles outbreak--california measles elimination efforts and - outbreak, france. emerging infectious diseases crucial lessons from the recent measles outbreak. the huntington post vaccine-preventable outbreaks: still with us after all these years the timing of pertussis cases in unvaccinated children in an outbreak year: oregon increase in measles cases -united states the impact of epidemics of vaccine-preventable disease on vaccine uptake: lessons from the - us pertussis epidemic association between vaccine refusal and vaccine-preventable diseases in the united states: a review of measles and pertussis notes from the field: community outbreak of measles cost of washington measles outbreak tops $ m. the oregonian processes for obtaining nonmedical exemptions to state immunization laws religious healing in the courts: the liberties and liabilities of patients, parents, and healers paper presented at: webinar at northwest center for public health practice (nwcphp) ; school of public health identifying communities in patterns of exemptions to school immunizations. paper presented at: national immunization conference national, regional, state, and selected local area vaccination coverage among adolescents aged - years--united states the association between intentional delay of vaccine administration and timely childhood vaccination coverage improving nonmedical vaccine exemption policies: three case studies vaccine controversy: oregon senator's school bill renews exemption fight hundreds rally outside capitol to oppose bill that would limit vaccine exemptions in oregon over , descend on wa state capitol to challenge vaccine mandate bills to oregon lawmakers: reject vaccine bill mandatory health care provider counseling for parents led to a decline in vaccine exemptions in california conditional admission, religious exemption type, and nonmedical vaccine exemptions in california before and after a state policy change elimination of nonmedical immunization exemptions in california and school-entry vaccine status impact of immunizations on the disease burden of american indian and alaska native children haemophilus influenzae type b disease and vaccine booster dose deferral, united states prevention and control of haemophilus influenzae type b disease: recommendations of the advisory committee on immunization practices (acip) haemophilus influenzae type b disease among amish children in pennsylvania: reasons for persistent disease human papillomavirus vaccination series initiation and completion understanding the reasons why mothers do or do not have their adolescent daughters vaccinated against human papillomavirus effects of the covid- pandemic on routine pediatric vaccine ordering and administration -united states, . mmwr morbidity and mortality weekly report provision of pediatric immunization services during the covid- pandemic: an assessment of capacity among pediatric immunization providers participating in the vaccines for children program -united states please continue vaccinating patients during covid- maintaining childhood immunizations and well-child care during covid- pandemic routine vaccination during the covid- outbreak decline in child vaccination coverage during the covid- pandemic -michigan care improvement registry vaccinations have sharply declined nationwide during the covid- pandemic: rates of childhood immunization have fallen across the u.s., raising the risk of vaccine-preventable disease outbreaks the dual epidemics of covid- and influenza: vaccine acceptance, coverage, and mandates exclusive: a quarter of americans are hesitant about a coronavirus vaccine. -reuters/ipsos poll one in three americans would not get covid- vaccine american academy of family physicians. inside look at using telemedicine during covid- pandemic - estimated influenza illnesses, medical visits, hospitalizations, and deaths averted by vaccination flu vaccine coverage, united states - influenza season estimated influenza illnesses, medical visits, hospitalizations, and deaths in the united states- - influenza season planning for a covid- vaccination program the reemergence of vaccine-preventable diseases: exploring the public health successes and challenges. testimony before the committee on health, education, labor and pensions, united states senate group shape vaccine delivery working group. from refrigerator to arm: issues in vaccination delivery vaccine refusal, mandatory immunization, and the risks of vaccine-preventable diseases. the new england journal of medicine > polio: > mmr: > hib: > hepb: > varicella abbreviations: dtp/dtap = diphtheria and tetanus toxoids and whole cell pertussis vaccine or diphtheria and tetanus toxoids and acellular pertussis vaccine mmr = measles-mumps-rubella vaccine hib = haemophilus influenzae type b vaccine hep b = hepatitis b vaccine; varicella= varicella vaccine; and pcv = pneumococcal conjugate vaccine abbreviations: dtp/dtap = diphtheria and tetanus toxoids and whole cell pertussis vaccine or diphtheria and tetanus toxoids and acellular pertussis vaccine mmr = measles-mumps-rubella vaccine hib = haemophilus influenzae type b vaccine hepb = hepatitis b vaccine varicella=varicella vaccine pcv = pneumococcal conjugate vaccine hepa = hepatitis a vaccine *selected vaccines and dosages are in accordance with immunization objectives from healthy people and follow the cdc's recommended immunization schedule for children and adolescents ages years or younger : : *: : : ) includes ≥ doses of dtap, ≥ doses of poliovirus vaccine, ≥ dose of measles-containing vaccine, the full series of hib (≥ or ≥ doses, depending on product type figure . vaccine coverage among preschool-aged children -united states abbreviations: dtp/dtap = diphtheria and tetanus toxoids and whole cell pertussis vaccine or diphtheria and tetanus toxoids and acellular pertussis vaccine mmr = measles-mumps-rubella vaccine hib = haemophilus influenzae type b vaccine hep b = hepatitis b vaccine; varicella= varicella vaccine pcv = pneumococcal conjugate vaccine rv = rotavirus vaccine hep a = hepatitis a vaccine + from the united states immunization survey note: no data are available for - . children in the united states immunization survey and national health interview survey were ages - months centers for disease control and prevention. coverage among children - months by state, hhs region, and the united states national, regional, state, and selected local area vaccination coverage among adolescents aged - years -united states centers for disease c, prevention. benefits from immunization during the vaccines for children program era -united states race/ethnicity non-hispanic white *selected vaccines and dosages are in accordance with immunization objectives from healthy people and follow the cdc's recommended immunization schedule for children and adolescents aged years or younger. , **includes those with >= doses, and those with doses when the first hpv vaccine was initiated prior to age years and there was at least five months minus four days between the first and second dose. ***among adolescents with no history of varicella. † numbers in parentheses refer to the number of doses of that vaccine being reported in this figure. key: cord- - ou ubb authors: weiss, martin m.; weiss, peter d.; mathisen, glenn; guze, phyllis; henderson, donald a.; inglesby, thomas v.; o'toole, tara title: rethinking smallpox date: - - journal: clin infect dis doi: . / sha: doc_id: cord_uid: ou ubb the potential consequences of a competently executed smallpox attack have not been adequately considered by policy makers. the possibility of release of an aerosolized and/or bioengineered virus must be anticipated and planned for. the transmission and infectivity of variola virus are examined. arguments for and against pre-event vaccination are offered. the likely morbidity and mortality that would ensue from implementation of a mass pre-event vaccination program, within reasonable boundaries, are known. the extent of contagion that could result from an aerosolized release of virus is unknown and may have been underestimated. pre-event vaccination of first responders is urged, and voluntary vaccination programs should be offered to the public. two defenses against a vaccine-resistant, engineered variola virus are proposed for consideration. methisazone, an overlooked drug, is reported to be effective for prophylaxis only. the extent of reduction in the incidence of smallpox with use of this agent is uncertain. it is useless for treatment of clinical smallpox. n- respirators (face masks) worn by uninfected members of the public may prevent transmission of the virus. conventional wisdom holds that smallpox presents an unlikely threat to the public health [ ] [ ] [ ] [ ] . that wisdom asserts that the virus is sequestered in secure sites [ ] and that, even if it somehow released, vaccine will abort any potential epidemic [ ] . moreover, conventional wisdom holds that promising drugs are in development to treat smallpox [ ] [ ] [ ] [ ] and that the virus is not highly contagious [ ] . such considerations could prove to be overly optimistic and do not take into account the many uncertainties regarding transmission and infectivity of the smallpox virus. in addition to the possible existence of more-virulent "weaponized" strains, further advances in genetic engineering may permit construction of strains able to evade the current vaccine. australian workers markedly increased mousepox virulence by splicing a mouse il- gene into a laboratory strain [ ] ; similar constructions might be assembled using human smallpox virus (variola major) or another pox virus (e.g., monkeypox virus) and human genes [ ] . this article critically examines some of the current tenets of public health policy and highlights the uncertainty of much of the data. we also examine potential defenses against a release of smallpox virus and make recom-mendations regarding immunization and the development of prophylactic medications. smallpox may be transmitted via respiratory droplets or via fine-particle aerosol. the distinction between the two has critical public health implications. respiratory droplets (i.e., sputum and saliva) have a range likely no more than m (∼ ft) and are therefore a threat only to persons in the immediate vicinity of the affected patient. epidemiological studies support the finding that respiratory droplet spread is the prime route of transmission; the geographic locus of transmission is described as being almost always at the bedside, rather than public areas [ , ] . freefloating aerosolized virions, on the other hand, would have a considerably more extensive range. in , dixon [ ] reviewed the evidence for the alternative mode-aerosolized spread-and concluded that true airborne infection was extremely rare. nonetheless, epidemiological evidence suggests that transmission by means of aerosolized particles may be a real occurrence. in , persons on floors of a german hospital developed smallpox, despite isolation of the coughing, smallpox-infected patient in a single room [ ] . seventeen cases of smallpox developed; none of the patients had direct contact with the initial patient. subsequent "smoke" testing demonstrated air flows consistent with an aerosol spread [ ] . the last recorded death due to smallpox, according to world health organization investigators, was likely associated with virus that had been transmitted by aerosol [ ] . in , janet parker, a medical photographer at the university of birmingham medical school in england, became ill with smallpox and subsequently died. her darkroom was story above and several rooms down the hall from the laboratory of dr. henry bedson, a prominent smallpox researcher. smallpox virus can also be transmitted by fomites, such as clothing and bedding [ ] . laundry workers have developed smallpox. one study found a much higher recovery of smallpox virus from pillows and bedclothes than from air samples of the patient's coughs [ ] . the length of time that these objects remain infectious is unclear, but on the basis of the historical pattern of epidemics, it is likely no more than a few days. current wisdom holds that smallpox, contrary to its popular reputation, is not a highly infectious disease [ , ] . examinations of outbreaks in india and pakistan in the s showed that each case of smallpox gave rise to only new cases during the infectious (dry) season and to new case during the humid season [ ] . such observations-along with the long incubation period of smallpox (mean, - days; range, - days)suggest that there would be adequate time to vaccinate the public and prevent a more widespread outbreak. not revealed in these reports is the extent to which the affected public had already been vaccinated. if the percentage of the population that had been vaccinated was high, the aforementioned findings may merely reflect the population's immune status, rather than a low attack rate. another report placed the vaccination level in india at that time at % [ ] . if accurate, this would support the reason for the low attack rate as being a consequence of a public protected by immunization, rather than due to a virus with low inherent infectivity. indeed, there are data that smallpox is highly contagious. during the period of endemic smallpox, in field studies in africa, % of susceptible contacts became infected [ ] . other sources report attack rates of anywhere from % to % among unvaccinated contacts [ ] . potentially fatal reactions to smallpox vaccination include encephalitis, progressive vaccinia, eczema vaccinatum, and myopericarditis. postvaccinial encephalitis or encephalomyelitis has been reported to occur at an incidence of case per , vaccinations [ ] . in recent data from an ongoing department of defense (dod) study, there was case of encephalitis reported among , vaccinations [ ] ; the patient recovered. there was no evidence by either viral culture or pcr for vaccinia being the etiology. progressive vaccinia (a postvaccination viral dissemination with subsequent shock and localized gangrene) occurs in persons with immunodeficiencies, and eczema vaccinatum (a generalized spread of vaccinia to skin beyond the vaccination site) occurs in persons with atopic dermatitis; neither was reported in the dod study [ ] . fifty cases of contact transfer of vaccinia occurred, primarily in spouses and adult intimate contacts [ ] . the lower-than-expected incidence of adverse events may reflect more-careful screening of vaccination candidates for immunosuppression and eczema (for whom vaccination is contraindicated), the generally healthy status of the population being vaccinated, the previous vaccination in up to two-thirds of vaccine recipients, and covering of the vaccination site, which reduces inadvertent inoculation of contacts. (in previous vaccination campaigns, the vaccination site was left exposed.) an unexpected finding in the dod study above was the occurrence of cases of myopericarditis [ ] [ ] [ ] . there was death among these cases [ ] . other than for that fatality, in all cases for which there was follow-up cardiac testing, there was normalization of electrocardiograms, echocardiograms, exercise testing, and functional status [ ] . there was no increased incidence of coronary events in the dod program [ , ] , but in the much smaller civilian vaccination program (involving , vaccinees), the number of myocardial infarctions observed ( cases) was higher than would have been expected ( cases) [ ] . plaque-purified tissue culture vaccines are in clinical trials and may have a lower incidence of adverse reactions than does the standard calf lymph vaccine [ ] . in addition, attenuated and dna subunit smallpox vaccines are under development [ ] and may prove to be safer for immunocompromised persons. there have been attempts to answer the question of how many deaths would arise from preemptive mass vaccination of the public. depending on the percentage of the population vaccinated, the number of deaths is estimated to be in the range of - [ , , ] . the likely deaths and morbidity that would ensue from a vaccination program must be weighed against the likelihoodand consequences-of a smallpox attack. the conventional wisdom, as noted above, is that smallpox "does not spread rapidly under natural conditions" and, in fact, spreads at a "leisurely" pace [ , p. ]. transmission usually requires "close prolonged contact" for spread [ , p. ]. each case of smallpox "gives rise to (only) about three new cases" [ , p. ]. the long incubation period of - weeks "provides the time to intervene and limit secondary spread" [ , p. ]. we can "readily stop outbreaks within two infective generations (about weeks) after recognition of the initial cases" [ , p. ]. there is a problem in basing public policy on these principles. even if the above is an accurate representation of the contagiousness of smallpox, this paradigm reflects the spread of natural smallpox. unfortunately, any future smallpox epidemic would likely be an unnatural, man-made event. the natural history of an unnatural event may not be natural. a second misconception regards vaccination. contrary to the widely held belief that vaccination is equally successful after implantation of the variola virus, "postexposure vaccination is at best of limited effectiveness" [ , p. ]. the most optimistic report on postexposure vaccination, plotting efficacy against time, utilized a presumed average incubation period. it concluded that postexposure vaccination reduced the clinical case rate by % when administered up to days postexposure [ ] . concerns over the effectiveness of postexposure vaccination have been raised by others [ , ] . bozzette et al. [ ] calculate that there would be , deaths in a "high-impact airport attack," despite the presence of an aggressive postevent immunization program. it could be argued that his calculation may be an underestimation. in their model, bozzette et al. [ ] used a pattern of spread based on outbreaks that occurred after world war ii in a largely smallpox-immune population. vis-à-vis smallpox, the immune status of the older portion of our population is uncertain. it was generally accepted that the immunity provided by vaccination deteriorates with time. two-thirds of persons with smallpox in the s had preexisting vaccination scars [ ] . however, hammarlund et al. [ ] found substantial humoral and or cellular immunity against vaccinia persisting in persons who had been vaccinated - years earlier and cite epidemiological studies that argue for long-term protection. regardless, the immune status of our younger population (i.e., those aged ! years), with regard to smallpox, probably resembles the status of the aztec, inca, and th century american indian populations, rather than that of a vaccinated people. it is possible, therefore, that each index case would give rise to considerably more than just the secondary cases in the outbreaks that occurred after world war ii. as is reported in a consensus statement by smallpox authorities, "a clandestine release of smallpox, even if it infected only - persons to produce the first generation of cases, would spread rapidly in a now highly susceptible population, expanding by a factor or - times or more with each generation of cases" [ , p. ]. this pattern of spread likely occurred in the population of central mexico, which, according to aztec tribute rolls taken before their exposure to smallpox in the early s, was million. the spanish, in , estimated that the population was . million, but other factors, including measles, also probably played a role in the decline [ ] . bozzette et al. [ ] ascribe a mortality rate of . % to the unimmunized population. however, there are data showing a mortality rate of % in an unvaccinated population [ ] . the same long incubation period that some authorities hold to be an advantage in control of the disease [ ] could actually prove to be our achilles' heel. even within the limits of the shortest possible incubation period ( days), high-impact attacks could be repeated-at the same site or at different sites, with no one aware that attacks were taking place. to make a cogent assessment of the consequences of a smallpox attack, several questions must be answered. otherwise, we are engaged in no more than guesswork. the questions are these: ( ) can smallpox virus be aerosolized? ( ) if it can be aerosolized, for how long does it remain viable, and how far can it be carried? ( ) even if it can remain aerosolized and viable for a prolonged period of time, just how infectious is it by this route? smallpox virus can be aerosolized [ ] . however, the current opinion on how long the virus can remain viable in this state is that the viability rapidly decreases after min ("no more than %- % survived" [ , p. ] ), implying that there is nil viability left soon thereafter and, thus, that aerosolization does not represent much of a threat [ ] . unfortunately, closer scrutiny of the science underlying that assertion shows less reason to be sanguine. the great majority of the loss in variola virus viability was already present when first measured min into the study. thereafter, there was but modest further decline over the remaining -min length of the study [ ] . the virus may therefore persist at a relatively stable level of viability for hours. how long the virus can actually remain aerosolized is unknown, as is its infectivity in this mode. if one extrapolates from the results of studies of vaccinia, aerosolized variola virus that is protected from uv light survives for h [ ] . a critical caveat that was not addressed above is that the discussion has been limited to natural smallpox in a natural setting. the soviet union is known to have engaged in an active program to aerosolize bioweapons, including smallpox, for use in bioweapons [ ] . if modified or attached to the appropriate carrier, variola virus could possibly remain suspended and infectious for a considerable period. on the other hand, dissemination of variola virus into the air (e.g., via crop dusters or bomblets) subjects the virus to variables such as uv light, thermal factors, humidity, and wind. the virus might not survive, or it might be dispersed in the atmosphere into such low concentrations that it is no longer infective. because the minimal infective dose has not been determined, the efficacy of such dissemination is unknown. the current bush administration sought widespread preevent vaccination of the public over concern as to whether an effective vaccination program could be implemented after an attack on an unvaccinated public [ ] . the public health com-munity, however, citing safety issues, has opposed immunizing the public [ ] . animal studies demonstrate that cidofovir (vistide; gilead) has activity against poxvirus infections [ ] [ ] [ ] [ ] , but only when it was administered either concurrently or, in one study, within days after the initial challenge with the virus. if its effectiveness extends to humans, this drug would have a prophylactic effect only. it would not be of benefit for treatment of established clinical smallpox. cidofovir has been modified to render the drug bioavailable by the oral route. this modification (adding a lipid tail to produce hexadeclyoxypropyl-cidofvir [hdp-cidofovir]) resulted in a new drug, which, in vitro, is times more effective against variola than is unmodified cidofovir [ ] . methisazone, a thiosemicarbazone, has been reported to be effective for smallpox prophylaxis. a clinical trial in india in the s involving contacts claimed a % reduction in the incidence of the disease ( ) [ , ] . however, p ! . this study has been criticized elsewhere [ ] . treatment and control groups were incompletely randomized, with a possible bias in favor of methisazone. a subsequent fully randomizedbut considerably smaller-trial reported favorable but lessimpressive results (the incidence of smallpox in the control group was almost double that in the methisazone group) [ ] . this finding did not reach statistical significance. methisazone was stated to be effective prophylaxis in the eighth edition (from ) of harrison's principles of internal medicine [ ] , but it is doubtful that many made note of it. by then, smallpox had essentially been eradicated, and there was little reason to pay much attention to the entry. later editions of harrison's virtually eliminated the smallpox chapter, along with discussion of the drug. the agent has since fallen off of our radar screens [ ] . a panel of smallpox authorities assessed methisazone and determined that it had only modest benefit, probably reducing the incidence of smallpox by only %- % [ ] . this reduction should not be dismissed as inconsequential. in the event of a smallpox attack with an engineered virus, even such modest efficacy could prove critical. not addressed, however, is the question of just how effective methisazone would be without coadministration of vaccine. (vaccine could be useless in an attack with a modified virus.) in all of the aforementioned studies, contacts simultaneously received postexposure vaccination and methisazone. one study, on a related poxvirus, suggests an answer to this question. methisazone was investigated as prophylaxis for variola minor (alastrim), where contacts were not vaccinated, and was found to be effective for the prevention of alastrim at a significance level of . [ ] . methisazone is not without side effects. nausea and vomiting have been reported in one-tenth to two-thirds of persons who receive the drug [ , ] . for prophylaxis, the drug must be given within days of the initiation of infection with variola major [ ] . methisazone has a significant weakness: without patent protection, it is essentially an orphan. a pharmaceutical company is unlikely to expend research effort or promotion on such a drug. that weakness, however, is also a strength: in the public domain, it would likely be inexpensive to produce. the smallpox virus is - nm in size. n- respirators, with ulpa (ultra-low penetration air) filters, are . % efficient in filtering particles of у nm in size [ ] . the retail cost of these masks is $ . n- respirators, which are less effective respirators, have been reported to be protective in preventing transmission of severe acute respiratory syndrome coronavirus (size, nm) in health care workers [ , ] , but use of these respirators failed to prevent a cluster of cases in one hospital [ ] . concerns have been raised over leakage around the mask, especially in the absence of fit testing [ ] . nonetheless, these masks, if distributed to the public, could prove to be critical for the control of a smallpox epidemic that was overwhelming our health care system, and they might also prove to be effective in limiting contagion of smaller viruses, such as influenza virus (either natural virus, as in , or engineered virus [ ] ). additionally, an aerosolized smallpox attack would likely paralyze our cities. availability of masks might allow some measure of confidence for essential services to continue. a focus on the hazards of smallpox vaccination without consideration of the potential consequences of a competently executed smallpox attack may lead to skewed analyses and flawed decisions. in particular, the use of a more virulent, "weaponized" strain of smallpox virus could mean that the epidemic would outrun the currently planned postevent vaccination/isolation measures. although conventional wisdom suggests that smallpox, in its natural state, is largely limited to spread via respiratory droplets, concern about the potential for aerosol transmission is real and might be a greater problem in a developed society with large urban populations. despite the potential hazards, we believe that greater efforts should be made to promote pre-event immunization-especially in emergency providers and health care workers. furthermore, consideration should be given to allowing the public voluntary access to the vaccine. with proper informed consent and careful screening to minimize the risk of adverse side effects, such a program could reduce the risk of a runaway epidemic. because of the possibility of an attack involving bioengineered smallpox virus that is resistant to the current vaccine, methisazone should be reexamined, and research should be continued on other antiviral agents. also, an adequate supply of masks should be assured. although unlikely at the present time, the possibility of a future bio-engineered attack using smallpox should not be arbitrarily rejected. because of scientific advances (the polio virus has recently been synthesized de novo) [ ] and ready access to those advances (complete genomes for viruses, including variola, are available on the internet), we face a potential vulnerability. although that threat may not be immediate (variola would be a complex genome to synthesize, and its dna requires the activity of associated proteins to be infectious) [ ] , it may not be long in coming. board on health promotion and disease prevention, institute of medicine. review of the centers for disease control and prevention's smallpox vaccination program implementation: letter report # evaluation of st-century risks of smallpox vaccination and policy options smallpox vaccine policy is bad science harrison's principles of internal medicine bio-terrorism, nih-cdc grand rounds us hunting antiviral drug to use in case of smallpox ammo for the war on germs in vitro activity of potential anti-poxvirus agents expression of mouse interleukin- by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox smallpox: anything to declare? a different view of smallpox and vaccination smallpox and its eradication. geneva: world health organization the recent outbreak of smallpox in meschede, west germany the demon in the freezer the recovery of smallpox virus from patients and their environment in a smallpox hospital transmission potential of smallpox in contemporary populations in: office of the surgeon general, department of the army. virtual naval hospital. textbook of military medicine: medical aspects of chemical and biological warfare diagnosis and management of smallpox smallpox as a biological weapon us military smallpox vaccination program experience department of defense smallpox vaccination program. smallpox vaccination safety summary myocarditis following smallpox vaccination among vaccinia-naive us military personnel incidence and follow-up of inflammatory cardiac complications with smallpox vaccination update: cardiac-related events during the civilian smallpox vaccination program-united states smallpox vaccine: problems and prospects. immunol smallpox vaccine: looking beyond the next generation expected adverse events in a mass smallpox vaccination campaign the case for voluntary smallpox vaccination smallpox and smallpox vaccination the smallpox outbreak in khulna municipality, bangladesh can postexposure vaccination against smallpox succeed? smallpox vaccination after a bioterrorism-based exposure a model for smallpoxvaccination policy duration of antiviral immunity after smallpox vaccination the greatest killer smallpox in europe, - assessment of aerosol mixtures of different viruses the looming threat of bioterrorism rough and tumble behind bush's smallpox policy cidofovir in the treatment of poxvirus infections cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge treatment of aerosolized cowpox virus infection in mice with aerosolized cidofovir cidofovir in the therapy and short term prophlyaxis of poxvirus infections oral drug and old vaccine renew smallpox bioterror debate prophylactic treatment of smallpox contacts with n-methylisatin b-thiosemicarbazone prophylaxis of smallpox with methisazone smallpox and its eradication. geneva: world health organization field trial of methisazone as a prophylactic agent against smallpox harrison's principles of internal medicine smallpox and smallpox vaccination the research agenda utilizing variola virus: a public health perspective methisazone in prevention of variola minor among contacts remington's pharmaceutical services is the n respirator appropriate for occupational protection against sars? ecmaj effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) sars among critical care nurses cluster of severe acute respiratory syndrome cases among protected health-care workers-toronto, canada interim domestic guidance on the use of respirators to prevent transmission of sars influenza as a bioweapon active poliovirus baked from scratch a not-so-cheap stunt key: cord- -q b r ig authors: bushell, mary; frost, jane; deeks, louise; kosari, sam; hussain, zahid; naunton, mark title: evaluation of vaccination training in pharmacy curriculum: preparing students for workforce needs date: - - journal: pharmacy (basel) doi: . /pharmacy sha: doc_id: cord_uid: q b r ig background: to introduce and evaluate a university vaccination training program, preparing final year bachelor of pharmacy (bpharm) and master of pharmacy (mpharm) students to administer vaccinations to children and adults in community pharmacy and offsite (mobile and outreach) settings. methods: final year bpharm and mpharm students were trained to administer intramuscular vaccinations to adults and children. the education program embedded in pharmacy degree curriculum was congruent with the requirements of the australian national immunisation education framework. the training used a mix of pedagogies including online learning; interactive lectures; and simulation, which included augmented reality and role play. all pharmacy students completing the program in were required to carry out pre- and post-knowledge assessments. student skill of vaccination was assessed using an objective structured clinical assessment rubric. students were invited to complete pre and post questionnaires on confidence. the post questionnaire incorporated student evaluation of learning experience questions. results: in both cohorts, student vaccination knowledge increased significantly after the completion of the vaccination training program; pre-intervention and post-intervention mean knowledge score (sd) of bpharm and mpharm were ( . ± . vs. . ± . ; p < . ) and ( . ± . vs. . ± . ; p < . ) respectively. there was no difference between the bpharm and mpharm in the overall knowledge test scores, (p = . ; p = . ) pre and post scores respectively. using the osca rubric, all students (n = ) were identified as competent in the skill of injection and could administer an im deltoid injection to a child and adult mannequin. students agreed that the training increased their self-confidence to administer injections to both children and adults. students found value in the use of mixed reality to enhance student understanding of the anatomy of injection sites. conclusion: the developed vaccination training program improved both student knowledge and confidence. pharmacy students who complete such training should be able to administer vaccinations to children and adults, improving workforce capability. mixed reality in the education of pharmacy students can be used to improve student satisfaction and enhance learning. vaccination and injection skills training has been taught in some australian pharmacy degree curriculums since [ ] . indeed, training was being taught in pharmacy schools before pharmacists were administering vaccinations in the practice setting [ , ] . the rationale for this was that both the profession and pharmacy schools were anticipating regulation change to expand the scope of practice to enable pharmacist-administered vaccination [ ] . teaching and upskilling pharmacy students to vaccinate would enable a work-ready graduate. in , queensland became the first jurisdiction, outside a pilot program, to modify regulations to enable pharmacists to vaccinate [ ] . since then, regulations across all australian states and territories have been modified to allow appropriately trained pharmacists to administer vaccinations to adults and more recently children aged and over [ ] [ ] [ ] [ ] [ ] . many pharmacy students across australia have now completed vaccination training embedded within their university degree; however, until march , training was not formally recognized. that is, students would complete university vaccination training, and then, once registered (provisionally or fully, dependent on jurisdictional regulation), complete training delivered by an external provider (e.g., pharmaceutical society of australia or pharmacy guild of australia) to be certified competent to vaccinate [ , ] . this resulted in duplication of training for many early career pharmacists and an inherent lag time between original knowledge and skills development and administration of vaccines in the practice setting. in march , the australian pharmacy council (apc), the body responsible for the accreditation of pharmacy education in australia and new zealand, published the standards for the accreditation of programs to support pharmacist administration of vaccines version . [ ] . the apc amended the standard to enable pharmacy students enrolled in an accredited pharmacy degree program, to complete a vaccination training program delivered either within the degree program curriculum or via an external provider, during their period of study [ ] . this change enabled universities to train and certify students to vaccinate. however, authorization to administer vaccinations is determined by state and territory legislation; at the time of writing, regulations preclude pharmacy student vaccinations in all australian states and territories. however, the move by the apc to recognize vaccination training embedded in pharmacy degrees removes duplicity of vaccination training and enables students to be ready to vaccinate once they register. the scope of practice of the australian pharmacist vaccinator is constantly evolving to include more vaccinations and expand the age groups that pharmacists can vaccinate to. the eligible age of patients that pharmacists can vaccinate varies across jurisdictions. interestingly, even within a state or territory, the eligible age to vaccinate differs between vaccines. from may , appropriately trained pharmacists across all states and territories can administer the influenza vaccine to children aged and over [ , , , ] . in most jurisdictions, pharmacists can administer measles-mumps-rubella (mmr) and whooping cough (dtpa) to individuals and over. while in victoria, pharmacists can administer the mmr and dtpa vaccines to people aged years and over [ ] . there is a clear trend to lower the age limit eligibility and increase the type of pharmacist-administered vaccinations, improving accessibility and vaccine uptake. more recently, regulation has been modified to enable pharmacists to administer vaccines outside the pharmacy setting via both mobile and outreach services [ ] . therefore, it is appropriate that pharmacy students are trained and certified competent to deliver a vaccination service to both children (aged and up) and adults. to date, most australian pharmacy schools have integrated vaccination training into undergraduate and postgraduate pharmacy degrees, with a focus on administering vaccinations to adults [ , ] . the vaccination training program developed by the authors and evaluated in this paper, used the learning outcomes for the national immunization education framework for health professionals [ ] . this paper describes and evaluates the teaching and learning of vaccination training embedded in the pharmacy curriculum at the university of canberra. a vaccination training program (vtp) was developed in line with the national immunization education framework for health professionals (the framework) [ ] . this framework was designed to facilitate the development of nationally consistent, quality education programs for australian health professionals, who are not medical practitioners, who want to be recognized as competent to administer vaccinations within their scope of practice. the university vtp adopted the core learning objectives and outcomes from the framework, and then the teaching team adapted them to be pharmacy specific. to do this, the standards and guidelines specific to pharmacy (professional practice standards, practice guidelines for the provision of immunization services within pharmacy) [ , ] were considered and integrated where appropriate. vaccination training has been embedded in the bachelor and master of pharmacy degrees at the university of canberra since . the training, co delivered by pharmacists, pharmacy and nursing academics (all authorized immunizers), focused on teaching the knowledge and skills to administer vaccinations to adults. in , to ensure that teaching and learning is congruent with contemporary pharmacy practice, this training was expanded to include content and skills assessment of injections to children. as the pharmacist vaccinators did not have, at that point, experience administering vaccinations to children, a nurse practitioner qualified to provide immunizations, delivered the content, theory, skills training, and assessment related to children. pharmacists work as part of a broader health care team. the developed vaccination training program was taught via an interprofessional teaching team, which included pharmacist and nurse vaccinators. with reference to and consistent with the literature on pharmacy student vaccination training, there were a variety of educational pedagogies used to promote understanding and skill competency [ ] . teaching included both face-to-face (internal) and non-face-to-face learning opportunities and delivery of content. see table . students were given access to the online non-face-to-face content at semester commencement. this learning material could be completed by students in an asynchronous fashion prior to the intensive workshops. the face-to face content was delivered over four intensive whole day sessions. students were taught the knowledge and skills to administer both im and subcutaneous (sc) vaccinations and how to appropriately manage anaphylaxis. to simulate environments and prepare students for real experience, the training program used the following: role-plays, mannequins, standardized patients, and mixed reality. students had to role play and administer vaccinations to both a pediatric and adult low fidelity mannequin. a mixed reality simulation technique using the microsoft hololens head-mounted devices along with the gigxr applications holohuman and holopatient were used in the face -to-face delivery. the two applications were used to augment the students understanding of anatomy and physiology and to view a simulated patient who was portraying symptoms of anaphylaxis. holohuman is an anatomy application that allows a student to gain a spatial understanding of anatomy and walk through the holographic body. as the student walks through the holographic image, layers of virtual anatomy peel away to reveal the underlying structures. this provided students with a unique way of identifying landmarks (i.e., deltoid muscle) for intramuscular (im) vaccination. it was used to enable students to visualize the shoulder (synovial) joint and to recognize why a shoulder injury related to vaccine administration (sirva) would occur if given too high. mixed reality has the power to engage the learner in a variety of interactive ways, which until this point have not been possible. students skill competency was assessed using an objective structured skills assessment (osca). see appendix a. an authorized immunizer assessed student skill competency to administer a vaccination to both an adult and child mannequin and provided feedback at the end of the assessment. students completed identical pre-and post-knowledge assessments on the content taught on the topic of vaccination. thirty questions assessed understanding of the topics taught. there were questions that assessed knowledge of the national immunization schedule, immunological principles of vaccination, vaccine preventable diseases, the different types of vaccines and how they elicit an immune response, current legislation and regulations related to pharmacist administered vaccination, vaccine cold chain, how to appropriately administer vaccines, documenting the vaccination service, and managing anaphylaxis. to enable matching of the pre-and post-vaccination knowledge tests, while enabling students to be deidentified, students had to provide an answer to questions, such as who was their first teacher and the day of the month they were born, on both the pre and post-tests. all students completing the vaccination training, embedded in the unit pharmacy practice , were invited to participate in the evaluation of the training program by completing a hard copy questionnaire at the completion of the training. participating in the evaluation questionnaire was voluntary and no payment or other incentive was provided. the questionnaire was developed by the authors of this paper. questionnaires were face validated by pharmacy and nursing academics, all authorized vaccinators. each evaluation questionnaire included questions that required students to rate their level of agreement on -point likert scale (strongly agree to strongly disagree) and two free text questions. one question asked what the student liked about the vaccination training, the other how the vaccination training could be improved. descriptive statistics were conducted. free text responses were analyzed to identify repeating themes. all subjects gave their informed consent for inclusion before they participated in the study. the study was conducted in accordance with the declaration of helsinki, and the project was approved by the human research ethics committee of the university of canberra (hrec - ). in total, in , students completed the vaccination training. of this, ( . %) were enrolled in the final year of bpharm and ( . %) were enrolled in the final year of the m pharm degree. see table . when combined, / ( . %) had a current first aid certificate, / ( . %) had a current mental health first aid certificate, and / ( . %) were currently working in a pharmacy. see table . there was no association between working in pharmacy, having a current first aid certificate and/or mental health first aid certificate and the mean knowledge score of the pre-test. the only statistically significant finding was that students who held a first aid certificate performed better than students who did not have a first aid certificate on the post-knowledge test (p = . ). the mean pre-intervention knowledge score for the cohort was / , while the post intervention knowledge score was / . the difference in mean vaccination knowledge scores pre and post educational intervention was better (p < . ) with a large effect size (cohens d = . ). see table . the results show that there was no statistically significant difference between the scores for the knowledge assessment between bachelor and master cohorts. bpharm students mean score pre-educational intervention was / , and for master of pharmacy students it was / . the mean score post-intervention was / for b.pharm students, and / for m.pharm students (p = . ). using the osca rubric, all students (mpharm and bpharm) completing the training program were identified as competent in the skill of injection. all students (n = ) scored a yes against the criteria of the osca rubric (appendix a). all students could administer an im deltoid injection to a child and adult mannequin. all students (n = , %) either agreed ( / , %) or strongly agreed ( / , %) that the vaccination training enhanced their knowledge of vaccination. all students (n = , %) either agreed ( / , %) or strongly agreed ( / , %) that the practical session of administering a vaccine was useful/beneficial. all students (n = , %) either agreed ( / , %) or strongly agreed ( / , %) that the practical session increased their confidence to administer vaccinations. when asked 'i feel confident that i know the correct vaccination technique for both adults and children', one student ( . %) responded neutral, / ( %) agreed and / ( %) strongly agreed. students voiced value in having the content delivered by an interprofessional teaching team, which included pharmacists and nurses. a sample of students provided simple but positive comments like: "good teaching team" pharmacy student a. students were both satisfied and valued the integration of mixed reality in the vaccination training. students voiced that it helped with the understanding of certain concepts, for example, shoulder injury related to vaccine administration (sirva). from the feedback evaluation form: "walking into the holohuman was really neat. i liked that the layers of the human peeled away and it felt like i looking inside a human layer by layer. it helped my understanding not only of anatomy but the importance of making sure when administering an injection, i administer it in the right spot." pharmacy student b. students' knowledge significantly increased post the educational intervention vaccination training. there was no difference between bpharm and mpharm student knowledge pre or post education intervention. this indicates that delivery of the training program in the final year of both degrees enables comparable understanding of the content and skills taught and a work ready graduate. one finding was that students who had completed a first aid certificate, had higher post vaccination training knowledge scores. this finding is interesting as students did not have a higher mean pre knowledge test score. one possible reason for this is that students complete first aid training as adjunct training, that is, while it is recommended, it is not compulsory for students to complete. students have gone above expectation to complete the training and have demonstrated commitment to continuing education. this attitude to study may be extrapolated to their commitment to the vaccination training and the larger unit in which the training is embedded. many recent studies have shown that an individual's grit, perseverance and passion for long term goals is associated with higher academic grades [ , ] . the training employed a range of teaching pedagogies to promote student understanding, skill competency and confidence. simulation is a learner-centred educational pedagogy that facilitates learning by exposing the learner to a situation which is based on or mimics a real-life event. simulation includes a broad range of activities. the use of simulation as an educational tool enables experiential learning and constructivism. it provides students with an opportunity to create their own meaning and co-construct knowledge in a safe environment, taking knowledge learnt from the lectures to application of the skill. consistent with the literature, this teaching evaluation shows that student's value and like to learn using simulation when being taught medical skills, such as vaccination [ ] . students learnt how to administer both an im vaccination to a child and adult low fidelity mannequin. a recent study showed that the use of high-fidelity simulation mannequins as a teaching tool resulted in lower or equal student performance of clinical skills when compared to low-fidelity simulation mannequins [ ] . the use of the different low fidelity mannequins enabled students to learn how to best position themselves to administer the vaccination safely at a -degree angle. students were educated to be seated when administering a vaccine to a seated individual. using appropriately sized mannequins showed students why vaccinations given by a standing immunizer to a seated individual are linked with increased risk of being administered too high. using the different mannequins provided students with a safe environment to problem-solve and learn prior to practicing in the professional setting [ ] . mixed reality (mr) is an emerging technology in health care education [ ] . consistent with previous studies exploring student acceptability, students enjoyed and valued the integration of this teaching tool in the vaccination training [ ] . to correctly identify the im deltoid injection site, pharmacy students were taught to use anatomical markers. they were taught to create a 'triangle' over the individuals' deltoid with their fingers, the centre of which the injection is administered. they were educated to locate the acromion process (shoulder tip) and place their index finger (or first finger) along it. then to place the second and third finger down underneath the index finger (the third finger becomes the base of the triangle). the fourth finger is then opened to create a 'side' of the triangle. in the middle (not the top or the bottom) of the triangle, the injection should be made. using mr enabled students to peel away the body to see these important anatomical markers, contextualizing and providing insight as to why the content was taught and the potential outcomes of incorrect vaccine administration. students using the mixed reality anatomical software could visually see, using the d animation, that vaccines that are administered too low can be injected into the radial nerve, while vaccines that that are given too far to the side can cause damage to the axillary nerve. this highlights the importance of administering the vaccination into the correct area. role play enabled the students to step through the process of delivering the vaccination service and encouraged both peer learning and formative feedback. using role play, students learnt to communicate appropriate, evidence-based information about benefits and the potential risks of vaccination and obtain valid consent. the active learning approach is widely used in higher education and allows learning across cognitive, psychomotor, and affective domains [ ] . pharmacists work as part of a broader health care team. one strength of the vaccination training program was that it used an interprofessional teaching team. in doing so, students were provided with an opportunity for interprofessional learning and practice. this strengthened program delivery and enabled students to see the value of interprofessional collaborative practice, which will continue in the practice setting [ ] . while both internationally and nationally there are only a small number of studies published on the delivery and evaluation of pharmacy vaccination training in pharmacy schools, the results of this study are consistent with other published evaluations [ , ] . across the studies, students' value gaining new knowledge and skills and report confidence to administer vaccinations on completion of training [ , , ] . consistent with this study, the two australian studies that outline the development of a pharmacy vtp also used national pharmacy standards to inform material [ , ] . in contrast, where this study reports adopting the learning outcomes from the national immunization education framework for health professionals, the other studies did not. this makes direct comparison between the training programs difficult. there are currently varied approaches to when vaccination training is embedded in degree programs. there are pharmacy schools that embed vaccination training in the earlier years of the curriculum, to enable students to see themselves as future 'clinical' health professionals [ , ] . in the published studies, students report satisfaction and skill acquisition. they also report enabling students to see that they will be touching patients as part of their future professional role when providing care [ ] . given pharmacy students in australia, can now complete a university vaccination training program and, when jurisdictional regulation allows, vaccinate without needing to complete additional training by an accredited external provider, the best year level to embed vaccination training should be further researched. in doing so, an evidence-based and consistent decision can be made about the best year level to introduce the training. further, to date, research in australia has not directly compared the delivery, skill acquisition, confidence, and competence of students across different university vaccination training programs, this too should be further explored. students, like authorized immunizers, completed vaccination training that is congruent with the national immunization education framework for health professionals and demonstrated competency. there is a case for jurisdictional regulations to be modified to enable pharmacy student-administered vaccinations. international research demonstrates that pharmacy students, under the supervision of a credentialled vaccinator, can administer vaccines safely [ , ] . the application of skill acquisition in the clinical setting improves students' self-confidence [ , ] . having pharmacy students ready to vaccinate on placement would enable a more work-ready graduate and a critical workforce that can be used to promote vaccination uptake. this skill is likely to be of greater use particularly in times when vaccination demand is high, for example a pandemic. if and when the covid- vaccine is available, mass immunization is likely to be needed in a relatively short period of time to mitigate the spread of the disease and enable international borders to reopen. pharmacy students could be used to improve workforce capability in australia. the vaccination training program described in this paper was embedded in the final year of mpharm and bpharm curriculum and enabled the same skill competency and knowledge acquisition across cohorts. the training program incorporated a suit of teaching methods, including mixed reality, which had high student acceptability. aligning with the changed scope of practice for australian pharmacists, pharmacy students learnt how to administer vaccinations to both adults and children. international research demonstrates that pharmacy students, under the supervision of a credentialled vaccinator, can administer vaccines safely. given student competency and readiness after completing vaccination training, there is a case for jurisdictional regulations to be modified to enable pharmacy student-administered vaccinations in australia. case for pharmacist administered vaccinations in australia current research: incorporating vaccine administration in pharmacy curriculum: preparing students for emerging roles australia's first pharmacist immunisation pilot-who did pharmacists inject? act government. medicines, poisons and therapeutic goods (vaccinations by pharmacists) direction poisons and therapeutic goods regulation queensland government. health (drugs and poisons) regulation , drug therapy protocol-pharmacist vaccination program victorian pharmacist-administered vaccination program expansion communique northern territory government. qualifications prescribed for pharmacist to supply and administer schedule vaccine. in department of health; northern territory government evaluation of a vaccination training program for pharmacy graduands in australia current research: a shot in the arm: pharmacist-administered influenza vaccine in new south wales standards for the accreditation of programs to support pharmacist administration of vaccines version . pharmacist-led immunisation in the northern territory: results from the pilot study development and design of injection skills and vaccination training program targeted for australian undergraduate pharmacy students national immunisation education framework for health professionals practice guidelines for the provision of immunisation services within pharmacy national competency standards framework grit: perseverance and passion for long-term goals building grit: the longitudinal pathways between mindset, commitment, grit, and academic outcomes the history of medical simulation high-fidelity is not superior to low-fidelity simulation but leads to overconfidence in medical students a brief history of the development of mannequin simulators for clinical education and training virtual reality in pharmacy: opportunities for clinical exploring the application of mixed reality in nurse education exploring the potential of role play in higher education: development of a typology and teacher guidelines interprofessional collaborative practice for medication safety: nursing, pharmacy, and medical graduates' experiences and perspectives managing vaccine-associated anaphylaxis in the pharmacy an introductory pharmacy practice experience emphasizing student-administered vaccinations integration of first-and second-year introductory pharmacy practice experiences introductory and advanced pharmacy practice experiences within campus-based influenza clinics a literature review of the impact of pharmacy students in immunization initiatives the authors would like to thank louise mcclean for helping to assess students. the authors declare no conflict of interest. the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. pharmacy , , appendix a table a . osce: administration of medication by intra-muscular injection (imi). demonstrates: the ability to administer imi into the deltoid muscle. assessor question: where would you find information regarding the drug class, action and side effects of this drug? key: cord- -b s stvz authors: guimarães, luísa eça; baker, britain; perricone, carlo; shoenfeld, yehuda title: vaccines, adjuvants and autoimmunity date: - - journal: pharmacological research doi: . /j.phrs. . . sha: doc_id: cord_uid: b s stvz abstract vaccines and autoimmunity are linked fields. vaccine efficacy is based on whether host immune response against an antigen can elicit a memory t-cell response over time. although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. the diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. in this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. these mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (asia syndrome). in conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future. vaccines have been a preventive treatment option available for over years. they have been proven to be effective in preventing infections that previously had high morbidity and mortality. an example of this is the eradication of small pox, which was mainly attributed to successful vaccination programs. preventing a high burden disease has since proven to be a cost effective measure and, as such, vaccines have become a part of multiple national health programs. these promising results led to the development of more and more vaccines and to the study of its applicability in other fields such as cancer prevention and treatment. vaccines are drugs administered to healthy individuals, and much like other drugs, vaccines are associated with adverse events. usually the described adverse events are transient and acute, but may rarely present with hypersensitivity and induction of autoimmunity that may be severe and fatal. these adverse events play an important role in the life of the vaccinated patients. immune mediated diseases arise from various different sources; these include environmental, genetic, hormonal and immune defects. the combination of these defects can be described as the mosaic of autoimmunity [ ] . patient background can be used as a clue to determine the response that may be elicited following drug administration. it has been proven that infectious agents may elicit an autoimmune disease in a prone subject through various mechanisms, including, but not limited to, molecular mimicry, epitope spreading and polyclonal activation [ ] . scientific findings suggest that autoimmunity may be triggered by vaccine adjuvants, of which aluminum compounds (aluminum hydroxide and phosphate) have been the most studied and the most widely used. adjuvants are molecules, which, in combination with antigens, enhance immunological response. this enables an easier and more effective recognition of "non self", which in turn permits the triggering of adaptive and innate immune responses [ ] . recently a new syndrome was described: "autoimmune/inflammatory syndrome induced by adjuvants" (asia). this embodies a spectrum of reactions, which are usually mild but may also be severe. these reactions are attributed to adjuvant stimulation, which can include chronic exposure to silicone, tetramethylpentadecane, pristane, aluminum, infectious components and other adjuvants. all of these environmental factors have been found to induce autoimmunity and inflammatory manifestations by themselves both in animal models and in humans. the mechanisms of this disease will be described in further detail [ ] . this review will focus on general mechanism of vaccines, adjuvant-induced autoimmunity, and on vaccines and the specific autoimmune diseases that they may trigger. adjuvants approved to date for human vaccines are: aluminum, mf in some viral vaccines, mpl, as , as b and as a against viral and parasitic infections, virosomes for hepatitis b virus (hbv), human papilloma virus (hpv), hepatitis a virus (hav), and cholera toxin for cholera. adjuvants may be composed of several different compounds. currently, oil based adjuvants, virosomes, toll-like receptors (tlrs) related adjuvants, mpl, adjuvants made of unmethylated cpg dinucleotides and tuftsin have all been described. it is of great interest the understanding of the mechanisms related to the adjuvant effect, as well as to aluminum salts. aluminum acts through multiple pathways, which do not depend solely on tlrs signaling. each of these pathways leads to an enhanced host immune response [ ] . there are many oil based adjuvants. one is incomplete freund adjuvant (ifa), which contains water in oil emulsion. another is complete freund adjuvant (cfa), which is the same as ifa, except that it also contains killed mycobacteria in addition to water in oil emulsion. usually, cfa is used for primary vaccination and ifa for boosting. recent oil based adjuvants that have been developed are mf (novartis ® ), as (glaxosmithkline ® ), advax tm which are based on inulin compounds (vaxine tm pty) and qs- /iscoms, which are immune stimulating complexes composed of cholesterol and phospholipid with or without antigen (table ) . virosomes are adjuvants that contain a membrane-bound hemagglutinin and neuraminidase obtained from the influenza virus. both components facilitate the uptake into antigen presenting cells (apc) and mimic the natural immune response [ ] . leucocyte membranes have membrane bound pattern recognition receptors (prrs) called tlrs, which are responsible for detecting most (although certainly not all) antigen-mediated infections. their activation leads to adaptive immune responses. for this reason, many adjuvants that are used today are directed to prrs. these adjuvants are called tlrs related adjuvants [ ] . mpl is a series of 'monophosphoryl lipid a obtained from the purification of a modified lipopolysaccharide (lps) of salmonella minnesota. bacterial deoxyribonucleic acid (dna) is immunostimulatory due to unmethylated cpg dinucleotides. vertebrate dna has relatively low amounts of unmethylated cpg compared to bacterial dna. the adjuvant effect of cpg is enhanced when conjugated to protein antigens. this adjuvant is being tested in vaccines directed at infectious agents, allergens and tumor cells [ ] [ ] [ ] . another type of adjuvant is tuftsin. tuftsin is an auto adjuvant, which is a natural self-immunostimulating tetrapeptide (thr-lys-pro-arg). this tetrapeptide is a fraction of the igg heavy chain molecule produced by enzymatic cleavage in the spleen [ ] . its functions include: binding to receptors on neutrophils and macrophages to stimulate their phagocytic activity, increasing tumor necrosis factor alpha (tnf␣) release from human kupffer cells enhancing secretion of il by activating macrophages, activation of macrophages expressing nitric oxide (no) synthase to produce no and enhancement of murine natural cell mediated cytotoxicity in vitro [ ] [ ] [ ] . in summary, it is an adjuvant with minor side effects with a promising effect in restoring innate immune mediated response. adjuvants may exert their immune enhancing effects according to five immune functional activities: . translocation of antigens to the lymph nodes where they can be recognized by t cells. . antigen protection enabling longer exposure. . enhanced local reaction at the injection site. . induction of the release of inflammatory cytokines. . interaction with prrs, specifically tlrs [ ] . a adjuvant effect the term "adjuvant effect" refers to the co-administration of an antigen with a microbial specific factor to enhance an antigenspecific immune response in vivo. the microbial components of adjuvants activate apcs to produce pro-inflammatory cytokines ("non-specific" signal ) and to up-regulate molecules essential for antigen presentation. these molecules include major histocompatibility complex (mhc) class ii (antigen-specific signal ) and b - / . these innate immune events allow a more effective presentation to the adaptive immune system, resulting in an augmented activation and clonal expansion of t cells [ ] . in accordance to this effect, if self-antigens are used, an autoimmune response can be elicited [ ] . it has been shown that auto-reactive t-cells that surpass tolerance mechanisms can be triggered by exogenous adjuvants to become auto-aggressive [ ] . infectious agents are able to naturally generate their adjuvant effect and can induce autoimmunity [ ] . an example of this is the causality between viral infection and myocarditis. half the cases of myocarditis are preceded by an acute viral infection. infectious myocarditis in humans can be reproduced in experimental murine models of myocarditis [ ] . it has also been shown that the autoimmune reaction elicited by an infectious agent can be effective in treating cancer. an example of this is that bladder administration of bcg (bacille calmette-guérin) has been shown to be effective against superficial bladder cancer development [ ] . it can be inferred that the adjuvant effect can be used against specific tumor derived molecules, so that these molecules can be recognized as "non self". prr-pamp (pattern recognition receptor-pathogen-associated molecular patterns) interactions activate the apcs to promote antigen-specific lymphocytic responses [ ] . the definition of pamps has now broadened, in that the recognized structures do not need to be pathogens. thus the concept of "microbe-associated molecular patterns" (mamps) and of "danger/damage-associated molecular patterns" (damps) were defined based on the notion that the endogenous host molecules signal danger or damage to the immune system [ ] . tlrs are single-transmembrane prrs localized on cell surface and endosomal membranes. from all the prrs, these are the most studied. tlrs play a crucial role in innate immune response to "non self" and are biosensors of tissue damage. the interaction between the four known tlrs adapters: myd , tirap/mal, tram and trif, in tlr signaling, shape the innate immune response. besides prrs the innate immune system also detects proteolytic enzymes generated during infection [ ] . merging the response to different prrs signaling may be the pathway for developing customized responses to different aggressions [ ] . b experimental models of adjuvants many animals have been used in experimental models of adjuvant-related autoimmune conditions [ ] . these include primates, salmons, rabbits and swine; however, the most common are murine models. murine models include autoimmune prone strains, models of autoimmune disease and autoimmune resistant strains ( table ). an interesting model is that described by lujan et al. the authors described that a commercial sheep, inoculated repetitively with aluminum-containing adjuvants vaccinations, developed an acute neurological episode with low response to external stimuli and acute meningoencephalitis few days after immunization. an excitatory phase, followed by weakness, extreme cachexia, tetraplegia and death appeared. this was suggested to be part of the spectrum of asia syndrome. moreover, the biopsy of the nervous tissue of experimental animals indicated the presence of alum [ ] . c toxicity of aluminum adjuvants aluminum nanoparticles have both a unique capacity of surpassing the blood brain barrier (bbb) and of eliciting immune inflammatory responses. these are probably the reasons why aluminums' most sensitive target is the brain, and also why documented side effects are mostly neurologic or neuropsychiatric [ , ] . aluminum is present in nature, not only as a vaccine adjuvant, but also in food, water and cosmetics. it has been described as a neurotoxin because even when a relatively small amount of aluminium reaches the brain [ ] , is can act as a genotoxin [ ] , a prooxidant [ ] , it can be proinflammatory [ ] , act as an immunotoxin [ ] and also as an endocrine disruptor [ ] . aluminum interferes with many essential cellular processes. memory, concentration, speech deficits, impaired psychomotor control, reduced seizure tolerance and altered behaviour are manifestations of aluminium neurotoxicity. moreover, alzheimer's [ ] , amyotrophic lateral sclerosis, parkinsonism dementia [ ] , multiple sclerosis [ ] , and neurological impairments in children have been linked to aluminum neurotoxicity [ ] . brain susceptibility to aluminum compounds is possibly due to the brain's high metabolic requirement, to the fact that it possesses a large area of biological membranes and to the relatively low concentration of antioxidants [ ] . aluminum adjuvants exert their immunostimulatory effect through many different pathways that activate both the innate and adaptive immune systems. one of the most significant is the activation of the nlrp inflammasome pathway [ ] . nlpr activation has been shown to trigger type diabetes. by using nlpr knockout mice it has been demonstrated that the absence of inflammasome components leads to a better maintenance of glucose homeostasis and higher insulin sensitivity [ ] . on the other hand, activation of the inflammasome and its downstream components: pro-inflammatory cytokines il- ␤ and il- are strongly implicated in the development of several central nervous system (cns) disorders [ ] . the vast majority of people are consuming higher amounts of aluminum through dietary and parenteral intake than what expert authorities consider safe. upper limits set by us food and drug administrations (fda) for aluminum in vaccines are set at no more than g/dose. these values were not based on toxicity studies, but on the minimum amount needed for aluminum to exert its effect as an adjuvant [ ] . the quantities of aluminum to which infants, in their first year of age are exposed, have been considered safe by the fda. however the scientific basis for this recommendation does not take into account aluminum persistence in the body. the concern about aluminum in dietary intake has been reinforced by the food and agriculture (fao) who expert committee, which lowered the provisional tolerable weekly intake of aluminum from mg/kg/bw ( mg/week, for an average kg human) to mg/kg/bw ( mg/week) [ ] . the amount of dietary intake of aluminum has risen in urban societies to up to mg/day considering the widespread use of processed convenience foods. however, only about . % of dietary aluminum is absorbed into systemic circulation and most of it is thereafter eliminated through the kidneys [ ] . absorption of aluminum by the skin from ointments and cosmetics containing aluminum has been shown. moreover, the presence of aluminum in breast tissue was associated with breast cancer [ ] . aluminum compounds persist for up to - years post vaccination in human body. this fact, combined with repeated exposure, may account for a hyper activation of the immune system and subsequent chronic inflammation [ ] . the clinical and experimental evidence collected so far identify at least three main risks associated with aluminum in vaccines: . it can persist in the body. . it can trigger pathological immunological responses. . it can pass through the bbb into the cns where it can trigger immuno-inflammatory processes, resulting in brain inflammation and long-term neural dysfunction. there is a link between allergies and autoimmunity since both are the result of an abnormal immune response [ , ] . metals such as mercury, aluminum, nickel and gold are known to induce immunotoxic effects in humans. the immunologic effects of these metals include immunomodulation, allergies and autoimmunity. they may act either as immunosuppressants or as immune adjuvants. metals bind firmly to cells and proteins and thus have the ability to modify autologous epitopes (hapetenization). t-cells then recognize the proteins as foreign and trigger an autoimmune response [ ] . hypersensitivity caused by metals may be referred to as type iv delayed hypersensitivity. the reaction is considered delayed because the first symptoms appear - h after exposure, because it is mostly t-cell mediated and the gold standard for diagnosis of delayed type hypersensitivity is patch testing [ ] . in mercury-sensitized patients, even mercury concentrations within the normal range might provoke neuroallergic reactions in the brain [ ] . identifying metal sensitivity and removal of the sensitizing metals, such as dental amalgam, have been proved successful by showing symptom improvement in patients with previous autoimmune diseases. these diseases included fibromyalgia, autoimmune thyroid diseases and orofacial granulomatosis [ ] [ ] [ ] [ ] (table ). the timeline regarding the field of vaccinology has been divided in two generations, the first regarding the administration of inactivated pathogens in whole or live attenuated forms (e.g., bacillus calmette guerin (bcg), plague, pertussis, polio, rabies, and small- pox) and the second regarding vaccines assembled from purified microbial cell components, also referred as subunit vaccines (e.g., polysaccharides, or protein antigens) [ ] . this latter approach there are obstacles to conventional vaccine development methods such as non-cultivable in vitro pathogens (e.g., hepatitis c, papilloma virus types and , and mycobacterium leprae), antigen hypervariability (e.g., serogroup b meningococcus, gonococcus, malaria), opportunistic pathogens (e.g., staphylococcus aureus) and rapid evolving pathogens such as human immunodeficiency virus (hiv) [ ] . vaccine research gained a new perspective as the genomics field emerged over the last decades. bacterial genomes have been sequenced and analyzed making it possible to choose the best candidate vaccine antigens by using the concept of reverse vaccinology [ ] . the main known factors influencing the observed heterogeneity for immune responses induced by vaccines are gender, age, ethnicity, co-morbidity, immune system, and genetic background. the interaction between genetic and environmental components will dictate the response to vaccines. studying the vaccine and the host will enable the development of customized treatment options. the combination of genetics, epidemiology and genomics in vaccine design has been denominated "vaccinomics" [ ] . the importance of genetic influence is supported by twins and siblings studies, which show familial aggregation. this suggests that genomics is crucial in inter-individual variations in vaccine immune responses [ ] . both human leukocyte antigen (hla) and non-hla gene markers have been identified as markers for immune response to vaccines. multiple studies have shown connections between hla gene polymorphisms and non-responsiveness to the hbv vaccine [ ] . hla region is divided in three sub regions: class i is associated with the induction and maintenance of cell-mediated immune response, class ii is associated with presentation of exogenous antigens to helper t cd + cells and class iii, where immune non hla related genes are located. normal human tissue has at least hla antigens, and although new recombinant haplotypes may occur, it is inherited mostly intact from progenitors [ ] . hla allelic differences are associated with different responses to vaccines, either by hyper or hypo responsiveness. we can infer that a similar response may be associated with different safety in relation to the development of autoimmune reactions to vaccines, particularly in the patients with genetic predisposition to an enhanced response to vaccine inoculation [ ] . furthermore, patients that share the same hla, for instance siblings, have been diagnosed with asia following similar environmental stimuli [ , ] . autoantibodies help to diagnose certain autoimmune diseases, however, they can also be found in healthy individuals. thus, autoimmune diseases cannot be diagnosed based solely on antibody detection [ ] . inoculation of vaccines triggers autoimmune responses that result in the development of autoantibodies. many studies have been carried out in animals, healthy subjects and patients with autoimmune diseases to understand if this development is of clinical significance [ ] [ ] [ ] [ ] . a difference in eliciting the production of autoantibodies in healthy humans has been observed between adjuvanted and non-adjuvanted influenza vaccines [ ] . the annual influenza vaccine has been the most heavily researched vaccine, along with hpv and pneumococcal vaccines as far as their relationship with patients who have previously been diagnosed with an autoimmune disease [ ] [ ] [ ] . autoantibody induction after hpv vaccination was also shown in adolescent girls with systemic lupus erythematosus (sle) [ ] . although induction of autoantibodies was proven following vaccine administration, there have been no proven relation with disease diagnosis in either of the specific groups studied so far [ , ] . it has been widely demonstrated that autoantibodies can develop years before the manifestation of a full-blown autoimmune disease [ ] . moreover, the development of a specific autoantibody is also genetically determined, and the link between genetic, autoantibodies and vaccines may become an even more intriguing area of research [ ] . silicones are synthetic polymers that can be used as fluids, emulsions, resins and elastomers making them useful in diverse fields. they were thought to be biologically inert substances and were incorporated in a multitude of medical devices such as joint implants, artificial heart valves, catheters, drains and shunts. of all the silicone-containing products, the most famous are most likely breast implants. silicon is one of the substances suspected to induce asia [ ] . it is currently believed that exposure alone is not enough to trigger the disease but that it requires the presence of additional risk factors (e.g., genetic susceptibility, other environmental factors) [ ] . silicone exerts local tissue reactions. some of these reactions are considered para-physiological, such as capsular tissue formation around an implant. other reactions are viewed as abnormal, like when capsular contractures and allergic reactions to silicone or platinum (catalyst used in silicone polymerization found in minute concentrations in implants) occur [ ] . cutaneous exposure to silicone with cosmetics or baby bottles could potentially sensitize patients [ ] . there is also a systemic component of silicone exposure related to diffusion of silicone through the elastomer envelope, commonly termed "bleeding". it may arouse systemic effects as it degrades and fragments in tissue, it can also spread throughout the body and lead to the development of cancer or autoimmune phenomena [ ] . patients with ruptured implants complain more frequently of pain and chronic fatigue when compared to patients with intact implants [ ] . anti-silicone antibodies were found to be present in human sera more frequently in patients who have undergone silicone breast implants, however, their pathological significance remains uncertain [ ] . the same was seen for other antibodies such as autoantibodies directed against dsdna, ssdna, ssb/la, silicone and collagen ii, which were found to be present in increased levels in patients after exposure to silicone [ ] . it has also been shown that the formation of autoantibodies is directly related to implant duration. several autoimmune diseases have been linked to silicone exposure including rheumatoid arthritis (ra), systemic lupus erythematosus (sle), polymyositis, systemic sclerosis (ssc) and fibromyalgia. although asia symptoms may arise years after the onset of exposure to silicone implants [ ] , most of the follow-up periods are short and concluding evidence is yet to come regarding this causality. there have been published case reports, epidemiologic and research studies that suggest a connection between several vaccines and certain autoimmune conditions, notwithstanding that, overall the benefits of vaccination outweigh the risks. thrombocytopenia has been reported as the main adverse event following mmr vaccine. after mmr vaccine the onset of immune thrombocytopenic purpura (itp) usually occurred within weeks at a risk rate of : , - , mmr vaccine doses, while the incidence of itp following infections is : for measles and : for rubella [ ] . as the risk of thrombocytopenia is higher in patients who experience natural infection with measles, mumps or rubella than in those receiving the vaccine, vaccination is encouraged. arthralgia complaints have also been reported and they may present as transient arthralgia, acute arthritis and rarely chronic arthritis [ ] . some risk factors have been found to be associated with the development of arthritis in vaccinated patients such as: female gender, older age, prior seronegativity and specific hla alleles [ ] . yf vaccine is only advisable to people in, or going to endemic areas. the risk of developing yf vaccine-associated neurologic disease (yel-and) is inversely proportional to age [ ] . this is why children aged < months cannot be vaccinated and < months, except during epidemics [ ] . vaccination is not advisable to people > years because of possible higher risk of severe adverse effects (saes) even though the incidence remains low [ ] . besides being a vaccine for mycobacterium tuberculosis (tb), the bcg has proved effective as immunotherapy for bladder cancer. although the mechanism is yet to be fully understood, it is thought that bcg binds to fibronectin forming complexes that enable the recognition as "non-self" by the innate immune response of th cells. ultimately the pathways result in the apoptosis of tumor cells [ ] . because of its effect in treating non-muscle-invasive urothelial carcinoma, as well as superficial bladder tumors, it was expected that bcg could play a role in treating other types of cancer, despite data having not corroborated this hypothesis so far. adverse events vary according to the site and method of administration. intradermal administration of bcg has been reported to elicit arthritis [ ] , dermatomyositis [ ] and takayasu's arteritis (ta) [ ] among others. intravesical treatment for bladder cancer can cause reactive arthritis (rea) [ ] . the risk relies on a systemic reaction composed of an early infective phase (pcr positive and response to anti-tb treatment) and a late hypersensitivity reaction [ ] . hbv is a dna virus of the hepadnaviridae family, responsible for acute and chronic liver disease. hbv vaccines are considered the first efficient vaccines against a major human cancer. hbv vaccines have reduced the risk of developing chronic infection and they also have proved to reduce the incidence of liver cancer in children [ ] . the vaccine has been associated mainly with autoimmune neuromuscular disorders. they include, but are not limited to: optic neuritis, guillain-barre syndrome (gbs), myelitis and multiple sclerosis (ms), systemic lupus erythematosus (sle), arthritis, vasculitis, antiphospholipid syndrome (aps) and myopathy [ ] . hbv vaccine is the most common immunization associated with acute myelitis. there are studies that indicate that the pathogenicity behind such vaccine and autoimmunity might be based on cross-reactivity between hbv antigen (hbsag) epitopes, yeast antigens, as well as other adjuvants contained in the vaccine itself [ ] . up to % of cervical cancer deaths, occur in developing countries that lack the ability to fully implement the papanicolau (pap) screening programs. hpv poses a special challenge in vaccine safety. hpv is necessary for the development of cervical cancer. however, most women infected with hpv will not develop the disease since % of infections will resolve within a year and up to % within years without specific treatment. over the course of decades, cancer may result in a small proportion of the remaining infected women. death rate from cervical cancer in - year old girls is zero and long-term benefits are yet to be proven. in this specific case, short term risks to healthy subjects can prove to pose a heavier burden than cervical cancer [ ] . there are at least types of hpv strains, of which have been pathologically associated with cancer. two vaccines, gardasil tm and cervarix tm , are commercially available against hpv. both contain the l capsid proteins of several hpv strains as antigens. gardasil tm contains serotypes , , , . these antigens are combined with aluminum (al) hydroxyphosphate sulphate as an adjuvant. cervarix tm contains a combination of the oil-based adjuvant monophosphoryl lipid a (mpl) and al hydroxide (aso ) as adjuvant and is directed at strains and [ ] . there have been several reports of post-licensure adverse events, some of which have even been fatal [ ] . compared to other vaccines, an unusually high proportion of adverse drug reactions has been reported associated with hpv vaccines [ ] . in , australia reported an annual adr rate of . / , , the highest since . this increase was almost entirely due to adrs reported following the commencement of the national hpv vaccination program for females aged - years in april ( out of a total of adrs records). the numbers only decreased after the cessation of the catch-up schedule. although the percentage of convulsions attributable to the hpv vaccine decreased, the overall report remained comparable between and ( % and % respectively). these reports do not prove the association, but show that there is a higher frequency of adrs related to hpv vaccines reported worldwide, and that they fit a consistent pattern (i.e., nervous system-related disorders rank the highest in frequency) that deserves further investigation [ ] [ ] [ ] . indeed, several autoimmune diseases have been linked to hpv immunization. examples include gbs, ms, acute disseminated encephalomyelitis (adem), transverse myelitis (tm), postural orthostatic tachycardia syndrome (pots), sle, primary ovarian failure (pof), pancreatitis, vasculitis, immune thrombocytopenic purpura (itp) and autoimmune hepatitis (ah) [ ] . influenza is an acute viral infection that affects the respiratory tract and is caused by influenza type a-c viruses of the orthomyxoviridae family [ ] . h n mortality rates in the outbreak showed high risk in those aged years and older, presence of chronic diseases and delayed admission. risk of infection was lower in those who had been vaccinated for seasonal influenza with / trivalent inactivated vaccine [ ] . studies have demonstrated that influenza vaccine is safe and immunogenic in patients with sle or rheumatoid arthritis (ra), diminishing the risk of respiratory infections [ ] . it has been shown that adjuvanted vaccine had more local reactions but did not increase systemic adverse reactions [ ] . molecular mimicry has been suggested as a mechanism to explain an autoimmune response following influenza vaccination. however, a causal relationship between influenza vaccines and induction of autoimmune diseases remains unproved [ ] . diseases or symptoms reported after influenza vaccination include mostly neurological syndromes such as gbs [ref] . nonetheless, influenza vaccines should be recommended for patients with ms, because influenza infection is associated with increased risk of exacerbations. that being said, influenza vaccinations showed increased risk of autoimmune responses suggestive of asia [ ] , vasculitis [ ] and aps [ ] among others. meningococcal disease is caused by neisseria meningitidis. one of the following five serogroups causes almost every invasive disease: a-c, y, and w- . vaccines available so far for its prevention encompass either pure polysaccharide vaccines that use purified bacterial capsular polysaccharides as antigens, or protein/polysaccharide conjugate vaccines, which use the polysaccharide molecule plus diphtheria or tetanus toxoid as tcell-stimulating antigens. n. meningitidis serogroup b (menb) menb glycoconjugate vaccines are not immunogenic and hence, vaccine design has focused on sub-capsular antigens [ ] . menb capsular polysaccharide is composed of a linear homopolymer of ␣( → ) n-acetyl-neuroaminic acid (polysialic acid; psa). menb psa and psa found on neural cell adhesion molecules are structurally identical. as a result of this, it has been proposed that infection with menb or vaccination with psa may be associated with subsequent autoimmune or neurological disease [ ] . no evidence of increased autoimmunity was found to be associated with meningococcal serogroup b infection [ ] . regarding vaccination, the inoculation does not cause autoimmune diseases but may unmask autoimmune phenomena in genetically predisposed individuals. local reactions are more frequent in individuals vaccinated with quadrivalent meningococcal conjugate vaccines compared to plain polysaccharide vaccines. the intramuscular administration of the conjugate vaccine (versus subcutaneous for that of polysaccharide) may, in part, explain the higher reactivity [ ] . diseases previously associated with meningococcal vaccines are gbs [ ] , henoch-schönlein purpura (hsp) [ ] and bullous pemphigoid (bp) [ ] . streptococcus pneumoniae (pneumococcus) is the main cause of bacterial community-acquired pneumonia and meningitis in western countries, as well as the cause of more than , children deaths in developing countries [ , ] . there are three anti-pneumococcal vaccines commercially available. two of these are conjugated to a protein carrier (pcv and pcv ) and one is not conjugated (ppv ). ppv was licensed in and consists of the capsular polysaccharides of twentythree different streptococcus pneumoniae serotypes ( - , b, f, , n, v, a, a, f, , b, f, c, f, a, , f, f, and f). it does not elicit immunological memory because the immune response it triggers is t-cell independent. it is usually administered to the elderly (above years), as it is believed to be less effective in children. pcv is composed of the most frequent serotypes , b, v, , c, f, and f. pcv is directed at serotypes , - , a, b, f, v, , c, a, f, and f. contrary to ppv both pcv and pcv have an aluminum adjuvant in their composition that elicits a t-cell mediated response [ ] . ever since vaccines were introduced in the healthcare system, prevalence, fatality and admissions for invasive pneumococcal disease have decreased significantly [ ] . vaccine adverse events vary depending on whether the vaccine is adjuvanted or not. in a non adjuvanted vaccine, local reactions are present in % of people vaccinated intra muscularly and in % of those immunized sub-cutaneously [ ] . in conjugated vaccines, this percentage rises to % [ ] . systemic reactions such as fever, irritability, decreased appetite and sleep disturbances occur in - % of recipients of pcv or ppv. symptoms like arthralgia, arthritis, myalgia, paresthesia and fatigue are more frequent in patients post ppv. this may be related to the fact that the vaccines are administered to different age groups. autoimmune risk following ppv vaccine is very low. only case reports were found after ppv vaccine. six of these referred to reactivation of a previous autoimmune disorder. studies directed to access vaccine safety in subjects with autoimmune diseases showed immunization was safe [ , ] . tetanus toxoid (tt) is a potent exotoxin produced by the bacteria clostridium tetani. the toxin has a predominant effect on inhibitory neurons, inhibiting release of ␥-aminobutiric acid (gaba). when spinal inhibitory interneurons are affected the symptoms appear [ ] . the vaccine against c. tetani contains deactivated tetanus toxoid plus an adjuvant (usually aluminium hydroxide). the most studied and prevalent disease associated with tt is antiphospholipid syndrome (aps), but cns complications have also been reported such as optic neuritis, acute myelitis and encephalomyelitis [ ] . in mice, the immune response to tt depends on genetic background and to the specific adjuvant used for immunization. naive balb/c mice, immunized with tt, developed antibodies directed to tt, dsdna and ␤ gpi and were extremely sick [ ] . aps is an autoimmune disease characterized by the occurrence of thrombotic events. patients suffering from this condition have recurrent fetal loss, thromboembolic phenomena, thrombocytopenia as well as neurological, cardiac and dermatological involvement [ ] . the serological marker of aps is the presence of antiphospholipid antibodies (apl), which bind negatively charged phospholipids, platelets and endothelial cells mainly through the plasma protein beta- -glycoprotein-i (b gpi). the presence of igg and igm anti-cardiolipin antibodies (acl) and lupus anticoagulant is associated with thrombosis in patients with aps [ ] . ␤ gpi was identified as the most important antigen in aps. ␤ gpi has several properties in vitro which define it as an anticoagulant (e.g., inhibition of prothrombinase activity, adenosine diphosphate-induced platelet aggregation, platelet factor ix production) [ ] . passive transfer of anti-␤ gpi antibodies induce experimental aps in naïve mice and thrombus formation in ex vivo model [ ] . evidence suggests that the molecular mimicry mechanism between ␤ gpi and tt is one of the possible causes for aps. besides tt, aps has also been reported following hbv and influenza virus vaccination, although data are scarce [ , ] . sle is a multisystem autoimmune disease characterized by the production of a variety of autoantibodies. igg isotype antibodies to double-stranded dna (dsdna) are thought to be diagnostic markers and their presence correlates with disease pathogenesis. several factors including genetic, hormonal, environmental and immune defects are involved in the induction of autoantibodies in this disease [ ] . post vaccination manifestations of sle or lupus like syndrome have been reported and range from autoantibody induction to full blown clinical disease. reports have been published associating sle to hbv, mmr, dtp, hpv, influenza, bcg, pneumococcal and small pox vaccinations [ ] . vaccination in sle diagnosed patients is associated with disease exacerbation and decreased antibody response, which may be due to the underlying disease and the frequent use of immunosuppressive drugs [ ] . a temporal link between sle and hbv vaccination is the only relation that has been demonstrated [ ] . several studies have demonstrated an increased prevalence of hpv in individuals with lupus compared to the general population, which has increased awareness for the need to vaccinate this high-risk population [ ] . to do so, the association between immunization with hpv vaccines and sle like symptoms, as well as the higher incidence of flares in known lupus patients must be taken into account. vasculitis is the name given to a group of autoimmune mediated diseases, which involve blood vessels of different types and sizes. they can be categorized according to several disease features indluding: the type of vessel affected, organ distribution, genetic predisposition and clinical manifestation [ ] . so far, cases of large vessel vasculitis have been detected. this includes cases of giant cell arteritis (gca) following influenza vaccination, cases of takayasu disease (td), and one case of large cell arteritis involving subclavian and renal arteries following hbv vaccines. two of these patients had previous received the diagnosis of ankylosing spondylitis and polymyalgia rheumatica (pmr)-like illness [ ] . one case of polyarteritis nodosa (pan) following the administration of tetanus and bcg vaccine is described. all other cases of pan in adults follow the administration of hbv vaccine [ ] [ ] [ ] . case reports of medium vessels vasculitis -both polyarteritis nodosa and kawasaki disease (kd) -have also been published in pediatric patients. kd has been described one day after the second dose of hbv vaccine and following yellow fever vaccine [ , ] . two cases of pediatric patients with pan have been reported two months after receiving the hbv vaccine [ , ] . eosinophilic granulomatosis with polyangiitis (egpa) after tetanus vaccination [ ] and following hbv vaccine [ ] have been reported. there are also cases of microscopic polyangiitis (mpa) and cases of granulomatosis with polyangiitis (gpa) following influenza vaccines in the literature [ , ] . henoch schönlein purpura (hsp) is the most common vasculitis of childhood. it is generally benign and self-limited. it is mediated by iga immune complex deposition in various tissues as well as in small-sized blood vessels. genetic risk factors play an important role in the pathogenesis of the disease: it is associated with hla-drb* , and . hsp was associated with seasonal influenza, influenza a (h n ), pneumococcal and meningococcal disease, hepatitis a virus (hav), hbv, anti-human papilloma virus (hpv) vaccines, and following multiple combinations of vaccines, such as typhoid, cholera and yellow fever [ , [ ] [ ] [ ] . leukocytoclastic vasculitis has been associated with several vaccines, including influenza vaccine [ ] , hav vaccine [ ] , hbv vaccine [ ] , pneumococcal vaccine [ ] , varicella [ ] , rubella, smallpox [ ] and the anthrax vaccine [ ] . dermal vasculitis with pan uveitis has also been described following mmr vaccine [ ] . ra is the most prevalent chronic inflammatory arthritis affecting the synovial membrane of multiple diarthrodial joints. although its etiology has not been completely clarified, deregulation of the immune system is evident with a preponderance of inflammatory cytokines and immune cells within the joints. ra has an estimated heritability of %, leaving a substantial proportion of risk to environmental factors. immunizations have previously been proposed as potential environmental triggers for ra. in the norfolk arthritis register database, of the first patients reported receiving a tetanus vaccination within weeks prior to the onset of arthritis. similarly, a transient rise in rf titer was recorded in out of military recruits - weeks after receiving concomitant immunization against tetanus, typhoid, paratyphoid, mumps, diphtheria, polio and smallpox. however, only showed a persistent elevation in titer and none developed arthritis [ ] . several mechanisms have been proposed to explain the putative association between vaccination and the initiation of ra, the most prominent of which are molecular mimicry and non-specific immune system activation [ ] . vaccines who have been associated with ra include rubella vaccine in which reactive arthritis occurs in % of recipients. controlled studies failed to show persistent arthritis or arthralgia in these patients [ ] . patients following hbv vaccine showed an increase of arthritis in a vaers study, but this was not seen in a large retrospective epidemiological study [ ] . data so far suggest that vaccines carry an insignificant role in the pathogenesis of ra. several mechanisms are being studied to produce vaccines mainly targeting inflammatory cytokines as "antigens" such as tnf, aiming to induce high titers of endogenous neutralizing anticytokine antibodies with the goal of breaking natural th tolerance to auto antigens. other cytokines, namely il- il- , mif, rantes, il- , mcp- are also being tested [ ] . another vaccine related therapy uses autologous t cell lines to induce a specific immune response by the host's t cells directed against the autoimmune (vaccine) t cells [ ] . this strategy has been successful in mouse models and has shown encouraging results in a small pilot study of ra patients, where patients showed a clinical response, defined by acr improvement criteria [ ] . uctd is a clinical condition characterized by signs, symptoms and laboratory tests suggestive of a systemic autoimmune disease but that does not fulfill the criteria for any defined connective tissue disease (ctd). such patients with clinical manifestations suggestive of systemic connective tissue disease but not fulfilling any existing criteria are quite frequent: - % of the patients initially asking for a rheumatologic evaluation may at least temporarily be diagnosed as affected by 'undefined' or 'undifferentiated' connective tissue disease. comparing studies on these diseases is unfeasible because of the inexistence of defined criteria for diagnosis [ ] . within years of follow-up, patients usually evolve to defined ctds, which include sle, systemic sclerosis (ssc), primary sjögren's syndrome (pss), mixed connective tissue disease (mctd), systemic vasculitis, poly-dermatomyositis (pm/dm) and ra. maintaining an undefined profile for years makes evolving into ctds less probable and the diagnosis of "stable uctd" reliable [ ] . disease etiology is a concern and it has been associated with vitamin d deficiency and silicone implants, both of which lead to an imbalance in proinflammatory and anti-inflammatory cytokines [ ] . vaccines have also been associated with this disease, namely the hbv vaccine [ ] . etiopathogenesis of uctd is unknown and it has been suggested it might fall on asia spectrum since symptomatic similarities are striking and uctd etiopathogenesis has been associated with adjuvants [ ] . aa is an autoimmune disease, characterized by one or more well demarcated oval and round non-cicatricial patches of hair loss. the disease may affect any hair bearing part of the body and has a great impact on a patient's self-esteem and quality of life. depending on ethnicity and location, aa is the most prevalent skin disease. aa prevalence varies and is estimated to be between . - . % in the united states and . % in singapore [ , ] . as with any other autoimmune disease, the development of aa encompasses genetic and environmental factors. environmental factors associated with aa development are emotional and/or physical stress, infections and vaccines [ ] . secondary syphilis is one of the most well studied examples, however epstein barr virus [ ] and herpes zoster [ ] infections have also been related to the development of the disease. as far as vaccines go, hbv vaccine has been associated with aa development. in one study of patients, developed aa after vaccination with hbv vaccine. of those patients, were rechallenged, and the reappearance of disease was witnessed [ ] . in mice this association failed to be established [ ] . one case of aa was witnessed following tetanus toxoid, as well as two case reports following hpv and mmr vaccine [ ] [ ] [ ] . itp is an autoimmune disease defined by a platelet count of less than platelets/l without overlapping diseases. it can present with or without anti-platelet-antibodies. thrombocytopenia is relatively common and the overall probability of developing itp was , % in a cohort of patients. it was also found that % of patients developed an overlapping aid other than itp [ ] . the etiology of the disease is yet to be fully understood but it has been detected following infectious diseases, such as helicobacter pylori, hepatitis c virus (hcv), novel influenza a infection, rotavirus infection and human immunodeficiency virus (hiv) [ ] . itp onset has also been reported, although rarely, as a severe adverse event following vaccine administration. this was more often observed after measles-mumps-rubella (mmr), hepatitis a and b, diphtheria-tetanus-acellular pertussis (dtap), and varicella vaccinations [ ] . molecular mimicry has been suggested as a possible mechanism for the development of itp, namely following helicobacter pylori infection. its eradication has been shown to increase platelet count and diminish the levels of anti-caga antibody in a subset of h. pylori infected subjects with itp [ ] . these data point towards a beneficial role of h. pylori eradication in chronic itp. two cases of itp following anti-rabies vaccine have been reported and one after hpv vaccine. reactivation of itp was reported two weeks after a tick-borne encephalitis vaccination [ ] . the most consistent association with itp is with the mmr vaccine [ ] . however, it should be emphasized that the number of cases are fewer than expected without vaccination. t d is due to antigen specific reactions against insulin producing beta cells of the pancreas. much like other autoimmune diseases, t d results from a combination of genetic, environmental, hormonal and immunological factors. environmental factors such as pathogens, diet, toxins, stress and vaccines are believed to be involved in the beginning of the autoimmune process [ ] . although the mechanisms by which viral infections cause autoimmune diabetes have not been fully clarified, there is some evidence to suggest a role for natural infections in the pathogenesis of t d mellitus in susceptible individuals [ ] . it has been hypothesized that vaccination could trigger t d in susceptible individuals. although post-vaccination t d may be biologically plausible, cumulative evidence has not supported an increased risk of t d following any vaccine [ ] . several experimental data have suggested that, depending on the timing, vaccination might exert a protecting or aggravating effect on the occurrence of diabetes [ ] . a study suggests that haemophillus influenza type b vaccine might be a risk factor in the induction of islet cell and anti-gad antibodies measured at one year of age [ ] but there are previous studies that show no association between hib and t d [ ] . in a cohort of american military officers diagnosed with t d, there was no association found between vaccination and t d diagnosis [ ] . available data about a relation between the mumps vaccine and t d are still incomplete and their interpretation is difficult because of miscellaneous confounding factors associated with the development of t d [ ] . association between hemagglutinin neuraminidase (h n ) vaccines and t d is so far unproven [ ] . in humans, it has been hypothesized that early-age bcg vaccination is associated with the risk of t d. the few studies conducted to date provided no consistent evidence of an association. there are, however, studies showing a possible temporary boost of the immune function after vaccination [ ] . studies also show that among bcg-vaccinated children who test positive for islet autoantibodies, there is a higher cumulative risk of t d [ ] . in animal experiments it has been observed that bcg seems to have a protective effect against diabetes, however researchers have yet to translate this benefit to humans [ ] . in all, studies results do not support any strong association between vaccination and t d. narcolepsy is a sleep disorder described as excessive sleepiness with abnormal sleep pattern characterized by uncontrollable rapid eye movement (rem) events which occur at any time during the day. these event and may or may not be accompanied by a loss of muscle tone (cataplexy) [ ] . a plethora of data indicates that narcolepsy is caused by the lack of orexin (also known as hypocretin), an important neurotransmitter, which is involved in the regulation of the sleep cycle. in narcolepsy patients, a loss of orexin producing neurons in the hypothalamus and low levels of orexin in the cerebrospinal fluid (csf) has been reported [ ] . narcolepsy has been shown to have an autoimmune background. antibodies against tribbles (trib ) have been found in these patients, which may be related to the pathogenesis of disease. an experimental model of narcolepsy in mice has been made by passive transfer of total igg from narcolepsy patients into the animal's brains through intra ventricular injection [ ] . environmental factors like influenza a virus and streptococcal infections have been associated with disease onset. interestingly, fever by itself without the diagnosis of an infectious etiology was found to be a risk factor for narcolepsy [ ] . several groups have studied and found an increase in the incidence of narcolepsy diagnosis following the introduction of influenza vaccination, specifically, aso -adjuvanted pandemrix tm vaccine. this association was shown in finland especially in [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] year-olds, but also in case reports from other countries [ ] . other studies failed to find an association. the actual infection with h n has been associated with disease development in china, however no such relationship has been noted in europe [ ] . the above-mentioned associations are specifically related to the aso -adjuvanted pandemrix tm vaccine. the same association has not been reported for other h n adjuvanted or non-adjuvanted vaccines. the major difference between the aso and the mf adjuvants is the presence of the ␣-tocopherol. ␣-tocopherol is unique in that it can achieve the highest and longest antibody response by producing an enhanced antigenspecific adaptive immune response. in vitro it was shown that ␣-tocopherol could increase the production of orexin as well as increase the proteosome activity. this increased production of orexin fragments may facilitate antigen presentation to mhc class ii, thus triggering an autoimmune process [ ] . all these data together support the relationship between the h n pandemrix tm vaccine and the development of narcolepsy. gluten induced enteropathy, gluten sensitive enteropathy, or more commonly called celiac disease (cd) is a life-long autoimmune condition mainly of the gastrointestinal tract, specifically affecting the small intestine. the abnormal immune response crates autoantigens which are directed towards tissue transglutaminase (ttg). the two main autoantibodies and the most widespread serological markers to screen for the disease are anti ttg and anti endomysium. two additional auto-antibodies, namely: anti deaminated gliadin peptide and anti-neoepitope ttg were found recently to be reliable for cd screening as well [ ] . cd is an autoimmune disease induced by well-known nutritional environmental factors. the non-dietary ones are less studied and established. several infectious disease have been linked to its development, the so-called infectome [ ] . a clear cause-effect relation is yet to be established for most of the pathogens associated with cd. what has been shown, however, is that in countries with low economic status, inferior hygiene conditions and higher infectious load, cd prevalence is lower [ ] . an epidemiologic relationship was established in between rotavirus infection and cd. data showed that in genetically predisposed individuals, rotavirus infection was related to childhood cd development [ ] . in subsequent research studies, a celiac peptide was recognized and proved to share homology with rotavirus major neutralizing protein vp and with the cd autoantigen ttg. the antibodies directed against the viral protein vp were shown to predict the onset of cd and induce typical features of cd in the intestinal epithelial cell-line t [ ] . it has also been suggested that rotavirus vaccine alters b and t behavior, as the percentage of b-cells was higher in the vaccinated infants [ ] . rotavirus vaccine as an inducer of cd is still in discussion and warrants further study. pmr is an autoimmune inflammatory rheumatic disease characterized by raised inflammatory markers with pain and morning stiffness of shoulders and pelvic girdles and synovitis of proximal joints and extra-articular synovial structures. its diagnosis is clinical and it is typically a disease of the elderly occurring mainly in subjects above . etiopathogenesis of pmr remains unknown, but genetic and environmental factors play a role [ ] . a close temporal relationship has been ascertained concerning epidemics of mycoplasma pneumoniae, chlamydia pneumonia, parvovirus b and peaks of cases of pmr and giant cell arteritis, however this is not clearly proven [ ] . cases of pmr following vaccination have rarely been reported. however, it is believed that post vaccination pmr may be underreported due to its symptomatic similarities with the transient effects of vaccines, namely: arthralgia, myalgia and low-grade fever. this leads to failure in establishing a chronological relationship when the disease is diagnosed. most of the reported cases are associated with seasonal influenza vaccine (inf-v). often, the time interval between vaccine administration and symptoms onset varies from one day, to three months. three cases were reported with associated giant cell arthritis. a case report of relapsing pmr after four years of remission following tetanus vaccination has also been reported [ , ] . acute disseminated encephalomyelitis (adem) is an inflammatory demyelinating disease of the central nervous system (cns). adem is usually poly-symptomatic with encephalopathy (i.e., behavioral change or altered level of consciousness). it affects mostly children and young adults and has higher prevalence in males. its incidence is . - . per per year [ ] . although there is no concrete evidence of a clear pathogenic association, adem has been associated with immunization or previous viral infection. post-vaccination adem accounts for only - percent of all cases, while post-infectious adem accounts for percent of all cases of adem [ ] . the hypothesis that better describes these associations is molecular mimicry. t-cells targeting human herpesvirus- (hhv- ), coronavirus, influenza virus and epstein-barr virus (ebv) have been shown to cross-react with myelin basic protein (mbp) antigens. anti-mbp t-cells were detected in patients following vaccination with simple rabies vaccine [ ] [ ] [ ] . in a post experimental therapy for alzheimer's disease with a vaccine that contained aggregates of synthetic a␤ fragments of amyloid precursor protein, adem was shown to develop in mice [ ] . the experimental model of ms, eae mice, may be induced with injection of a␤ , but only when the latter is administered together with the complete freund's adjuvant [ ] . this observation points to the importance and central role of the adjuvants in induction of adem and autoimmunity in general [ ] . the overall incidence of post vaccination adem is estimated to be . - . per and a higher risk has been reported following immunization against measles. other vaccines accountable for post-vaccination adem include vaccines against the varicella zoster, the rubella, the smallpox and the influenza viruses [ ] . surprisingly, certain vaccines such as anti-tetanus vaccine were shown to have a negative correlation with adem (statistically significant decreased risk) [ ] . hbv immunization has been studied as a possible cause for adem but was later associated with clinically isolated syndrome (cis) (a first time occurring demyelinating episode that may, or not develop to ms) and complete conversion to ms [ ] . as far as case reports are concerned, adem was associated with vaccination with influenza, hepatitis a and b, mmr, hpv and tetanus [ , , ] . bullous dermatoses are characterized by the presence of blisters and autoantibodies against structural components of the skin: desmosomal proteins (in pemphigus), adhesion molecules of the dermal-epidermal junction (in pemphigoid diseases), and epidermal/ tissue transglutaminase (in dermatitis herpetiformis). the most frequent autoimmune bullous diseases are bullous pemphigoid (bp) and pemphigus vulgaris (pv). bp is more frequently observed in the elderly, while the age of onset of pv is between and years. neither of the diseases have any gender preference [ ] . bp and pv etiology is, so far, poorly understood. both diseases have been associated with various environmental factors, which include emotional and/or physical stress, infections and vaccinations [ ] . genetic predisposition has also been studied with overexpression of certain hla class ii alleles. these include hla-dqb * , drb * , drb * , and dqb * . these alleles have been found to be more prevalent in bp patients than in the general population [ ] . pv is associated with certain hla class ii loci such as hla-dr and hladr alleles (drb * and drb * , which is prevalent in ashkenazi jews, iranian and sardinian patients). other loci include drb * (common among japanese and italian patients) and two dqb alleles (dqb * and dqb * ), which are strongly associated with pv. bp and pv patients' sera were found to have significantly higher prevalence of antibodies to hepatitis b virus, hepatitis c virus, helicobacter pylori, toxoplasma gondii and cytomegalovirus [ ] . as far as vaccination is concerned, bp developed in patients following influenza, diphtheria, tetanus, pertussis, hepatitis b, bcg, polio and herpes zoster vaccines [ , , ] furthermore, reactivation of bp following influenza vaccination was reported in one case report [ ] . new onset pv was associated with: influenza vaccine, hepatitis b vaccine, anthrax vaccine, typhoid booster and rabies vaccination. in addition, exacerbation of pv after vaccination was also reported following influenza vaccine and tetanus vaccine [ ] . iim compose a group of skeletal muscles diseases in which myositis without a recognized cause occurs. iim is usually subdivided in entities: dermatomyositis (dm), polymyositis (pm), inclusion body myositis (sibm) non-specific myositis (nsm) and immune mediated necrotizing myopathy (iam) [ ] . iim prevalence is around . × − cases, with a bimodal age of distribution that peaks in childhood and again between and years. dm is the most common inflammatory myopathy while pm is the least frequent. despite exhibiting similar clinical symptoms, the subsets of iim exhibit significant immunopathological variation. dm begins with the activation of the complement and formation of membrane attack complexes (mac). in pm and sibm the fundamental process is related to cd + t cells mediated cytotoxicity [ ] . it is unclear what breaks the tolerance and drives the immune response to induce iim. so far, dm, pm and sibm have been linked to vaccination. several cases have been reported in the literature associating different vaccines with the development of idiopathic inflammatory myopathies. cases of iim had been reported to vaers database up to june . out of these cases, were classified as pm, as dm and an only one as a sibm. dm has been reported after almost any vaccine, however only a few studies have attempted to clarify the possible relationship between dm and vaccination. pm is a frequent misdiagnosed disorder. some reports have associated previous immunization, especially hepatitis b vaccine with pm [ ] . despite being recently differentiated from other iim, sibm has already been related to hbv vaccine [ ] . some vaccines associated with myositis are mmr vaccine, smallpox vac-cine, poliomyelitis (ipv), diphtheria and tetanus toxoid, influenza, hpv and bcg [ ] . fms is an entity that is related to the inability of the cns to modulate pain. the conditioned pain modulation process in the cns appears to be compromised among many fms patients, which might explain the enhanced pain sensation experienced by these patients [ ] . the etiology of fms is yet to be unveiled. genetic predisposition, physical trauma (particularly to the cervical spine), emotional stress (to various stressors) as well as a variety of infections have been linked with fms. vaccines have been associated with the triggering of fms namely rubella and lyme disease vaccines [ ] . there are several reports of fibromyalgia-like disease after vaccination, specifically hpv (martinez-lavin journal of clinical rheumatology ). the medical community and regulatory agencies should be aware of these possible adverse effects aiming at defining their magnitude. chronic fatigue syndrome (cfs) is a disease characterized by disabling fatigue, headaches, concentration difficulties and memory deficits ( %). other symptoms such as sore throat ( %), tender lymph nodes ( %), skeletal muscle pain and feverishness ( %), sleep disruption ( %), psychiatric problems ( %) and rapid pulse ( %) are often observed. it more frequently affects women and has a prevalence of . - . % [ ] . although disease etiology is still unknown, there are several pathogens, such as epstein-barr virus (ebv), which have been associated with cfs. patients often have higher titers of igm to the ebv viral capsid antigen. cytomegalovirus and human herpes virus antibodies were also detected more often in cfs patients, although other reports failed to replicate these results. parvovirus b infection has also been suggested as a trigger to cfs [ ] [ ] [ ] . vaccine inoculation has also been appointed as a probable cause. vaccinations against rubella, q fever and hepatitis b were found to be associated with higher risk of developing cfs while meningococcal vaccine, poliovirus and influenza vaccine were not. surprisingly, staphylococcus toxoid vaccine appeared to have a protective effect [ , , ] . defined in by shoenfeld and agmon-levin asia syndrome is characterized by hyperactive immune response to adjuvants [ ] . as previously stated, asia incorporates four known medical conditions: siliconosis, gws, mmf, and post-vaccination phenomena [ ] . recently, the sick building syndrome (sbs) was proposed as a candidate for the asia spectrum [ ] . all of these diseases satisfy several criteria for fms and seid [ ] . a macrophagic myofasciitis (mmf) mmf has been described as an emerging condition of unknown cause characterized by a pathognomonic lesion in muscle biopsy mixing large macrophages with submicron to micron-sized agglomerates of nanocrystals in their cytoplasm and lymphocytic infiltrates. these lesions were related to aluminum deposits in muscle following immunization with aluminum containing vaccines [ ] . mmf lesion is now universally recognized as indicative of a long-lasting persistence of aluminum adjuvant at the site of prior intramuscular immunization. the long-lasting mmf lesion should be considered as a biomarker of aluminum bio persistence in a given individual. patients with mmf have higher reported myalgia with incidence being up to %. its etiology is not clear but genuine muscle weakness is rare and the diagnosis of fibromyalgia is also rare. higher prevalence of chronic fatigue syndrome (cfs) in patients with mmf has been reported as well. cognitive impairment has been associated with mmf: in one series of mmf patients, up to % had attention and memory complaints and neuropsychological tests were abnormal in % [ ] . b gulf war syndrome (gws) gws is a clinical entity specifically related to a certain time and place in history. it was described among veterans of the military conflict occurring in - in the persian gulf. the syndrome is characterized by chronic fatigue, musculoskeletal symptoms, malaise and cognitive impairment. it clinically overlaps with post traumatic stress disorder (ptsd), fms, cfs and other functional disorders [ ] . the unique conditions that have been associated so far with disease development are the exposure to extreme climate in the persian gulf, exposure to various chemicals (pesticides, depleted uranium), stress provoked by prolonged waiting without actual combat and the intense exposure to vaccinations of the soldiers for fear of biological weaponry [ ] . comparing gulf war veterans and veterans of the bosnian conflict, multiple vaccinations administered to servicemen in the gulf war was identified as a unique exposure [ ] . the mechanism through which vaccination exposure may lead to the development of functional symptoms is not completely understood. the possibility that a shift from th to th type reactions could be of pathogenic significance was raised and is supported by an increased frequency of allergic reactions, low natural killer cell activity and low levels of interferon ␥ and il- in these patients [ ] . one study with gws patients showed a connection between anti-squalene antibodies and symptoms development. this was refuted by a larger study that found no association between antisqualene antibodies and chronic multi-symptom illness [ ] . c asia registry a registry is a collection of data related to patients with the same specific characteristic. it is often the first approach in the study of an area of inquiry. in rare diseases, registries are often the way to get a sufficiently sized sample of patients which can be used either for epidemiological or research purposes. asia syndrome may be underreported because of unawareness and failure to connect the syndrome with the exposure. this registry was created to fully understand the clinical aspects of disease and compare patients from all over the world in order to have fully validated criteria for disease diagnosis and also to define demographic and environmental history of disease. the asia syndrome registry website can be found on the following link: https://ontocrf.costisa.com/en/web/asia. only cases reported by physicians are accepted. to make an informed decision in medicine, there is always a need to weigh the pros and cons. ards may play an important role in deciding whether vaccination is or is not appropriate to a patient. in these cases, patients are immunosuppressed on account of their diagnosis and even more so if they are under specific immunomodelatory medication [ ] . if the efficacy of vaccination is reduced, there is a potential for development of disease flares following vaccination. in the case of live vaccines, its inoculation may even be enough to trigger disease in the host. for these specific reasons, live vaccines are generally contraindicated in patients receiving immunosuppressant medication. there is a need for screening and treatment of latent tuberculosis infection (ltbi) before starting anti-tnf-alpha therapy. the same is true for vaccination. preferably, even recommended vaccination (see table ) should be administered before the initiation of disease-modifying anti-rheumatic drugs (dmards) because these may reduce vaccine efficacy [ ] . immunosuppression equals high risk of infection and lower vaccine efficacy. taking into account safety concerns and efficacy, the eular recommendations for immunizations in aiird patients are: • assess vaccination status in initial investigation. • administer vaccines in a stable disease phase. • live attenuated vaccines are to be avoided especially if immunosuppressive agents are being administered. bcg is not recommended. • administer vaccines ideally before starting dmards and anti-tnf␣ agents. • influenza and -valent polysaccharide pneumococcal vaccination is recommended. • tetanus toxoid vaccination is recommended following recommendations of general population, in case of major and/or contaminated wounds in patients receiving rituximab in the previous weeks tetanus ig is indicated. • hpv and herpes zoster should be considered. • in hyposplenic/asplenic patients, influenza, pneumococcal, haemophilus influenza b and meningococcal c are advisable. • hepatitis a and b is recommended in patients at risk. • travel patients should be immunized according to general population guidelines except for live attenuated vaccines, which are to be avoided [ ] . vaccines have many beneficial effects in combating infectious diseases and preventing mortality and morbidity. they have also proved to be effective cancer treatments by immunomodulation, as demonstrated by the intravesical administration of bcg to treat superficial bladder cancer [ ] . vaccines are however, linked to autoimmunity. beneficial outcomes, like the adjuvant effect are based on immunity triggering and enhanced immunity mechanisms. these same responses account for autoimmunity exertion. vaccines induce the production of autoantibodies, but their pathologic effect is yet to be unveiled. although vaccines are widely considered safe, there are subjects with predispositions to whom vaccines pose a bigger threat. an example is the fact that animal models with autoimmune predispositions develop autoimmune disease following adjuvant exposure. as many as % of recipients of aluminum containing adjuvants may be sensitized to future exposure [ ] . silicon-induced inflammatory fibro proliferative response is irrefutable and well documented. the presence of anti-silicone antibodies and silicone-associated autoimmune phenomena seems very plausible. asia syndrome and aluminum safety studies show that the use of aluminum containing "placebo" in control groups in vaccine safety studies should be carefully evaluated. new studies must be performed using a proper placebo to adequately test vaccine safety. another evident failure in vaccine safety studies are the short-term periods which are evaluated. continued immune system activation has been observed to be a potential mechanism of disease. a disease which is poorly understood so far. vaccine recommendations should be reassessed frequently in different subsets of the population. this does not invalidate the need for vaccines, however, the lower the possibility of exerting adverse events, the easier it will be for the potential benefits to outweigh the risks. vaccinomics represents a major breakthrough in vaccine development and can lead to the development of targeted vaccines to peptides most likely to be immunogenic [ ] . a predictable response to vaccine can be achieved by differentiating the host variability. this can be achieved namely in genetics and pathogen variability. developing a vaccine accordingly will lead to increased specificity in treatment and leave less room for adverse events. by using immunomodulation, vaccinomics can also give rise to novel therapies for autoimmune diseases. there are several reports of cases of autoimmunity diseases following vaccines but despite in vitro positive results and due to both the limited number of cases and the long latency period of the diseases, every attempt for an epidemiological study has failed to deliver a connection. classification as asia syndrome, in detriment of classic specific autoimmune diseases, could be the key to finding effective preventative therapeutic strategies. it will enable the study of bigger patient clusters with earlier diagnoses. future studies that could help clarify the association between vaccinations, adjuvants and autoimmunity should ideally have a different design, more long-term data and should include autoimmune phenomena as well as large-scale epidemiological studies of autoimmune diseases. the mosaic of autoimmunity infections and autoimmunity-friends or foes? autoimmune/inflammatory syndrome induced by adjuvants (asia) : unveiling the pathogenic, clinical and diagnostic aspects asia-autoimmune/inflammatory syndrome induced by adjuvants adjuvants and autoimmunity adjuvant activity of immunopotentiating reconstituted influenza virosomes (irivs) interfaces questions and possibilities in toll-like receptor signalling immunotherapy with a ragweed-toll-like receptor agonist vaccine for allergic rhinitis immunotherapeutic strategies for the treatment of malignant melanoma does pegylated interferon alpha- b confer additional benefit in the adjuvant treatment of high-risk melanoma? tuftsin on the -year anniversary of victor najjar's discovery tuftsin a naturally occurring immunopotentiating factor. i. in vitro enhancement of murine natural cell-mediated cytotoxicity tuftsin and tuftsin conjugates potentiate immunogenic processes: effects and possible mechanisms the novel adjuvant ic strongly improves influenza vaccine-specific cellular and humoral immune responses in young adult and aged mice improving vaccine delivery using novel adjuvant systems prototype alzheimer's disease epitope vaccine induced strong th -type anti-abeta antibody response with alum to quil a adjuvant switch cpg oligodeoxynucleotides trigger protective and curative th responses in lethal murine leishmaniasis tuftsin-azt conjugate: potential macrophage targeting for aids therapy enhanced immune response induced by a potential influenza a vaccine based on branched m e polypeptides linked to tuftsin construction of a synthetic immunogen: use of the natural immunomodulator polytuftsin in malaria vaccines against resa antigen of plasmodium falciparum stimulating effect of tuftsin and its analogues on the defective monocyte chemotaxis in systemic lupus erythematosus immunological concepts of vaccine adjuvant activity recent advances in the discovery and delivery of vaccine adjuvants using eae to better understand principles of immune function and autoimmune pathology toll pathway-dependent blockade of cd + cd + t cell-mediated suppression by dendritic cells viruses as adjuvants for autoimmunity: evidence from coxsackievirus-induced myocarditis pathogenesis of myocarditis and dilated cardiomyopathy bacillus calmette-guerin immunotherapy of superficial bladder cancer pattern recognition receptors and control of adaptive immunity how dying cells alert the immune system to danger role of protease-activated receptors in inflammatory responses, innate and adaptive immunity novel signaling interactions between proteinase-activated receptor and toll-like receptors in vitro and in vivo autoimmune (auto-inflammatory) syndrome induced by adjuvants (asia)-animal models as a proof of concept the endogenous adjuvant squalene can induce a chronic t-cell-mediated arthritis in rats percutaneous exposure of adjuvant oil causes arthritis in da rats exacerbation of collagen-induced arthritis in rats by rat cytomegalovirus is antigen-specific comparative study of adjuvant induced arthritis in susceptible and resistant strains of rats. i. effect of cyclophosphamide aloh -adjuvanted vaccine-induced macrophagic myofasciitis in rats is influenced by the genetic background induction of plasma cell tumours in balb-c mice with , , , -tetramethylpentadecane (pristane) paraffin oil injection in the body: an obsolete and destructive procedure induction of lupus autoantibodies by adjuvants adjuvant immunization induces high levels of pathogenic antiphospholipid antibodies in genetically prone mice: another facet of the asia syndrome induction of the asia syndrome in nzb/nzwf mice after injection of complete freund's adjuvant (cfa) manifestations of systemic autoimmunity in vaccinated salmon comparison of three adjuvants used to produce polyclonal antibodies to veterinary drugs comparison of tissue reactions produced by haemophilus pleuropneumoniae vaccines made with six different adjuvants in swine delayed acquisition of neonatal reflexes in newborn primates receiving a thimerosal-containing hepatitis b vaccine: influence of gestational age and birth weight autoimmune/autoinflammatory syndrome induced by adjuvants (asia syndrome) in commercial sheep slow ccl -dependent translocation of biopersistent particles from muscle to brain aluminum hydroxide injections lead to motor deficits and motor neuron degeneration nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture the pro-oxidant activity of aluminum regulatory role of zinc during aluminium-induced altered carbohydrate metabolism in rat brain aluminum and alzheimer's disease: after a century of controversy, is there a plausible link? exposure to aluminium and the subsequent development of a disorder with features of alzheimer's disease elevated urinary excretion of aluminium and iron in multiple sclerosis aluminum-induced entropy in biological systems: implications for neurological disease the immunobiology of aluminium adjuvants: how do they really work? fatty acid-induced nlrp -asc inflammasome activation interferes with insulin signaling inflammasome signaling at the heart of central nervous system pathology summary and conclusions of the sixty-seventh meeting of the joint fao/who expert committee on food additives if exposure to aluminium in antiperspirants presents health risks, its content should be reduced macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle structural basis of metal hypersensitivity diagnosis and treatment of metal-induced side-effects mercury and multiple sclerosis the beneficial effect of amalgam replacement on health in patients with autoimmunity metal-induced inflammation triggers fibromyalgia in metal-allergic patients the role of environmental factors in autoimmune thyroiditis orofacial granulomatosis associated with hypersensitivity to dental amalgam, oral surg nephrotic syndrome due to ammoniated mercury endemic clustering of multiple sclerosis in time and place mercury exposure and antinuclear antibodies among females of reproductive age in the united states: nhanes, environ. health perspect gold nephropathy: serologic data suggesting an immune complex disease nickel-induced allergy and contact dermatitis: does it induce autoimmunity and cutaneous sclerosis? an experimental study in brown norway rats aluminum in the central nervous system (cns): toxicity in humans and animals, vaccine adjuvants, and autoimmunity six revolutions in vaccinology from pasteur to genomics: progress and challenges in infectious diseases systems vaccinology vaccinomics, adversomics, and the immune response network theory: individualized vaccinology in the st century studies of twins in vaccinology vaccinomics current findings, challenges and novel approaches for vaccine development the hla genomic loci map: expression, interaction, diversity and disease the link between genetic variation and variability in vaccine responses: systematic review and meta-analyses development of polyarthritis after insertion of silicone breast implants followed by remission after implant removal in hla-identical sisters bearing rheumatoid arthritis susceptibility genes autoimmune/auto-inflammatory syndrome induced by adjuvants (asia) after quadrivalent human papillomavirus vaccination in colombians: a call for personalised medicine anticardiolipin and anti-beta( ) glycoprotein i antibodies in sera of apparently healthy children at regular preventive visits autoimmunity and hepatitis a vaccine in children bacterial induction of autoantibodies to beta -glycoprotein-i accounts for the infectious etiology of antiphospholipid syndrome vaccination-induced systemic autoimmunity in farmed atlantic salmon autoimmune response following annual influenza vaccination in apparently healthy adults high non-specific t lymphocyte response to the adjuvanted h n vaccine in comparison with the h n /h n /b-brisbane vaccine without adjuvant short and long-term effects of pandemic unadjuvanted influenza a(h n ) pdm vaccine on clinical manifestations and autoantibody profile in primary sjögren's syndrome pneumococcal vaccination of patients with systemic lupus erythematosus: effects on generation of autoantibodies immunogenicity and safety of a quadrivalent human papillomavirus vaccine in patients with systemic lupus erythematosus: a case-control study safety and immunogenicity of the quadrivalent hpv vaccine in female systemic lupus erythematosus patients aged to years anti-phospholipid antibodies following vaccination with recombinant hepatitis b vaccine development of autoantibodies before the clinical onset of systemic lupus erythematosus genetics and autoantibodies silicone and autoimmunity platinum in the environment: frequency of reactions to platinum-group elements in patients with dermatitis and urticaria silicone and scleroderma revisited rupture of silicone gel breast implants and symptoms of pain and fatigue the association between silicone implants and both antibodies and autoimmune diseases a comparison of autoantibody production in asymptomatic and symptomatic women with silicone breast implants silicone implant incompatibility syndrome (siis): a frequent cause of asia (shoenfeld's syndrome) management of chronic childhood immune thrombocytopenic purpura: aieop consensus guidelines rubella-associated arthritis. i. comparative study of joint manifestations associated with natural rubella infection and ra / rubella immunisation risk of chronic arthropathy among women after rubella vaccination. vaccine safety datalink team efficacy and duration of immunity after yellow fever vaccination: systematic review on the need for a booster every years risk of yellow fever vaccine-associated viscerotropic disease among the elderly: a systematic review bacillus calmette-guérin immunotherapy for genitourinary cancer arthritis after bcg vaccine in a healthy woman dermatomyositis after b.c.g. vaccination aetiopathogenesis of takayas's arteritis and bcg vaccination: the missing link? reactive arthritis induced by intravesical bcg therapy for bladder cancer: our clinical experience and systematic review of the literature systemic granulomatosis and hypercalcaemia following intravesical bacillus calmette-guérin immunotherapy universal hepatitis b vaccination in taiwan and the incidence of hepatocellular carcinoma in children. taiwan childhood hepatoma study group vaccines and autoimmunity hepatitis b vaccination and undifferentiated connective tissue disease: another brick in the wall of the autoimmune/inflammatory syndrome induced by adjuvants (asia) adverse reactions to human papillomavirus (hpv) vaccines sustained efficacy and immunogenicity of the hpv- / as -adjuvanted vaccine up to . years in young adult women detection of human papillomavirus l gene dna fragments in postmortem blood and spleen after gardasilreg. vaccination-a case report human papillomavirus (hpv) vaccine policy and evidence-based medicine: are they at odds? annual report: surveillance of adverse events following immunisation in australia annual report: surveillance of adverse events following immunisation in australia influenza vaccine and autoimmunity infection and death from influenza a h n virus in mexico: a retrospective analysis altered response to a(h n ) pnd vaccination in pregnant women: a single blinded randomized controlled trial adverse events following immunization with vaccines containing adjuvants antineutrophil cytoplasmic antibody vasculitis associated with influenza vaccination hughes syndrome) met the autoimmune/inflammatory syndrome induced by adjuvants (asia) meningococcal group b vaccines comparative long-term adverse effects elicited by invasive group b and c meningococcal infections immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups a, c, w- , and y tetanus toxoid conjugate vaccine in adolescents and adults: results of an open, randomised, controlled study vaccines and guillain-barré syndrome henoch-schölein purpura and polysaccharide meningococcal vaccine infantile bullous pemphigoid developing after hexavalent, meningococcal and pneumococcal vaccinations the risk of sequelae due to pneumococcal meningitis in high-income countries: a systematic review and meta-analysis burden of disease caused by streptococcus pneumoniae in children younger than years: global estimates fda. pneumococcal -valent conjugate vaccine (diphtheria crm protein) prevnar ® decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine comparative reactogenicity and immunogenicity of valent pneumococcal vaccine administered by intramuscular or subcutaneous injection in elderly adults safety and immunogenicity of a -valent pneumococcal conjugate vaccine pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy eular recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases tetanus a review of the literature optic neuritis and myelitis after booster tetanus toxoid vaccination antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of patients crystal structure of human beta -glycoprotein i: implications for phospholipid binding and the antiphospholipid syndrome induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies characterization of antiphospholipid antibodies in chronic hepatitis b infection influenza vaccination and the production of anti-phospholipid antibodies in patients with systemic lupus erythematosus unraveling the soul of autoimmune diseases: pathogenesis, diagnosis and treatment adding dowels to the puzzle vaccines and autoimmune diseases of the adult effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the bliss- trial ten cases of systemic lupus erythematosus related to hepatitis b vaccine prevalence of cervical human papillomavirus infection in women with systemic lupus erythematosus revised international chapel hill consensus conference nomenclature of vasculitides large artery vasculitis following recombinant hepatitis b vaccination: cases etiology and precipitating factors of necrotizing angiitis with respiratory manifestations. case reports cutaneous polyarteritis nodosa in a child following hepatitis b vaccination systemic polyarteritis nodosa following hepatitis b vaccination kawasaki disease in an infant following immunisation with hepatitis b vaccine yellow fever vaccination and kawasaki disease churg-strauss vasculitis with brain involvement following hepatitis b vaccination anca-associated vasculitis following influenza vaccination: causal association or mere coincidence? influenza vaccination in anca-associated vasculitis henoch-schönlein purpura after hepatitis a vaccination henoch-schönlein purpura following influenza a h n vaccination henoch-schönlein purpura following influenza vaccinations during the pandemic of influenza a (h n ) leukocytoclastic vasculitis after influenza vaccination vasculitis related to hepatitis a vaccination hypersensitivity vasculitis after hepatitis b vaccination leukocytoclastic vasculitis after pneumococcal vaccination allergic reaction to varicella vaccine vasculitides associated with infections, immunization, and antimicrobial drugs lymphocytic vasculitis associated with the anthrax vaccine: case report and review of anthrax vaccination panuveitis and dermal vasculitis following mmr vaccination can immunisation trigger rheumatoid arthritis? risk of rheumatoid arthritis following vaccination with tetanus, influenza and hepatitis b vaccines among persons - years of age anti-cytokine vaccination in autoimmune diseases exploiting t. cell crosstalk as a vaccination strategy for rheumatoid arthritis vaccination with selected synovial t cells in rheumatoid arthritis undifferentiated ctd a wide spectrum of autoimmune diseases analysis of the evolution of uctd to defined ctd after a long term follow-up undifferentiated connective tissue disease after silicone-gel testicular implantation connective tissue disease following hepatitis b vaccination prevalence of alopecia areata in the first national health and nutrition examination survey tracing environmental markers of autoimmunity: introducing the infectome onset of alopecia areata after epstein-barr virus infectious mononucleosis hair loss after varicella zoster virus infection hair loss after routine immunizations recombinant human hepatitis b vaccine initiating alopecia areata: testing the hypothesis using the c h/hej mouse model alopecia universalis in an adult after routine tetanus toxoid vaccine telogen effluvium following bivalent human papillomavirus vaccine administration: a report of two cases acute-onset madarosis following mmr vaccination long-term outcome of otherwise healthy individuals with incidentally discovered borderline thrombocytopenia immune thrombocytopenic purpura (itp) associated with vaccinations: a review of reported cases epidemiology of paediatric immune thrombocytopenia in the general practice research database effect of eradication of helicobacter pylori in children with chronic immune thrombocytopenia: a prospective, controlled, multicenter study, pediatr immune thrombocytopaenic purpura: an autoimmune cross-link between infections and vaccines vaccination may be associated with autoimmune diseases viral infections and molecular mimicry in type diabetes childhood immunizations and type diabetes: summary of an institute for vaccine safety workshop. the institute for vaccine safety diabetes workshop panel stimulation of the developing immune system can prevent autoimmunity vaccinations may induce diabetes-related autoantibodies in one-year-old children lack of association between receipt of conjugate haemophilus influenzae type b vaccine (hboc) in infancy and risk of type (juvenile onset) diabetes: long term follow-up of the hboc efficacy trial cohort vaccination and risk of type diabetes mellitus in active component u. s. military difficulties in assessing the relationship, if any, between mumps vaccination and diabetes mellitus in childhood, pubmed,ncbi neurological and autoimmune disorders after vaccination against pandemic influenza a (h n ) with a monovalent adjuvanted vaccine: population based cohort study in bacille calmette-guérin vaccination and incidence of iddm in montreal, canada neonatal bacille calmette-guerin vaccination and type diabetes bacille calmette-guérin/dnahsp prime-boost is protective against diabetes in non-obese diabetic mice but not in the streptozotocin model of type diabetes narcolepsy: autoimmunity, effector t cell activation due to infection, or t cell independent, major histocompatibility complex class ii induced neuronal loss? passive transfer of narcolepsy: anti-trib autoantibody positive patient igg causes hypothalamic orexin neuron loss and sleep attacks in mice is narcolepsy a classical autoimmune disease? the pandemrix-narcolepsy tragedy: how it started and what we know today a novel algorithm for the diagnosis of celiac disease and a comprehensive review of celiac disease diagnostics infections may have a protective role in the etiopathogenesis of celiac disease rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study a subset of anti-rotavirus antibodies directed against the viral protein vp predicts the onset of celiac disease and induces typical features of the disease in the intestinal epithelial cell line t influence of early environmental factors on lymphocyte subsets and gut microbiota in infants at risk of celiac disease; the proficel study cervical human papillomavirus infection in mexican women with systemic lupus erythematosus or rheumatoid arthritis giant cell arteritis and polymyalgia rheumatica after influenza vaccination: report of cases and review of the literature postvaccine vasculitis: a report of three cases clinical study of childhood acute disseminated encephalomyelitis, multiple sclerosis, and acute transverse myelitis in fukuoka prefecture inflammatory/post-infectious encephalomyelitis high level of cross-reactivity in influenza virus hemagglutinin-specific cd + t-cell response: implications for the initiation of autoimmune response in multiple sclerosis cross-reactivity with myelin basic protein and human herpesvirus- in multiple sclerosis myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein acute/relapsing experimental autoimmune encephalomyelitis: induction of long lasting, antigen-specific tolerance by syngeneic bone marrow transplantation autoimmune/inflammatory syndrome induced by adjuvants (shoenfeld's syndrome): clinical and immunological spectrum post-vaccination encephalomyelitis: literature review and illustrative case vaccinations and risk of central nervous system demyelinating diseases in adults acute disseminated encephalomyelitis cohort study: prognostic factors for relapse neuromyelitis optica following human papillomavirus vaccination hbv vaccine and dermatomyositis: is there an association? autoimmune blistering diseases of the skin pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies does influenza vaccination induce bullous pemphigoid? a report of four cases bullous pemphigoid after herpes zoster vaccine administration: association or coincidence? reactivation of bullous pemphigoid after influenza vaccination pathophysiology of autoimmune polyneuropathies a review on the association between inflammatory myopathies and vaccination fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes etiology of fibromyalgia: the possible role of infection and vaccination infection and vaccination in chronic fatigue syndrome: myth or reality? review part : human herpesvirus- in central nervous system diseases pathogenesis of parvovirus b infection: host gene variability, and possible means and effects of virus persistence effects of staphylococcus toxoid vaccine on pain and fatigue in patients with fibromyalgia/chronic fatigue syndrome vaccination as teenagers against meningococcal disease and the risk of the chronic fatigue syndrome the sick building syndrome as a part of the autoimmune (auto-inflammatory) syndrome induced by adjuvants selective elevation of circulating ccl /mcp levels in patients with longstanding post-vaccinal macrophagic myofasciitis and asia cognitive functioning in gulf war illness health of uk servicemen who served in persian gulf war gulf war syndrome: is it due to a systemic shift in cytokine balance towards a th profile antibodies to squalene in us navy persian gulf war veterans with chronic multisymptom illness vaccination in adult patients with auto-immune inflammatory rheumatic diseases: a systematic literature review for the european league against rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheuma eular recommendations for vaccination in paediatric patients with rheumatic diseases vaccination against yellow fever among patients on immunosuppressors with diagnoses of rheumatic diseases updated consensus statement on the use of rituximab in patients with rheumatoid arthritis safety and efficacy of meningococcal c vaccination in juvenile idiopathic arthritis unexpectedly high incidence of persistent itching nodules and delayed hypersensitivity to aluminium in children after the use of adsorbed vaccines from a single manufacturer key: cord- - pggpbrq authors: doornekamp, laura; van leeuwen, leanne; van gorp, eric; voeten, helene; goeijenbier, marco title: determinants of vaccination uptake in risk populations: a comprehensive literature review date: - - journal: vaccines (basel) doi: . /vaccines sha: doc_id: cord_uid: pggpbrq vaccination uptake has decreased globally in recent years, with a subsequent rise of vaccine-preventable diseases. travellers, immunocompromised patients (icp), and healthcare workers (hcw) are groups at increased risk for (severe) infectious diseases due to their behaviour, health, or occupation, respectively. while targeted vaccination guidelines are available, vaccination uptake seems low. in this review, we give a comprehensive overview of determinants—based on the integrated change model—predicting vaccination uptake in these groups. in travellers, low perceived risk of infection and low awareness of vaccination recommendations contributed to low uptake. additionally, icp were often unaware of the recommended vaccinations. a physician’s recommendation is strongly correlated with higher uptake. furthermore, icp appeared to be mainly concerned about the risks of vaccination and fear of deterioration of their underlying disease. for hcw, perceived risk of (the severity of) infection for themselves and for their patients together with perceived benefits of vaccination contribute most to their vaccination behaviour. as the determinants that affect uptake are numerous and diverse, we argue that future studies and interventions should be based on multifactorial health behaviour models, especially for travellers and icp as only a limited number of such studies is available yet. vaccinations have proven to play a major role in the prevention and control of many infectious diseases. however, in the twenty-first century, vaccination programs face multiple challenges [ ] . the first one is the need for fast development of effective and safe vaccines for new (re-)emerging pathogens. the recent sars-cov- pandemic is an example in which a vaccination is highly desired and may reduce the enormous impact of the current pandemic. the second challenge in the field of vaccinology is the upcoming trend of vaccine hesitancy and declining vaccination uptake. vaccine hesitancy is recognised by the world health organization (who) to be one of the ten threats to global health [ ] . vaccination uptake is declining globally, resulting in a rise in outbreaks of vaccine-preventable diseases (vpd) [ ] . for instance, measles cases have increased-up to percentover the past years [ ] . vaccine hesitancy has predominantly received attention in the light of parents rejecting the national immunization programs. however, low vaccination uptake among adult populations also raises concerns [ ] . adults are progressively at risk for infectious diseases because life expectancy increases [ ] , the incidence of chronic diseases that require immunosuppressive treatment rises [ ] , and international travel expands [ ] . other determinants will play a role in vaccination uptake in adult populations as compared to children. adults who are recommended to get vaccinated can be divided into several risk groups. risk populations in this context are defined as groups of human individuals with an increased risk of acquiring a (severe) infection due to their behaviour, health, or occupation. to get a broad overview of determinants that play a role in the vaccination uptake among risk groups, this review will focus on three distinct risk groups which consult vaccination clinics frequently, namely: "travellers, immunocompromised patients (icp) and healthcare workers (hcw)". travellers comprise a risk population, as at their destinations they can be exposed to infectious diseases they have not encountered before. traveller vaccination guidelines are available to protect this population. these guidelines do not only differ per destination but are also dependent on the activities the travellers will undertake and the duration of their stay. additionally, the country of origin is of importance, because of the endemicity of infectious diseases and therefore natural exposure, and national immunization programs. moreover, travellers who are not properly vaccinated for their trip are not only at risk for getting sick themselves, they can also create a public health concern for communicable diseases, as they could carry an infection back home to a naïve population [ ] . icp have an increased risk for serious illnesses caused by infectious diseases due to a diminished function of their immune system. the compromised state of their immune system can be induced by either an underlying disease or the treatment of a disease. as a consequence of fast-developing immunosuppressive therapies for e.g., auto-immune diseases and malignancies, icp are a constantly growing population [ ] . therefore, optimal protection of this vulnerable group is of utmost importance. hcw are another risk category for acquiring infectious diseases. their occupation brings them in close contact with patients, that possibly carry an infectious disease. furthermore, hcw are not only personally at risk, they may also put their-mostly vulnerable-patients at risk when they work while carrying an infection [ ] . on top of that, hcw play an important role in providing their (immunocompromised or travelling) patients with information or recommendations regarding vaccinations. vaccination uptake varies between risk populations and there may be differences in determinants that play a role in this behaviour. to find general patterns each risk group will be studied separately. however, as travellers, icp, and hcw are interrelated, we aim to learn from similarities and differences between these groups. if we understand risk populations' motivations and concerns, we might be able to address these either separately or combined by effective interventions. to get a better overview of all determinants that have a possible impact on uptake, we classified these in a model of health behaviour change. an abundance of behaviour change models are available that describe determinants affecting preventive health behaviour [ ] . in , the integrated change (i-change) model was developed by de vries et al. [ ] . this model is derived from the attitude-social norm-self-efficacy (ase) model and integrates several other models, among which are the often-used health belief model (hbm) and the theory of planned behaviour (tpb) (supplementary table s ). according to the i-change model, vaccination behaviour is shaped by the intention to get vaccinated which is subject to barriers and facilitators. intention is established by motivation, awareness, information, and predisposing determinants. as this i-change model comprises a wide variety of determinants that are used by other studies, for example those based on the hbm and ase model, we use this model as a conceptual framework. with this comprehensive review, we aim to better understand determinants that play a role in the uptake of vaccinations in travellers, icp, and hcw and explore similarities and differences in these three groups. hereby, we aim to create a solid ground for the development of evidence-based interventions to increase vaccination uptake in the populations that need optimal prevention strategies for infectious diseases. we performed a systematic database search on february . we performed one search for all three risk groups (supplementary file s ). for each risk groups we combined search terms for vaccination uptake and health behavioural models. we searched the following databases: embase, medline, cinahl, web of science core collection, eric, psychinfo, and socindex. as determinants of vaccination uptake may vary over time, we limited our search to studies published during the last ten years (between january and january ). we excluded research papers written in another language than english. all records were retrieved into an endnote database. duplicates were removed and titles and abstracts were screened (by ld). thereafter, papers were sorted in the three different groups and full texts articles were reviewed for suitability using inclusion and exclusion criteria (by l.d. and l.v.l.) using endnote x . studies were included if they met all of the following criteria: ( ) at least % of the included respondents are either icp (patients with autoimmune diseases, malignancies, hiv, asplenia and solid organ or stem cell transplantations) or travellers (including travellers visiting friends and relatives (vfr), short-and long-term business travellers) or hcw (including general practitioners (gps), physicians and nurses working in a hospital); ( ) addressing self-reported cognitive determinants that may explain vaccination uptake; and ( ) being performed in western countries (defined as europe, north america, australia, and new zealand). we excluded studies that focussed on: ( ) children; ( ) hcw who care for populations other than the icp defined in our study (e.g., paediatricians, elderly home physicians) or who are not directly involved in the care for this group (e.g., pharmacists, dentists); ( ) future healthcare workers (e.g., medicine or nursing students); ( ) uptake of the national immunization programme (e.g., hpv vaccination); ( ) hypothetical vaccinations (e.g., a hiv vaccine); ( ) vaccinations administered in outbreak situations (e.g., h n vaccine, ebola vaccine); ( ) other very specific target groups (e.g., roma travellers, migrants, pregnant women; and ( ) predisposing factors exclusively. we also excluded qualitative studies and non-peer reviewed articles such as conference abstracts. in case any doubt or disagreement between the two researchers who performed the study selection (by l.d. and l.v.l.) arose, the specific papers were discussed in a plenary session with all co-authors. the following background characteristics from included studies were extracted: first author and year of publication; study design; enrolment period; enrolment site; sample size; study population; theoretical framework; and targeted outcome variables. extracted data was collected in microsoft excel and the presence and impact of determinants were rated in separate sheets per study group (by l.d. and l.v.l.). random samples were taken to check the data extraction and disagreements were discussed plenary with all co-authors. furthermore, the quality of studies was assessed using the the axis tool [ ] , which is a screening tool specifically designed for cross-sectional studies, as those in our review, and includes items relevant to this design. scores - are rates as low, - as medium and - as high. the i-change model was used to organize all determinants that could explain vaccination uptake. a simplified version of this model is shown in figure . the following concepts are used: ( ) predisposing factors, including baseline characteristics of studied populations; ( ) information factors, including information retrieved via media, social contacts and hcw; ( ) awareness, of the infectious agent being present or a vaccine being available; ( ) knowledge (either examined or self-evaluated), about the consequences of the infection, or about the efficacy and duration of protection of vaccination; ( a) perceived risk of the infection, which is divided into perceived severity of the disease and perceived susceptibility to get infected; ( b) perceived risk of vaccination, including vaccine-specific considerations such as fear of side-effects and trust in the effectiveness of the vaccine; ( ) attitude, defined as a person's disposition to respond favourably or unfavourably to vaccinations [ ] , often reflected by a person's general believes about vaccinations; ( ) social influence, which can be social norms imposed by family, friends or religion, but also recommendations from a healthcare professional or tour guide; ( ) self-efficacy, defined as beliefs in one's own capacity to perform certain behaviour [ ] ; ( ) intention to behaviour, expressed by people before they perform the behaviour; ( ) barriers and facilitators, that withhold individuals from or enable them to certain behaviour, such as time, costs, or accessibility. vaccines , , x for peer review of figure . simplified i-change model summarizing the studied determinants that could predict vaccination uptake. we used a simplified version of the i-change model applied to vaccination uptake. uptake is shaped by the intention to get vaccinated which is subject to barriers and facilitators. intention is established by motivation (attitude, social influence, and self-efficacy), awareness (awareness, knowledge, and perceived risk) and information and predisposing determinants. predisposing factors include baseline characteristics of studied populations and influence awareness, motivation and uptake. information factors include information retrieved via media, social contacts and healthcare workers. simplified i-change model summarizing the studied determinants that could predict vaccination uptake. we used a simplified version of the i-change model applied to vaccination uptake. uptake is shaped by the intention to get vaccinated which is subject to barriers and facilitators. intention is established by motivation (attitude, social influence, and self-efficacy), awareness (awareness, knowledge, and perceived risk) and information and predisposing determinants. predisposing factors include baseline characteristics of studied populations and influence awareness, motivation and uptake. information factors include information retrieved via media, social contacts and healthcare workers. the literature search generated hits ( figure ). after removing duplicates and excluding articles published before , articles were available on the topic. these were screened based on title and abstract, resulting in articles that were eligible for full-text assessment. these were divided into the three subgroups (some were included in more than one category): for travellers, for icp, and for hcw. finally, , , and articles were included in the data analysis for the three groups, respectively. the most common reason for exclusion was that no determinants (other than predisposing factors) were reported. table describes the characteristics and quality of included studies for travellers, icp, and hcw. determinants that play a role in vaccination uptake were retrieved from the articles and summarized in tables - for travellers, icp, and hcw respectively. the results of the quality assessment are presented in supplementary table s . the articles that studied determinants of vaccination uptake among travellers comprised cross-sectional surveys, two pre-and post-travel surveys, and three retrospective studies of which one was based on confirmed cases of vpd (table ). travellers that were studied originated from the usa ( studies), australia ( studies), europe ( studies), or mixed continents ( studies). sample sizes ranged from to , and comprised hajj pilgrims in three studies, travellers to africa in two studies and to asia in two studies. other studies had broader inclusion criteria. three studies hajj x x x vfr x x backpackers x vpd influenza x x x x x x x men x x x x x pneu x x x hav x x x x x hbv x x x x x x dtp/tdap x x x x mmr x x x vzv/hzv x x yf x x x je x x x rabies x x x typhoid fever x x x vaccines in general x x determinants predisposing factors age ↓ = ↓ ↓ ↑ = = = ↑ gender: male = = = = = = education level = ↑ ↑ travel purpose: vfr = ↓ = ↓ travel purpose: business ↑ ↓ travel duration = = ↓ = ↓ ↑ internet ‹ ‹ ‹ ‹ ‹ « tv/radio ‹ primary hcw (gp) ‹ ‹ ‹ ‹ « ‹ « « specialist hcw (travel clinic) ‹ ‹ ‹ ‹ ‹ family/friends ‹ ‹ ‹ ‹ ‹ ‹ travel organization « ‹ the following symbols are used: x applicable; = no significant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association (tested by multivariate analysis); ↑ significant positive association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association (tested by chi-square, univariate analysis or correlation coefficient); « (double caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; « (double caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population; ‹ (caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ‹ (caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population. * determinants were studied in relation to intention to be vaccinated instead of vaccination uptake. the following symbols are used: x applicable; = no significant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association (tested by multivariate analysis); ↑ significant positive association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association (tested by chi-square, univariate analysis or correlation coefficient); used: x applicable; = no significant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association alysis); ↑ significant positive association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association ariate analysis or correlation coefficient); « (double caret pointing upwards) significance was not tested, but determinant was positively linked to of the population; « (double caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake ; ‹ (caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ‹ s) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population. * determinants were studied (double caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association ve association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association n coefficient); « (double caret pointing upwards) significance was not tested, but determinant was positively linked to le caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ‹ (double caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population; ∧ (caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ∨ (caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population. * determinants were studied in relation to intention to be vaccinated instead of vaccination uptake. x internet/social media the following symbols are used: x applicable; = no significant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association (tested by multivariate analysis); ↑ significant positive association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association (tested by chi-square, univariate analysis or correlation coefficient); « (double caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; « (double caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population; ‹ (caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ‹ (caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population. the following symbols are used: x applicable; = no significant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association (tested by multivariate analysis); ↑ significant positive association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association (tested by chi-square, univariate analysis or correlation coefficient); used: x applicable; = no significant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association alysis); ↑ significant positive association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association ariate analysis or correlation coefficient); « (double caret pointing upwards) significance was not tested, but determinant was positively linked to of the population; « (double caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake ; ‹ (caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ‹ s) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population. * determinants were studied (double caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association ve association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association n coefficient); « (double caret pointing upwards) significance was not tested, but determinant was positively linked to le caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ‹ d, but determinant was negatively linked to vaccination uptake in ≥ % of the population. * determinants were studied (double caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population; ∧ (caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ∨ (caret pointing downwards) significance was not tested, but determinant was negativvely linked to vaccination uptake in ≥ % of the population. social media ↓ ↓ tv/radio ↓ evidence-based sources ↑ ↑ ↑ ↑ ↑ collegues ↑ * one scale (movac-flu scale) was used for following determinants: knowledge, attitude and self-efficacy. the following symbols are used: x applicable; = no significant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association (tested by multivariate analysis); ↑ significant positive association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association (tested by chi-square, univariate analysis or correlation coefficient); ↓↑ significant association, for one vaccine positive, for the other negative; « (double caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; « (double caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population; ‹ (caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ‹ (caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination * one scale (movac-flu scale) was used for following determinants: knowledge, attitude and self-efficacy. the following symbols are used: x applicable; = no significant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association (tested by multivariate analysis); ↑ significant positive association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association (tested by chi-square, univariate analysis or correlation coefficient); ↓↑ significant association, for one vaccine positive, for the other negative; x applicable; = no significant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association is); ↑ significant positive association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association te analysis or correlation coefficient); « (double caret pointing upwards) significance was not tested, but determinant was positively linked to the population; « (double caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake (double caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ‹ nificant difference; ↑ significant positive association (tested by multivariate analysis); ↓ significant negative association ve association (tested by chi-square, univariate analysis or correlation coefficient); ↓ significant negative association n coefficient); « (double caret pointing upwards) significance was not tested, but determinant was positively linked to le caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ‹ (double caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population; ∧ (caret pointing upwards) significance was not tested, but determinant was positively linked to vaccination uptake in ≥ % of the population; ∨ (caret pointing downwards) significance was not tested, but determinant was negatively linked to vaccination uptake in ≥ % of the population. prisk = perceived risk. prisk of infection (s/p): s = self; p = patient. the following abbreviations are used (in alphabetical order): cd = crohn's disease; dtp = diphtheria, tetanus, poliomyelitis; gp = general practitioner; hav = hepatitis a virus; hbv = hepatitis b virus; hcw = healthcare workers; hiv = human immunodefiency virus; hsct = hematological stem cell transplantation; hzv = herpes zoster virus; ibd = inflammatory bowel disease; is = immunosuppressants; je = japanese encephalitis; men = meningococcal disease; mmr = measles, mumps, rubella; pneu = pneumococcal disease; tdap = tetanus, diphtheria, acellular pertussis; sot = solid organ transplantation; vfr = travellers visiting friends and relatives. vzv = varicella zoster virus, yf = yellow fever. the articles that studied determinants of vaccination uptake among travellers comprised cross-sectional surveys, two pre-and post-travel surveys, and three retrospective studies of which one was based on confirmed cases of vpd (table ). travellers that were studied originated from the usa ( studies), australia ( studies), europe ( studies), or mixed continents ( studies). sample sizes ranged from to , and comprised hajj pilgrims in three studies, travellers to africa in two studies and to asia in two studies. other studies had broader inclusion criteria. three studies used kap (knowledge-attitude-practices) surveys and one study mentioned a health behavioural model (theory of planned behaviour) as theoretical background for their study. ten articles studied baseline characteristics of travellers that could be associated with vaccination uptake ( table ). the vaccinations that were studied were diverse, most papers discussed vaccinations for influenza (n = ), hepatitis b virus (hbv) (n = ), hepatitis a virus (hav) (n = ) and meningococcal disease (n = ). regarding age, three papers reported that younger people had a higher uptake [ , , ] . however, for influenza vaccination this was the opposite: older travellers were more likely to be vaccinated for seasonal influenza [ , ] . gender was not a significant predictor of vaccination uptake in any of the studies. education level was studied by three papers [ , , ] . two found this determinant to be positively associated with (intention to) obtaining recommended vaccinations [ , ] . seven studies reported travel purpose in relation to vaccination uptake, but the results were diverse. one study concluded vaccination uptake was highest if the reason of travelling was business or backpacking [ ] . however, work-related travel was associated with lower uptake in another study (or = . , ( . - . )) [ ] . travellers visiting friends and relatives (vfr) had a lower uptake in two studies [ , ] , but two other studies found no association [ , ] . six papers studied the relation between travel duration and vaccination uptake. two studies showed that uptake was significantly lower when people travelled longer [ , ] , while one found that it was higher (for rabies only) [ ] and three studies found no difference [ , , ] . no clear relationship between information sources and vaccination uptake was reported. however, eight studies reported a role for the gp, of which three said that the gp was very influential [ , , , ] . of all the cognitive determinants studied, perceived risk of infection was most frequently described in relation to vaccination uptake (n = ). only one study found a significant positive relation (or . ( % ci . - . )) [ ] , and another five reported this factor to play a role in the majority of the study population. although not often tested for significance, "not feeling at risk of the disease" was a common explanation of a lot of travellers for not receiving the recommended vaccinations. perceived risk of vaccination was sparsely discussed (n = ). social influence, which comprises mostly trust and recommendations of healthcare providers in this selection of studies, was reported in seven papers and was recognised as important by the majority of the study population in four papers. attitude was described in six papers, and was not found to be significant in two of them [ , ] ; reliance on natural immunity was mentioned three times as a reason to reject vaccination [ , , ] . awareness was also discussed in six papers; although it was not tested for significance, - % mentioned unawareness of the availability of the vaccination (or unawareness of the recommendation of the vaccination) as an important reason for non-uptake [ , , [ ] [ ] [ ] ] . five studies reported on knowledge of vpd; two found a significant positive relation between knowledge and vaccination uptake [ , ] , one found no relation [ ] . reported barriers could be classified in costs and lack of time. costs were the most described; however, it played a modest role in explaining non-uptake and differed per vaccination. for instance, for influenza vaccination uptake costs were mentioned to play a role in less than % of travellers, while for hbv ( %), japanese encephalitis ( %) and pneumococcal vaccination ( %) concerns about costs were much higher. in two papers lack of time was given as part of the explanation of non-uptake in more than % of the study population [ , ] . one paper described that - % of travellers require a reminder to complete their vaccination series [ ] . twenty-nine articles concerning icp were included. most of these studies were cross-sectional (n = ), but four were prospective (with a follow-up moment) and two retrospective ( table ) . studies were performed among european (n = ), american (n = ) and canadian (n = ) populations. sixteen studies involved patients with auto-immune diseases, of which four studies focussed completely on patients with inflammatory bowel disease. the vaccination uptake of hiv patients was studied in three papers. four papers studied populations with solid tumours, six papers studied patients who received haematological stem cell transplantation (hsct) and three papers investigated patients who received a solid organ transplantation (sot). almost all papers addressed the influenza vaccination uptake (n = ) and many also included the uptake of pneumococcal vaccinations (n = ). influenza vaccination rates varied from - % and pneumococcal vaccination rates from - %. lowest rates were reported in polish inflammatory bowel disease (ibd) patients [ ] and highest in american rheumatic patients [ ] . in icp, health behaviour models were cited slightly more than in the travellers population. two studies were based on the (hbm) and another three studies used kap surveys. most studies ( out of that studied age) found a positive association between age and vaccination uptake (table ) . especially for influenza vaccination, older patients tend to be more compliant with vaccination guidelines in the studied year. only in one study a negative association was found (or . , % ci ( . - . )) [ ] . most studies report that gender and education level are not significant predictors of vaccination uptake in icp, with a few exceptions. three studies showed in a multivariate analysis that males had a higher uptake. two studies showed a negative association between uptake and education level, while one showed a positive association. in five studies, the use of strong immunosuppressive medication was positively associated with vaccination uptake, whereas in two studies the association was negative and in three there was no association. generally, icp with comorbidities in their medical history tend to have a higher uptake in four [ , , , ] out of seven studies. one study reported a negative association [ ] and two found no significant difference [ , ] . all five papers that included vaccination history (for the same or another vaccination), concluded that there was a positive association between vaccination uptake in the past and current uptake [ , , , , ] . thirteen studies investigated where icp retrieve their information from. in general, gathering information from online media sources was somewhat associated with a lower vaccination uptake, while receiving information from hcw resulted in a higher uptake [ , ] . perceived risk of vaccination was the most frequently mentioned cognitive determinant, being discussed in of the articles. in all three papers that tested for significance, a negative correlation with vaccination uptake was found, meaning that a higher perceived risk of a vaccine results in a lower uptake. but also that a lower perceived risk, reflected for example by trust in the effectivity of this specific vaccine, increases the uptake. fear for side-effects or deterioration of their disease caused by the vaccination were mentioned often. another concern that was often expressed was the doubt of effectivity of vaccination, due to either the immunogenicity of the vaccine or due to the compromised state of the patients' immune system. distrust was reported more often for influenza than for other vaccinations [ ] . awareness of either the availability of or the indication for a vaccination was also widely discussed (n = ). while only found to be significantly correlated twice, this determinant played a role in the majority of the study population in seven papers. because icp often mention vaccination not being proposed as a reason for non-uptake, this determinant is related to the information factors, knowledge, and hcw recommendation. attitude, covering the attitude to vaccinations in general, was mentioned in studies and was found to be positively correlated twice in multivariate analysis. the effect of a favourable attitude to vaccinations in general was larger on uptake of influenza (adjusted odds ratio (aor) . ( % confidence interval (ci) . - . )) than on uptake of pneumococcal vaccination (aor . [ % ci . - . ]) [ ] . perceived risk of infection was mentioned equally often as attitude (n = ) and was also positively associated with uptake, in two of the four studies that tested for significance [ , ] . although knowledge was only addressed in four papers, in two out of the three articles that tested for significance a positive correlation was found. recommendation of an hcw was studied in out of the papers and a significant correlation was found in all eight papers that performed statistical analysis. in addition, a frequently reported reason for not being vaccinated was that vaccination was not offered or recommended, which we included under awareness. self-efficacy was reported in two papers. one reported that more than % of unvaccinated icp were unsure of how to arrange to receive the vaccines [ ] , while another reported that patients who find it easier to attend a gp for vaccination, have a higher intention to get vaccinated (p < . ) [ ] . regarding intention to behaviour, one high-quality study expressed that % of their ibd study population expressed to be willing to receive all of the recommended vaccinations, while only % had ever received a pneumococcal vaccination and only % was vaccinated against influenza at the time of participation in the study [ ] . in another study with % influenza and % pneumococcal vaccination uptake, the intention to be vaccinated next year was also high and not significantly different between the vaccinated ( %) and unvaccinated group ( %) [ ] . cost was only mentioned as a barrier in one paper that found a significant negative correlation with uptake [ ] . lack of time (n = ) and the inconvenience of another appointment (n = ) were more often given as reasons for declining vaccination. in hcw, influenza vaccination uptake is most widely studied. in articles out of the , seasonal influenza vaccination was the only vaccine studied, with uptake varying between % [ ] to % (mandatory policy) [ ] . most studies were conducted in italy (n = ), followed by france (n = ) and the usa (n = ). all but one were designed as cross-sectional surveys, with sample sizes ranging from [ ] to , [ ] . seven studies mentioned the use of a theoretical model for their study, which includes the hbm [ ] , the tpb [ ] , the risk perception attitude framework [ ] , the triandis model of interpersonal behaviour [ ] , the cognitive model of empowerment [ ] or mixtures of different models [ , ] (table ). thirty-six articles studied at least one predisposing factor in relation to vaccination uptake (table ) . of the articles that studied age, found that older healthcare workers had a significantly higher uptake. on the other hand, in the case of hepatitis b [ , ] and measles [ , ] , younger hcw's had higher compliance. in the papers that studied gender, being male was associated with higher vaccination uptake in studies. five papers mentioned a significantly higher uptake in women, one for rubella only [ ] , and another for hepatitis b only [ ] . occupation was studied in relation to vaccination uptake in articles. sixteen papers showed that physicians had a significantly higher uptake than other hcw. this also complies with the significant positive association between education level and uptake that was found in five papers. presence of a chronic disease resulted in significantly higher uptake in seven studies. in three other studies investigating this factor, no association was found. having children at home was studied in nine papers, but six found no significant role for this factor in vaccination uptake. good vaccine compliance in the past turned out to be an excellent predictor of uptake in all studies investigating this factor. the role of information sources in vaccination uptake was studied in six articles. when information was gathered from evidence-based sources, uptake was significantly higher in all five studies that investigated this source. on the other hand, uptake was lower when information was retrieved from social media, television, or radio [ , ] . only one study found that gaining information from colleagues was associated with a higher uptake [ ] . perceived risk was the most frequently described determinant in hcws. more specifically, perceived personal risk of infection reflects the perceived risk to contract the vpd, including the perceived susceptibility to get infected and the perceived severity of the disease if contracted. in out of papers mentioning perceived risk of infection, a significant positive relation was found between this determinant and vaccination uptake (n = ), or these reasons were mentioned in a considerable part of the study group (n = ). furthermore, in papers a high perceived risk to infect patients was given as a reason for vaccination uptake. perceived risk (vs. benefit) of vaccination was mentioned in papers. fifteen studies reported a significant negative relation between perceived risk and uptake, indicating that high perceived risk or low perceived benefit of the vaccination resulted in lower uptake. additionally, five papers mentioned that this determinant played a role in the majority of the study population. adequate knowledge of recommendations, effectiveness, and side-effects of vaccinations was significantly positively associated with uptake in papers; in four studies, no significant association was found. attitude towards vaccination was studied in articles. in half of them, a significant positive association with vaccination uptake was found. social influence (encouragement of colleagues, managers, family) was analysed in almost half of the studies (n = ). in only one study no association was found [ ] , but the others showed either a significant (n = ) or considerable (n = ) positive relation with vaccination uptake. specific for hcw are the social arguments 'i got vaccinated because it's my duty as an hcw' or 'as an hcw, i have a role in the prevention of epidemics/spread of diseases', that we collected under the term 'professional norms'. this determinant was positively associated with uptake in all studies focusing on this factor; in seven out of studies that tested for significance, this factor remained a strong predictor for uptake in multivariate analysis. in comparison with the previous determinants, barriers and facilitators are relatively less studied. of the barriers, time-related factors were mentioned most frequently and played a considerable role (> %) in hindering uptake in seven studies. costs turned out to be no barrier. the fact that the vaccines were free of charge even appeared to be a reason for uptake in two studies [ , ] . on the other hand, facilitators stimulating uptake were getting a reminder (n = ), convenient time/place of distribution (n = ), and getting a reward (n = ). however, in none of the studies were the potential rewards specified. our review of the currently available literature shows that there are clear differences in determinants that play a role in vaccination uptake in travellers, icp, and hcw. for travellers, low perceived risk of infection and low awareness of vaccination recommendations are most accountable for low uptake. for icp, awareness of the indication of vaccination plays an important role, together with receiving vaccination recommendations from their treating physician. icp have a high perceived risk of vaccination, due to not only fear for general side-effects but also concerns about potential consequences for their illness. for hcw, perceived risk of (the severity of) infection for themselves and for their patients together with perceived benefits of vaccination contribute most to their vaccination behaviour. regarding predisposing factors, there is a clear positive relationship between age and influenza vaccination uptake in all risk groups. this could be explained by the additional indication older people have for influenza vaccination. however, for other vaccinations, this relationship is either inverted or non-existent. higher vaccination uptake was seen in males in hcw and icp, which could be associated with the fact that females worry more about vaccine safety and efficacy than males [ ] . indeed, more side-effects are reported by females, while on the other hand, from a biological perspective, females typically mount higher antibody responses [ ] . although we did not find a clear relationship between education level and vaccination uptake in the risk groups, in hcw the uptake was markedly higher in physicians compared to other hcw. overall, vaccination history seems to be an excellent universal predictor of future vaccination uptake, probably due to unaltered cognitive determinants. regarding cognitive determinants, the greatest diversity between risk groups was found in awareness. in icp, almost two-thirds of the studies mentioned limited awareness, compared to one-third in travellers and none in hcw. with their education and occupation, it seems quite obvious that hcw are aware of the opportunities and indications for vaccinations. the fact that icp seem less aware than travellers might have to do with travellers taking an active decision to go abroad realizing that they have to prepare themselves, while patients get passively diagnosed with a disease, and are more dependant of the hcw for information provision. in all groups, hcw as a source of information has a positive effect on uptake. the strong relationship between hcw recommendations and vaccination uptake in icp (reaching odds ratios up to [ ] and [ ] ), underline the importance of positive attitudes towards vaccination in hcw themselves [ , ] . in general, knowledge has a positive influence on uptake in all risk groups. however, since several studies showed no relation between knowledge and uptake [ , , , , , ] , improving education alone will probably not be sufficient to increase uptake. in all groups, the perceived susceptibility and severity of diseases on one hand and the perceived effectiveness and risks of vaccinations on the other hand are important determinants predicting uptake. especially icp and hcw express concerns about the safety and effectiveness of vaccines particularly for influenza vaccination [ , ] . and although the effectiveness of influenza vaccination varies with the coverage of circulating strains each year, another part of the perceived lack of effectiveness could also be explained by the lack of protection for other common cold viruses that can cause influenza-like symptoms [ ] . travelers seem to have low risk perceptions for the diseases they could be vaccinated for as well as for the potential negative effects of vaccination. despite the high morbidity and mortality of some vpd such as yellow fever, hepatitis b, and influenza, in all risk groups, some participants stated they preferred natural immunization or were against vaccinations in general. remarkably, attitudes differ for specific vaccinations, for instance, people tend to have a more positive attitude towards pneumococcal vaccination in comparison to the seasonal influenza vaccination [ ] . interestingly, the mistrust of icp and hcw towards the vaccinations produced by the pharmaceutical industry seems disproportionate to therapeutics manufactured by the same pharmaceutical companies [ , , , ] . here, the difference between prevention and treatment might play a role, where the latter provides a more direct and visible effect. another possible reason for the negative general attitude towards vaccination, also described in decision making for childhood vaccinations [ ] , is the increasing tendency for self-empowerment towards personal health decisions. in this view, individuals stand up against imposed policies and want to make their own decisions, which could also be judged by peers as independent and smart decision making [ , ] . at the same time, sources that are being used to make personal health decisions, such as the internet, contain a lot of negative stories [ ] . practical barriers and facilitators play a limited role in vaccination uptake compared to the other determinants. in all three groups, a reminder is an important facilitator and (lack of) time an important barrier. especially for hcw, this factor is interesting. physicians report this factor most frequently [ ] . they do not only experience lack of time to get vaccinated, they also feel that lack of time impedes their duty to recommend vaccinations to their patients [ ] . again, as hcw recommendations are strongly positively associated with uptake, not only in the other risk groups, but also for hcw themselves (by colleagues for example) [ , ] , removing this barrier can result in achieving optimal care for all groups. only of the articles that were analysed in this review were based on a health behaviour model. many of those found determinants which contributed to vaccination uptake to a greater or lesser extent [ , , , , ] . interventions that focus on a single determinant, such as knowledge, repeatedly proved to be ineffective in the past [ ] , while multifactorial cognitive intervention strategies are effective to improve uptake [ , ] . therefore, all determinants that play a role have to be taken into account. predisposing factors could be used to target specific subgroups and personalize uptake strategies [ ] . facilitators and barriers could be added or taken away to increase vaccination uptake. but, most importantly, interventions need to address cognitive determinants. interventions that increase awareness and risk perception of infectious diseases are more effective than those decreasing risk perceptions of vaccination by providing scientific information [ ] . social norms can be influenced in the case of hierarchical relationships, for instance, the employer will have an effect on the vaccination decision of hcw and hcw will impact icp's decisions. therefore, multifactorial interventions are needed that address the most important cognitive determinants. as these include awareness and risk perceptions, reminders and incidence data could help. reminders for travellers could be disseminated in general media before holidays, while for icp patient associations and hcw could play a role. to improve risk perceptions for the infections, cases of vaccine-preventable diseases should be made public. to decrease risk perceptions of negative effects of vaccinations (e.g., adverse events) new studies should compare the number of influenza-like illnesses in vaccinated and non-vaccinated groups. furthermore, social norms can be included by making the decisions of vaccination uptake public. for example, in hcw trials have been implemented to test the effects of providing a pin that vaccinated hcw may wear that is saying "deliberately vaccinated", which could affect both colleagues and patients [ ] . vaccination decisions of travellers and icp are less well studied than those of hcw. additionally, data on uptake of vaccinations other than influenza are limited. as the available data show large differences in determinants predicting uptake of influenza versus other vaccinations, further studies are required regarding the uptake of recommended vaccinations for diseases other than influenza. reaching a more comprehensive understanding of vaccination uptake in different risk groups for the different vaccinations that are indicated, interventions can be developed based on evidence. moreover, this understanding could help with the implementation of new vaccines for certain risk groups, for instance when a novel sars-cov- vaccine will be recommended for hcw. a number of limitations have to be taken into account when interpreting the results of this review. first, articles were only included if they discussed any cognitive determinants that were possibly related to vaccination uptake. this resulted in the exclusion of papers that looked only, although thoroughly, into predisposing factors. secondly, there was a high level of heterogeneity in the determinants reported, as studies used various health behaviour models as a framework for their studies, and many did not even use a model but just reported results of questionnaires with either open-ended or multiple-choice questions. furthermore, the influence of determinants on vaccination uptake was measured with different statistical analyses, which also contributed to the high heterogeneity of the data. therefore, we choose to report the significance and direction of the association, instead of the magnitude. in addition, we choose to compare three different risk groups that we think are important, thereby we could not discuss all determinants in depth. finally, included studies were based on self-reported vaccination behaviour. therefore, we have to take into account a certain level of social desirability and recall bias. to our knowledge, this is the first review that provides a comprehensive overview of health behavioural determinants explaining vaccination uptake in three different risk groups, namely travellers, icp, and hcw. we showed that there is a large diversity of determinants that affect uptake to a greater or lesser extent. therefore, we argue that future studies and interventions should be based on multifactorial health behaviour models, especially for travellers and icp as only a limited number of such studies is available yet. supplementary materials: the following are available online at http://www.mdpi.com/ - x/ / / /s , table s : health behaviour theories on the basis of the i-change model; table s : quality assessment of included articles, supplementary file s : search strings databases. vaccinology in the third millennium: scientific and social challenges ten threats to global health in association between vaccine refusal and vaccine-preventable diseases in the united states: a review of measles and pertussis who. new measles surveillance data for vaccinating adults with chronic disease: we can do better life expectancy and healthy life expectancy the prevalence of immunocompromised adults: united states unwto. international tourism highlights. available online the spread of vaccine-preventable diseases by international travellers: a public-health concern vaccination of healthcare workers: a review. hum. vaccines immunother systematic literature review to examine the evidence for the effectiveness of interventions that use theories and models of behaviour change: towards the prevention and control of communicable diseases reasons for non-attendance in cervical cancer screening programmes: an application of the integrated model for behavioural change development of a critical appraisal tool to assess the quality of cross-sectional studies (axis) the theory of planned behavior in organizational behavior and human decision processes social cognitive theory predictors of protective behaviors among american travelers to the hajj influenza vaccination among australian hajj pilgrims: uptake, attitudes, and barriers a survey of us travelers to asia to assess compliance with recommendations for the use of japanese encephalitis vaccine hepatitis b: a cross-sectional survey of knowledge, attitudes and practices amongst backpackers in thailand awareness of meningococcal disease among travelers from the united kingdom to the meningitis belt in africa online survey: knowledge about risks, prevention and consequences of infections with hbv among travellers from four european countries pre-travel advice, attitudes and hepatitis a and b vaccination rates among travellers from seven countries † attitudes on vaccination among portuguese travelers and brazilian migrants: a pilot study in portugal refusal of recommended travel-related vaccines among u.s. international travellers in global travepinet risk activities and pre-travel health seeking practices of notified cases of imported infectious diseases in australia meningococcal disease awareness and meningoccocal vaccination among greek students planning to travel abroad a cross-sectional survey to evaluate knowledge, attitudes and practices (kap) regarding seasonal influenza vaccination among european travellers to resource-limited destinations travel health attitudes among turkish business travellers to african countries pre-travel health care utilization among travelers who visit friends and relatives barriers of vaccinations against serious bacterial infections among australian hajj pilgrims understanding why low-risk patients accept vaccines: a socio-behavioral approach knowledge, attitudes, and practices of us travelers to asia regarding seasonal influenza and h n avian influenza prevention measures vaccination attitudes among patients with cancer receiving chemotherapy predictors of reported influenza vaccination in hiv-infected women in the united states factors predicting influenza vaccination adherence among patients in dialysis: an italian survey. hum. vaccines immunother vaccination coverage in systemic lupus erythematosus-a cross-sectional analysis of the german long-term study (lula cohort) attitudes toward vaccination for pandemic h n and seasonal influenza in patients with hematologic malignancies botelho-nevers, e. vaccine coverage in plwh: disparities and potential impact of vaccine hesitancy. hum. vaccines immunother the uptake of influenza and pneumococcal vaccination among immunocompromised patients attending rheumatology outpatient clinics predictors for and coverage of influenza vaccination among hiv-positive patients: a cross-sectional survey predictors for influenza vaccine acceptance among patients with inflammatory rheumatic diseases influenza vaccination in patients with haematologic malignancies: analysis of practices in patients in a single center attitude, knowledge and factors associated with influenza and pneumococcal vaccine uptake in a large cohort of patients with secondary immune deficiency pneumococcal and influenza vaccine uptake in adults with inflammatory bowel disease in france: results from a web-based study vaccination in inflammatory bowel disease patients: attitudes, knowledge, and uptake. j. crohn's colitis sociodemographic and psychological determinants of influenza vaccine intention among recipients of autologous and allogeneic haematopoietic stem cell transplant: a cross-sectional survey of uk transplant recipients using a modified health belief model low influenza vaccination rate among patients with systemic sclerosis an audit of influenza vaccination status in adults with inflammatory bowel disease friis-møller, n. factors associated with influenza and pneumococcal vaccine uptake among rheumatoid arthritis patients in denmark invited to participate in a pneumococcal vaccine trial (immunovax_ra) influenza vaccination perception and coverage among patients with malignant disease understanding influenza vaccination rates and reasons for refusal in caregivers and household contacts of cancer patients determinants of influenza vaccination among solid organ transplant recipients attending sicilian reference center adherence to a predefined vaccination program in patients with inflammatory bowel disease poor adherence to vaccination guidelines in dermatology patients on immunosuppressive therapies: an issue that needs addressing understanding vaccination rates and attitudes among patients with rheumatoid arthritis awareness and uptake of recommended vaccines among immunosuppressed patients immunization after renal transplantation: current clinical practice schiefke, i. vaccination coverage in immunosuppressed patients: results of a regional health services research study perception about influenza and pneumococcal vaccines and vaccination coverage among patients with malignancies and their family members can we better protect patients with inflammatory bowel disease against infections-patient attitude and personal immunization knowledge the immunization status of patients with ibd is alarmingly poor before the introduction of specific guidelines factors affecting uptake of influenza vaccination among family physicians factors effecting influenza vaccination uptake among health care workers: a multi-center cross-sectional study attitudes, believes, determinants and organisational barriers behind the low seasonal influenza vaccination uptake in healthcare workers-a cross-sectional survey beliefs and opinions of health care workers and students regarding influenza and influenza vaccination in tuscany, central italy trends in influenza vaccine coverage among primary healthcare workers in spain beliefs, attitudes, and activities of healthcare personnel about influenza and pneumococcal vaccines immunization status against measles of health-care workers operating at three sicilian university hospitals: an observational study attitudes towards vaccination against seasonal influenza of health-care workers in primary health-care settings in greece physician attitudes towards influenza immunization and vaccine mandates knowledge of and attitudes to influenza vaccination in healthy primary healthcare workers in spain determinants of adherence to seasonal influenza vaccination among healthcare workers from an italian region: results from a cross-sectional study perceived risks of adverse effects and influenza vaccination: a survey of hospital employees low vaccination coverage for seasonal influenza and pneumococcal disease among adults at-risk and health care workers in ireland, : the key role of gps in recommending vaccination knowledge and attitudes on influenza vaccination among italian physicians specialized in respiratory infections: an italian respiratory society (sip/irs) web-based survey opinions and behavior of family doctors concerning vaccinating against influenza self-reported influenza vaccination rates and attitudes towards vaccination among health care workers: results of a survey in a german university hospital knowledge, risk perception and attitudes toward vaccination among austrian health care workers: a cross-sectional study. hum. vaccines immunother determination of factors required to increase uptake of influenza vaccination among hospital-based healthcare workers knowledge and attitudes towards influenza vaccination of health care workers in emergency services the decision to receive influenza vaccination among nurses in north and south dakota vaccination coverage of general practitioners: a cross-sectional study from greece the association between vaccination confidence, vaccination behavior, and willingness to recommend vaccines among finnish healthcare workers predictors of hepatitis b vaccination status in healthcare workers in belgrade, serbia sociocognitive predictors of the intention of healthcare workers to receive the influenza vaccine in belgian, dutch and german hospital settings skepticism toward emerging infectious diseases and influenza vaccination intentions in nurses healthcare workers' knowledge, beliefs, and coverage regarding vaccinations in critical care units in italy external cues to action and influenza vaccination among post-graduate trainee physicians in toronto identifying attitudes, beliefs and reported practices of nurses and doctors as immunization providers qualitative motivators and barriers to pandemic vs. seasonal influenza vaccination among healthcare workers: a content analysis voluntary to mandatory: evolution of strategies and attitudes toward influenza vaccination of healthcare personnel healthcare worker's attitude to seasonal influenza vaccination in the south tyrolean province of italy: barriers and facilitators using a validated health promotion tool to improve patient safety and increase health care personnel influenza vaccination rates seasonal influenza vaccine compliance among hospital-based and nonhospital-based healthcare workers attitudinal variables and a possible mediating mechanism for vaccination practice in health care workers of a local hospital in l'aquila (italy). hum. vaccines immunother factors contributing to declination of annual influenza vaccination by healthcare workers caring for cancer patients: an australian experience attitude toward immunization and risk perception of measles, rubella, mumps, varicella, and pertussis in health care workers working in hospitals of florence acceptance of seasonal and pandemic a (h n ) influenza vaccination by healthcare workers in a french teaching hospital motors of influenza vaccination uptake and vaccination advocacy in healthcare workers: development and validation of two short scales vaccine hesitancy among general practitioners and its determinants during controversies: a national cross-sectional survey in france seasonal and pandemic a (h n ) influenza vaccination coverage and attitudes among health-care workers in a spanish university hospital obstacles in the motivation of health care workers for pertussis vaccination. procedia vaccinol seasonal influenza self-vaccination behaviours and attitudes among nurses in southeastern france. hum. vaccines immunother vaccine hesitancy and self-vaccination behaviors among nurses in southeastern france nurses' knowledge and risk perception towards seasonal influenza and vaccination and their vaccination behaviours: a cross-sectional survey seasonal influenza vaccination knowledge, risk perception, health beliefs and vaccination behaviours of nurses sex and gender differences in the outcomes of vaccination over the life course vaccine hesitancy among healthcare workers and their patients in europe-a qualitative study influenza-like illness incidence is not reduced by influenza vaccination in a cohort of older adults, despite effectively reducing laboratory-confirmed influenza virus infections trusting blindly can be the biggest risk of all': organised resistance to childhood vaccination in the uk. sociol. health illn mmr talk' and vaccination choices: an ethnographic study in brighton the impact of the web and social networks on vaccination. new challenges and opportunities offered to fight against vaccine hesitancy an exploratory qualitative assessment of factors influencing childhood vaccine providers' intention to recommend immunization in the netherlands an effective strategy for influenza vaccination of healthcare workers in australia: experience at a large health service without a mandatory policy strategies for addressing vaccine hesitancy-a systematic review countering antivaccination attitudes hospital-based cluster randomised controlled trial to assess effects of a multi-faceted programme on influenza vaccine coverage among hospital healthcare workers and nosocomial influenza in the netherlands this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the authors wish to thank sabrina meertens-gunput from the erasmus mc medical library for developing and updating the search strategies. the authors declare no conflict of interest. key: cord- -yf lvbs authors: von linstow, marie-louise; nordmann winther, thilde; eltvedt, anna; bybeck nielsen, allan; yde nielsen, alex; poulsen, anja title: self-reported immunity and opinions on vaccination of hospital personnel among paediatric healthcare workers in denmark date: - - journal: vaccine doi: . /j.vaccine. . . sha: doc_id: cord_uid: yf lvbs background: denmark has no general recommendations for vaccination of healthcare workers (hcws). we explored the self-reported immunity to varicella, measles, mumps, and rubella, reasons for receiving the influenza vaccine or not, and opinions on vaccination of hcws against varicella, mmr, pertussis, diphtheria, and influenza among staff from departments with a high risk of exposure to infectious agents. methods: from may to august , a structured questionnaire was distributed to clinical and non-clinical hcws at a tertiary and a general paediatric department in denmark. self-reported immunity was defined as either previous infection or vaccination against the disease. results: of employed hcws, ( %) were included. a large proportion were unsure of or denied previous vaccination or infection with measles ( . %), mumps ( . %), rubella ( . %), varicella ( . %), pertussis ( . %), and diphtheria ( . %). non-clinical personnel and employees born in – had the lowest level of self-reported immunity. mandatory vaccination of non-immune hcws was approved by – . % of participants, and any kind of vaccination (mandatory or as an offer at hospitals) was approved of up to . % of all participants depending on the disease. during the season / , ( . %) hcws received the influenza vaccine, including . % of non-clinical staff, . % of nurses and . % of doctors (p < . ). reasons for lack of vaccine uptake were mainly employees considering themselves rarely sick, the vaccine was not regarded as necessary, forgetfulness or lack of time. only . % was in favour of mandatory influenza vaccination. conclusions: a large proportion of paediatric hcws were not aware of their immune status against important vaccine-preventable diseases. > % supported vaccination of hcws, with two out of three supporting mandatory mmr, pertussis and diphtheria vaccination. better information and an official immunisation policy of non-immune hcws in denmark is warranted. healthcare workers (hcws) in paediatric settings are often exposed to communicable diseases and represent a source of infection for susceptible patients, parents, and colleagues. measles, mumps, rubella, varicella, influenza and pertussis are highly conta-gious infectious diseases that can cause serious complications, particularly in immunocompromised patients, infants and pregnant women. the child vaccination programme in denmark includes two doses of measles, mumps, rubella (mmr) vaccine and a + regimen of diphtheria, tetanus, acellular pertussis, polio, and haemophilus influenzae type b (dtap-ipv-hib) vaccine with a booster dose of dtap-ipv at five years. varicella vaccination and further booster doses of dtap are not implemented in the program and influenza vaccination is only given to certain risk groups. despite high vaccination coverage (> % for most vaccines), and a measles elimination status since , cases of measles occurred in denmark in , six of them as imported cases [ ] . https://doi.org/ . /j.vaccine. . . - x/ published by elsevier ltd. many vaccine-preventable diseases (vpds) spread rapidly in closed settings even before onset of symptoms or when symptoms are mild and unspecific. vaccination is the best way to protect susceptible individuals and prevent transmission of infections, but vaccination status and immunity of danish hcws have only attracted little attention. it is estimated that hcws have a - fold increased risk of acquiring measles compared to the general population [ ] and numerous outbreaks of measles, rubella, pertussis, varicella, and influenza have been traced to hcws [ ] [ ] [ ] [ ] [ ] [ ] . in a recent italian study, five of hcws involved in a nosocomial measles outbreak had no direct contact to patients [ ] . denmark experienced a national pertussis epidemic from june until lockdown of the country due to covid- in mid-march with up to cases/ . per year in some areas [ ] . to date, no outbreaks in hospital settings were recorded. a national initiative was taken to vaccinate pregnant women for pertussis until the end of . no booster vaccination programme of front-line hcws was undertaken and no booster vaccinations in teenagers and adults were implemented. during each season, % of hcws are estimated to contract influenza [ ] , and a large group of hcws continue to go to work despite of symptoms [ , ] . a recent study showed that nearly half of hcws with laboratory-confirmed influenza were afebrile, posing a risk of influenza transmission to patients and coworkers [ ] . influenza vaccination of hcws is an inexpensive and safe way to reduce transmission [ ] . as opposed to many other european countries [ ] , denmark has no national recommendations for vaccination of hcws except for hepatitis b to specific groups, and there is no requirement of up-to-date vaccinations for new employees. vaccination of hcws is highly debated globally and mandatory vaccination against e.g. influenza, pertussis, mmr and diphtheria has been implemented as a requirement to be employed at some institutions in the united states and europe [ , ] . refusal of mandatory vaccination may result in transfer to a post with no patient contact, a fine or employment termination. however, not all countries have a regulatory policy or penalty in case of mandatory vaccine refusal [ ] . before considering implementing recommendations for vaccination of hcws it is important to know the magnitude of the need and understand staff attitudes and perceptions of such an initiative. we explored the self-reported immunity to varicella and the mmr diseases, reasons for receiving the influenza vaccine or not, and opinions on vaccination of hcws against varicella, mmr, pertussis, diphtheria, and influenza among staff from two departments with a high risk of exposure to infectious agents. denmark has general paediatric departments and tertiary referral paediatric departments employing approximately hcws. in this cross-sectional survey, all hcws employed at the department of paediatrics and adolescent medicine, rigshospitalet, a tertiary care centre including oncology, cardiology and bone marrow transplant units, and the department of paediatrics and adolescent medicine, hillerød hospital, a general hospital including a neonatal ward were invited to participate in the study in the period from may to august . both centres have a paediatric emergency ward and outpatient clinics. hcws included nurses, physicians, medical and nursing students, secretaries, dieticians, cleaning staff, clowns and others with direct or indirect con-tact to patients or access to patient rooms. hcws were full-time employed or only temporarily associated to the departments. initially, hcws were informed about the project by flyers distributed to all units followed by short information meetings. during the study period, all hcws were approached personally and offered the opportunity to participate in the study. interested staff received oral and written information from one of four physicians involved in the project. after written informed consent, participants filled-in a hard copy of a structured questionnaire including ) sociodemographic and professional characteristics (sex, age, number of children at home, profession, year of graduation, years in present job, work place (ward, outpatient clinic or both)), ) self-reported immunity status and vaccine uptake (history of infection or vaccination against the following vpds: varicella, measles, mumps, rubella, pertussis and diphtheria, and history of influenza vaccination), ) knowledge of side-effects to vaccines against the above mentioned diseases marked as ''great knowledge", ''little knowledge" or ''no knowledge"), and ) attitudes towards vaccination of hcws in denmark (registered as the answer ''yes", ''no" or ''don't know" to the question ''do you approve mandatory vaccination of hcws" and ''do you approve vaccination as an offer to hcws" for each of the investigated diseases) . reasons for rejecting or accepting influenza vaccination were written in free text promoting open-minded answers and later arranged into appropriate categories. the questionnaire was developed for the purpose of the study and was pilot-tested in a subset of nurses and doctors. it was reviewed and approved by the ethics committee of the capital region of denmark and the data protection agency before project start. data was registered anonymously. we defined self-reported immunity against varicella and the mmr diseases as either previous infection or vaccination against the disease. susceptibility was defined as either no history or no knowledge of previous infection or vaccination. pertussis and diphtheria were not included in these definitions due to waning immunity following disease or vaccination. chi-square tests were applied to compare the associations between self-reported history of disease and vaccination with age and occupation. further, chi-square tests were used to investigate the association between reasons for influenza vaccine refusal and occupation, and to compare opinion on mandatory vaccination with age and own influenza vaccine uptake. logistic regression analysis was applied to investigate factors significantly associated with self-reported immunity to vpds. self-reported immunity as the outcome variable was coded as a binary variable (yes/no) with yes defined as answering yes to either vaccination or previous infection and no defined as answering no or uncertain to both vaccination and previous infection. the following independent variables were assessed in the univariate analysis: sex, age, profession, children in household, workplace, years in present job, knowledge of sideeffects. variables with a significance level of p < . in the univariate analysis were entered in the multiple regression model (forward selection). a p-value < . was considered significant. data were analysed using the spss software, version for windows. we included ( %) of all hcws from the two departments. seventeen ( . %) declined participation, and ( . %) were never approached mainly due to variable work schedules. characteristics of participants are shown in table . almost % were females, and more than half were nurses. of note, at both centres almost one third of participants had been less than two years in their present job, including . % of physicians, which is mainly due to planned rotation among young doctors, and . % of nurses, indicating a great deal of replacement on these wards. participants' self-reported vaccination status and disease history are shown in table . a high proportion of hcws was not aware of their vaccination status. the lack of knowledge regarding previous vaccination to the mmr diseases was highest in the age group - (born in - ), with % of respondents in doubt. similarly, a high proportion of hcws did not know if they had previously been infected, ranging from . % for varicella to . % for pertussis. as for vaccination, the age group - years was the group with least knowledge regarding previous infection. self-reported immunity was seen in . % for varicella, . % for measles, . % for mumps and . % for rubella. . % of female hcws below the age of years, and therefore potentially fertile, reported to be non-immune to rubella. of those with no or uncertain previous infection with measles, mumps or rubella, between % and % had a positive vaccination status (fig. ) . the relation between self-reported immunity and age group is illustrated in fig. . for mumps, immunity declined by age, and for all diseases, immunity was more prevalent in the youngest age group compared to the - year-olds. non-clinical personnel had the lowest level of self-reported immunity for all four diseases (fig. ) , while dieticians and physiotherapists had the highest level of immunity to measles and varicella, followed by physicians. age and profession were the only variables associated with immunity in the multiple logistic regression analysis: compared to the oldest age group, self-reported immunity to mumps was higher in the youngest age group (adjusted odds ratio (aor) . ), and immunity to measles was lower in the - year-olds (aor . ). compared to nurses, physicians had an aor of . of reported immunity to measles, while non-clinical staff had an aor of . for immunity to all three mmr diseases (suppl . table) . there was no difference in immunity according to sex, workplace, or years in present job. during the season / , ( . %) hcws from the two departments received the influenza vaccine, including . % of non-clinical staff, . % of nurses and . % of doctors (p < . ). staff > years were vaccinated in . % of cases compared to . % of those below years (p < . ). only . % of those with no knowledge of side-effects received the influenza vaccine compared to . % of those with great knowledge and . % of those with little knowledge (p < . ). all but one recipient stated self-protection as the reason to get the vaccine, and all recipients mentioned the protection of patients and others as the reason. three nurses felt a pressure from colleagues to receive the vaccine. reasons for vaccine refusal are illustrated in table . decliners most frequently regarded themselves as healthy individuals who rarely got sick and therefore considered the influenza vaccine redundant. only . % did not want the vaccine and . % were concerned of side-effects. physicians most often did not have time or forgot to get vaccinated. most participants were in favour of mandatory vaccination of non-immune hcws ranging from % for varicella to . % for measles. as seen from table , significantly more personnel from the younger age group < years favoured mandatory vaccination. an exception was the influenza vaccine, where only . % of all participants were positive to mandatory vaccination. only . % of hcws in favour of mandatory influenza vaccine received the vaccine themselves in the season / . a large group ( - % depending on the disease) was in doubt regarding their opinion for or against mandatory vaccinations. however, among those not in favour of mandatory vaccinations, between . % and . % thought vaccinations should be offered hcws at hospitals. in total, any kind of vaccination (mandatory or as an offer at hospitals) was approved by . % (varicella) to . % (rubella) of all participants depending on the disease. there was no difference in attitudes between occupational groups (data not shown). a quarter of participants anticipated to have great knowledge of side effects to the varicella, mmr, pertussis and diphtheria vaccines. however, half mentioned they had limited knowledge. a quarter did not know anything about the side effects, and this group was more often in doubt about their opinion on mandatory vaccination or not. a great difference in knowledge was seen according to profession (fig. ) . physicians was the only occupational group with> % having great knowledge of side-effects. despite a significant reduction and control of several infectious diseases after universal implementation of vaccination programs, outbreaks of vpds continue to occur. in our study, a high proportion of hcws was not aware of their immunity status to the vpds investigated. another large proportion claimed not to be immune, so totally - % of hcws were potentially at risk of transmitting diseases in the health-care setting. in paediatrics, diseases like measles and pertussis and their complications are well-known, and hcws regularly provide advice and remind parents to vaccinate their children. therefore, it is of concern that such a large proportion of the staff had not thought of their own immunity and risk of getting sick. for both measles and rubella, the lack of self-reported immunity was highest in employees born in - . in denmark, the mmr vaccine was introduced in with a catch-up program for those born in - . a proportion from this generation may not have received the vaccine, and due to herd immunity, they have not had the diseases either. this age group constitutes a large part of the workforce in most centres including ours, making it of outmost importance to act upon. non-clinical personnel have previously been involved in outbreaks of vpds [ , ] . in our study, this occupational group had the lowest level of self-reported immunity, emphasizing the importance of including all groups of hcws in immunisation programs. likewise, healthcare students can go unnoticed because of their shared time between hospital wards and universities. implementing (mandatory) immunisation programs at medical and nursing schools could contribute to the promotion of a sense of care and increase immunity of future employed hcws [ ] . the uptake of influenza vaccination in our study was . %. other european countries have reported influenza vaccine cover-age ranging from % to . % in / [ ] , and uptakes of . - . % are reality in places with a mandatory vaccination policy [ , ] . like in our setting, most studies report lower vaccination uptake by nurses compared to physicians, which is of concern as nurses commonly spend more time with the patients than physicians do. the finding reflects different levels of knowledge and attitudes about influenza and its prevention, suggesting a need for specific and profession-tailored programs [ ] [ ] [ ] [ ] . self-protection and protection of patients were the main motivators for getting the influenza vaccine, which is in line with findings from others that self-protection is the strongest and most consistent driver of hcw's decisions to accept vaccination followed by prevention of illness in patients [ , ] . vaccine refusal was mainly explained by the assumption that healthy individuals were not in need of the vaccine. inattention and a lack of time as a barrier to vaccination was more than tripled in physicians compared to nurses and increased six-fold compared to other occupational groups, emphasizing a need for easier vaccine access for certain groups. in our study, - % of hcws supported a mandatory vaccination policy for measles, mumps, rubella, varicella, pertussis and diphtheria, most pronounced in those under years of age. on the other hand, the majority of hcws did not support the idea of mandatory occupational influenza vaccination. reasons for this can be many such as suboptimal efficacy, which varies by influenza season, and the fact that the vaccination is needed every year. the finding is different from attitudes in paediatric hcws in greece with . % supporting mandatory vaccinations, less for mumps ( . %) and most for influenza ( . %) [ ] . in a paediatric tertiary care hospital in philadelphia, . % of employees supported a mandatory influenza vaccination policy, but a majority also felt that the policy was coercive [ ] . a recent study involving european countries found an overall of . % hcws favouring mandatory immunisation for hcws involved in clinical work. however, rates differed significantly among countries [ ] . interestingly, when asking the public, > % agree that hcws have an obligation to be vaccinated against influenza and pertussis and just as many support vaccination for childcare workers [ ] . several ethical issues are associated with hcw immunisation and mandatory vaccination is far from danish principles. a voluntary vaccination program seems the best approach to foster greater employee cooperation and trust in the system [ ] . education regarding the potential health consequences for patients, diagnosis, treatment, modes of transmission and easy access to free vaccines including worksite vaccination during all shifts will undoubtedly increase vaccination uptake and must be prioritised before considering mandatory programs. however, in countries experiencing increasing vaccination hesitancy and refusal, mandatory vaccination policies might increasingly be implemented in the next years [ ] . a strength of this study is the high response rate of %, which was possible due to in-person contact with each employee and distribution of hard-copy questionnaires, which would not have been possible in a larger setting. we are not aware of similar studies involving all hcw categories including non-clinical personnel, students and volunteers thus considering the voice of groups that are often not perceived as hcws. the opportunity to provide anonymous responses increases the probability of honest responses and comments. however, the findings that just over half of those supporting the idea of mandatory influenza vaccination were vaccinated themselves, could lead to the assumption that some workers stating they would accept vaccination, would in reality not. however, the main reason for abstaining was a lack of time and not an active choice against vaccination. this study has some limitations. information about previous disease and vaccination was self-reported based on memory and knowledge and not on vaccination cards or health files. a larger part than registered in this study may have been protected from vpds. a mandatory electronic vaccination registry was implemented in , but vaccinations given prior to are not all found electronically explaining why some respondents could not find proof of previous vaccinations and had to rely on information from their parents if possible. this could, however, lead to both an under-and overestimate of immunity. as this is a cross-sectional study the results are limited in time. in conclusion, large immunity gaps might exist in danish paediatric hcws. there is a great interest in improving protection from vpds with up to . % of all hcws supporting vaccination depending on the disease and two out of three hcws supporting mandatory mmr, pertussis and diphtheria vaccination of unprotected employees. however, the support for mandatory influenza vaccination was markedly lower. educational campaigns about the benefit of vaccinations and implementation of national recommendations for vaccination of hcws in denmark is warranted. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. epi-nyt week / - measles among healthcare workers: a potential for nosocomial outbreaks variation in risk for nosocomial chickenpox after inadvertent exposure a nosocomial outbreak of pandemic influenza a(h n ) in a paediatric oncology ward in italy nosocomial rubella-consequences of an outbreak and efficacy of a mandatory immunization program nosocomial influenza in children measles in health-care settings nosocomial pertussis in neonatal units a nosocomial measles outbreak in italy epi-nyt week - incidence and recall of influenza in a cohort of glasgow healthcare workers during the - epidemic: results of serum testing and questionnaire working with influenza-like illness: presenteeism among us health care personnel during the - influenza season a systematic review of infectious illness presenteeism: prevalence, reasons and risk factors influenza among afebrile and vaccinated healthcare workers effectiveness of influenza vaccine in health care professionals: a randomized trial vaccination of healthcare personnel in europe: update to current policies influenza vaccination coverage among health care personnel -united states surveillance network of catalonia, the measles elimination program. implication of health care personnel in measles transmission: the need for updated immunization status in the move towards eradication of measles in catalonia vaccinations among medical and nursing students: coverage and opportunities seasonal influenza vaccination in europe -vaccination recommendations and coverage rates for - and - . european centre for disease prevention and control employee designation and health care worker support of an influenza vaccine mandate at a large pediatric tertiary care hospital influenza vaccination of health care workers in hospitals-a review of studies on attitudes and predictors influenza vaccination: opinions of health care professionals working in pediatric emergency departments selfreported influenza vaccination rates and attitudes towards vaccination among health care workers: results of a survey in a german university hospital knowledge and attitudes towards influenza vaccination of health care workers in emergency services factors associated with healthcare worker acceptance of vaccination: a systematic review and meta-analysis attitudes regarding occupational vaccines and vaccination coverage against vaccine-preventable diseases among healthcare workers working in pediatric departments in greece immunization related behaviour among healthcare workers in europe: results of the hproimmune survey should professionals caring for children be vaccinated? community perspectives on health care and child care worker immunisation the authors want to thank the healthcare workers who replied to the questionnaire for their great interest in participating in the study. we are grateful to the danish health foundation and aase and ejnar danielsens foundation for supporting the study. author's contributions mll, ap and ayn initiated and designed the study. mll, tnw, ae and abn coordinated the study, organized recruitment, and collected data. mll performed statistical analyses and prepared the first draft of the manuscript. all authors participated in manuscript preparation and approved the final manuscript. the study was funded by the danish health foundation grant no -b- and aase and ejnar danilelsens foundation, denmark grant no - - . the sponsors were not involved in study design, in the collection, analysis and interpretation of data, or in the writing of the report. supplementary data to this article can be found online at https://doi.org/ . /j.vaccine. . . . key: cord- -y ji k authors: connell, anna r.; connell, jeff; leahy, t. ronan; hassan, jaythoon title: mumps outbreaks in vaccinated populations—is it time to re-assess the clinical efficacy of vaccines? date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: y ji k history illustrates the remarkable public health impact of mass vaccination, by dramatically improving life expectancy and reducing the burden of infectious diseases and co-morbidities worldwide. it has been perceived that if an individual adhered to the mmr vaccine schedule that immunity to mumps virus (muv) would be lifelong. recent mumps outbreaks in individuals who had received two doses of the measles mumps rubella (mmr) vaccine has challenged the efficacy of the mmr vaccine. however, clinical symptoms, complications, viral shedding and transmission associated with mumps infection has been shown to be reduced in vaccinated individuals, demonstrating a benefit of this vaccine. therefore, the question of what constitutes a good mumps vaccine and how its impact is assessed in this modern era remains to be addressed. epidemiology of the individuals most affected by the outbreaks (predominantly young adults) and variance in the circulating muv genotype have been well-described alluding to a collection of influences such as vaccine hesitancy, heterogeneous vaccine uptake, primary, and/or secondary vaccine failures. this review aims to discuss in detail the interplay of factors thought to be contributing to the current mumps outbreaks seen in highly vaccinated populations. in addition, how mumps diagnoses has progressed and impacted the understanding of mumps infection since a mumps vaccine was first developed, the limitations of current laboratory tests in confirming protection in vaccinated individuals and how vaccine effectiveness is quantified are also considered. by highlighting knowledge gaps within this area, this state-of-the-art review proposes a change of perspective regarding the impact of a vaccine in a highly vaccinated population from a clinical, diagnostic and public perspective, highlighting a need for a paradigm shift on what is considered vaccine immunity. muv is an enveloped, non-segmented, negative-sense, single stranded rna virus that varies between a spherical and pleiomorphic shape of ∼ nm ( - nm) ( , ) . muv is responsible for an acute viral infection, spread by respiratory droplets (via coughs, sneezes) and urine ( , ) . with an incubation period of - days, muv replicates in the nasopharynx and regional lymph nodes, with a secondary viremia occurring late in the incubation period ( , ) . muv can be detected from saliva up to days prior, and as late as days after clinical onset of parotitis ( ) . the muv genome of seven genes consists of , nucleotides, and encodes six structural proteins and at least two non-structural proteins; the nucleocapsid protein (np), v protein (v), phosphoprotein (p), matrix (m) protein, fusion (f) protein, small hydrophobic (sh) protein, hemagglutininneuraminidase (hn) protein, and large (l) protein. the role of the i protein is not known ( , , ) . the sh gene is the most variable region of the muv genome; a - % intravariation and - % inter-variation has been documented ( ) . this gene is used in molecular phylogeny for genotyping and to identify transmission patterns in populations ( ) . despite being serologically monotypic, muv genotypes (a to l) have been described to date (muv genotypes e and m are omitted, as the muv previously assigned to these groups were later re-assigned) ( , , ) . the geographic distributions of the muv genotypes varies worldwide but can co-circulate and thus drive temporal shifts in their distribution. genotype a was frequently isolated in europe until the 's. currently genotypes c, d, e, g, and h are prevalent in europe and the united states of america (usa) whereas genotypes b, f and i are more common in asian countries ( table ) ( , , , ) . since numerous mumps vaccines have been developed worldwide, varying in efficacy and safety profiles but primarily consisting of an attenuated live muv without an adjuvant ( , ( ) ( ) ( ) . currently in europe and for the majority of the g countries who have a mumps vaccine in their immunization schedule (table ) , the mumps vaccine is included as part of the trivalent measles, mumps rubella (mmr) vaccine, and is primarily administered in two doses ( , ) . the jeryl lynn (jl) vaccine, derived from the genotype a muv strain was first developed in the usa and has been used extensively in the united kingdom (uk), ireland and usa since it was licensed in ( ) . derived from a single clinical sample, and propagated in a chick embryo cell culture, two viral isolates (jl and jl ) are present, differing by ∼ nucleotides and amino acid changes ( ) ( ) ( ) . the rit mumps vaccine, developed from the dominant viral component (jl ) in the jl vaccine strain appears to have comparative safety and efficacy (seroconversion) profiles to the jl vaccine strain ( , ( ) ( ) ( ) . however, since no controlled clinical trials of efficacy have been published to compare the two doses of the two vaccines, the clinical significance of this observation is not known. despite the integration of the mmr vaccine into childhood immunization programs, cyclical outbreaks [defined as two or more cases linked by place and time ( ) ] of muv have been documented in several highly vaccinated populations such as ireland and the united kingdom ( , ( ) ( ) ( ) ( ) ( ) ( ) ( ) . between august -and january , , mumps cases were notified in ireland, primarily affecting individuals between the ages of - years. of the % of cases that stated vaccination status, % had received two doses of the mmr vaccine ( ) . an upsurge of mumps cases has also occurred in states of the united states over the last decades, primarily affecting people between and years in close contact/shared settings ( ) . in indiana, . % of mumps cases ( . % of university affiliated and % of community cases) had documented evidence of mmr vaccination ( ) . this results in a significant resource burden for public health departments to control. several reviews, both observational and systematic have demonstrated the clinical benefit of a mumps vaccine ( , ) , the pathogenesis and genomic diversity of the muv ( , , ) and the epidemiology surrounding the outbreak ( , , ) . it is not clear why these mumps outbreaks occur, although it has been alluded to be due to a number of interrelated factors, such as sub-optimal vaccine uptake ( , , ) , primary or secondary vaccine failure or failure of the mumps vaccine to protect individuals from infection (vaccine efficacy) ( ) (figure ). history depicts the remarkable public health impact of mass vaccination. previously inevitable childhood diseases with potentially debilitating or deadly outcomes have seen their rates plummet worldwide or become successfully eradicated. immunizations of vaccine preventable diseases are estimated to prevent ∼ - million deaths per annum and increase life expectancy by ∼ years ( ) . more recently there has been a shift in the public and media perception of vaccines to their safety, which has facilitated outbreaks such as mumps ( ) . organized opposition to vaccinations has a long history; public outcry and resistance following the introduction of the smallpox vaccine in the nineteenth century led to the introduction in england of the vaccination act of ( ) . with one in eight children in the usa under the age of currently thought to be unvaccinated due to parental choice, the who now considers vaccine hesitancy as one of the ten threats to global health in ( ) . vaccine hesitancy, defined as a "delay in acceptance or refusal of vaccines despite availability of vaccination services" involves a multitude of social, political, cultural and emotional factors in highly vaccinated, western populations ( , ) . one of the main issues is the parental concerns regarding the perceived risk of a vaccine to their child (such as timing/schedules of vaccines, associated pain of administration, and potential adverse effects) vs. the disease morbidity and mortality associated with the vaccine preventable disease ( , ) . the retracted paper published in the lancet in ( ) and "anti-vaccination" opinions on social media have also contributed to the persistent and insistent misinformation ( ) , despite vast follow-up epidemiological studies showing no relationship between the mmr vaccine and autism, or differing cognitive development/intelligence ( ) ( ) ( ) . however, the resultant reaction of the public led to the uptake of the first mmr vaccine falling sharply from , with uptake falling to below % in ( , ) . the age demographic that are experiencing the most cases of mumps in ireland during the current ongoing outbreak would have been scheduled to have received the first mmr vaccine between and . nevertheless, no deductions can be made, due to the lack of vaccination status information provided with reported cases ( ) . frontiers in immunology | www.frontiersin.org heterogeneity of immunization coverage in specific populations or geographic locations of susceptibility is also becoming an important epidemiological issue in maintaining proficient population immunity for mumps ( , , ) . the who recommends a > % mmr vaccine coverage for herd immunity. maintenance of such coverage is well-demonstrated in finland, where a country-wide -dose mmr vaccination program initiated in the 's eliminated measles, mumps and rubella within years ( , ) . recent publications from around the world indicate that the level of mmr vaccine uptake is far lower than what is recommended [reviewed in ramanathan et al. ( ) ] ( , ( ) ( ) ( ) ( ) . of the g nations that implement a mumps vaccine within their vaccination schedule, only countries have maintained vaccine coverage levels of > % (table ) . however, poor uptake/incomplete vaccination alone may not be the only issue relating to mumps outbreaks. in the netherlands, mumps outbreaks still occurred with an overall herd immunity threshold of - %, and where and % received the first and second mmr at months and years, respectively ( , ) . the clinical presentation of mumps is pathognomic (bi-lateral parotitis); therefore supporting laboratory diagnosis was rarely employed in the past. as the classical symptoms of mumps are not always typical, there may have been a significant number of individuals in the past who may have been infected but were not identified as such. when mumps vaccination was introduced in , the criteria the vaccine had to meet was the proof that it was clinically effective, i.e., that it reduced the risk of disease in vaccinated individuals in real-world conditions over a set period. such an example was seen the usa; the reported cases (i.e., diagnosis of clinical symptoms) of mumps declined from > cases per , population before (pre-vaccine era) to cases per , population in , a reduction of % ( , , , ) . to note, clinical efficacy was probably based upon the reduction of the "classical bilateral presentation" rather than the milder mumps presentation. therefore, one could argue that the original vaccine efficacy for clinical manifestations was over estimated. currently the laboratory diagnosis of mumps infection in ireland is based upon two approaches: detection of mumps rna by reverse transcriptase pcr (rt-pcr) in a buccal swab containing saliva, throat swab or urine specimen, and serological detection of immunoglobulin m (igm) using a capture assay ( , ) . both approaches for diagnosis are impacted significantly by the quality and timing of sample collection post-onset of symptoms and also if the subject is mumps naïve or had received mumps containing vaccine ( , , , ) . there are challenges in using standard serological laboratory diagnostic methods to reliably confirm mumps re-infection of individuals who had been previously naturally infected or vaccinated ( , ) . briefly, vaccinated individuals re-infected with muv may only generate a weak or undetectable igm response ( ) . although a rise in igg titer may also not occur in vaccinated individuals ( , ) , numerous studies have documented a rapid, variable increase in mumps-specific igg levels, with neutralization antibody concentrations present up to months post-infection ( , , ) . therefore, reverse transcriptase-polymerase chain reaction (rt-pcr) is recommended ( , ) , and was formally introduced in as the principle diagnostic tool in ireland to detect mumps in oral fluids ( ) . rt-pcr can identify current mumps infection more effectively in vaccinated individuals than serological techniques alone as it identifies the presence of the muv vs. the immunological response (igg, igm), and has been previously shown to % correlate with viral culture results ( , ) . the case numbers of more recent mumps outbreaks should always be assessed with this question in mind; are the number of mumps cases increasing, or/and are we better at diagnosing an acute infection? the latter seems to be the most probable, as many individuals who are being tested do not present with classical symptoms. in addition to enhanced surveillance of mumps cases, further optimizations of technologies are also occurring; the utilization of next-generation sequencing demonstrated that by editing one -fold degenerate nucleotide in the forward primer and three -fold degenerate nucleotides in the probe sequence optimized the fluorescence intensity and clinical sensitivity of the real-time rt-pcr when compared to the cdc-developed and who-recommended rt-pcr target [(np) gene] leading to ∼ % increase in clinical sensitivity (i.e., ct values that were ∼ . cycles lower) ( ) . much is not known about the immunological response to the mumps vaccine strain. however, a number of young adults who were vaccinated as children over the last two decades have demonstrated an increased risk of muv infection with time, which is assumed to be related to a decline of antibodies to sub-protective levels of immunity ( , , , , ( ) ( ) ( ) ( ) . primary vaccine failure is defined as the lack of a sufficient initial antibody response to a vaccine in a recipient resulting in a lack of protective immune responses ( , ) . although this type of vaccine failure may be because of improper storage/handling or administration of the vaccine, impacting its efficacy, it may also be due to the initial immunological response of an individual to the vaccine, which is usually quantified by the presence of antibodies that should be detectable in the weeks following vaccination. primary vaccine failure was attributed to primaryschool outbreaks of both mumps and measles in ireland, which subsequently resulted in reducing the age for the second dose of mmr vaccine from - years in to - years of age ( ) . with the cyclical outbreaks occurring, it has been proposed that primary vaccine failure could again be a factor. how is a response to a vaccine determined? in pre-licensure studies of the jl and urabe mumps vaccines, high seroconversion and low failure rates were observed in children after the first vaccine dose (> and . %, respectively), demonstrating that the vaccine induced an antibody response ( ) ( ) ( ) ( ) ( ) ( ) . a more recent study by ong et al. demonstrated that a ≥ fold increase in mumps antibodies -days post-vaccination was considered to be an adequate response of immunity ( ) . vaccine effectiveness (i.e., seroconversion post-vaccination) of vaccine doses has only been conducted on the jl strain; studies provided a median vaccine efficacy of %. these studies have shown that doses of mmr were more effective (but not statistically significant) than a single mmr dose to combat the incidence of mumps infection ( , , , , , ) . mumps-specific antibodies have been detected - years postvaccination and without substantial decline for years after mumps vaccination, with the immunogenicity and efficacy of the mmr vaccine showing comparable immunogenicity levels to post-vaccination levels at years ( , ) . however, most studies of this vaccine (involving either a mumps-specific vaccine or a combined vaccine) only followed-up to - days postvaccination ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . despite few follow-up studies estimating post-vaccination antibody titers specific to the vaccine mumps strain, the evidence of seroconversion post-vaccination in a number of studies indicate that primary vaccine failure does not seem to be a significant contributor to the outbreaks that have been recently observed ( , , , , , ( ) ( ) ( ) ( ) . it has been noted that a small percentage of the population do not seroconvert post-vaccination; < % who received the mmr vaccine were seronegative - years after the first dose of mmr (n = ) ( ) . poor immune responses to primary vaccination has been shown to be a good indicator of infection susceptibility ( ) . this is in agreement with the correlation of pre-outbreak jl virus neutralization titres and elisa results being significantly lower in individuals who became infected compared to non-infected individuals ( ) . further studies of these individuals may provide insights of which immunological process are integral to develop immunity. the current methods used to determine immunity against mumps cannot discriminate between primary and secondary vaccine failure; only the timing of these tests can assess whether an individual ever mounted an immune response postvaccination or whether the response is detectable years postvaccination. primary vaccine failure encompasses the failure to mount an immune response to a dose of a vaccine, secondary vaccine failure refers to a more gradual loss of immunity after a successful initial response that occurs over a number of years post-vaccination ( ) . several factors have been proposed to be implicated with secondary vaccine failure, such as waning immunity, a lack of cross-neutralization, and natural boosting. waning immunity is defined as a decline in immunological protection proportional to time since vaccination. potential waning immunity has been documented in the current mumps outbreaks seen in europe and the usa, mostly affecting young adults within highly vaccinated populations attending tertiary education who have received two doses of the mmr vaccine in early childhood ( , , , , , ( ) ( ) ( ) ( ) ( ) ( ) ( ) . a number of studies from the usa, where a jl vaccine has been used since have demonstrated waning immunity within the population. the risk of developing clinical mumps was shown to increase by - % for every year post-mmr vaccination ( ) , with the rates of mumps infection rising from . cases per , in those who received the second dose of the vaccine within years of the outbreak, to . cases per , in those who received it over years prior. using a mathematical model with analytical limitations, a recent metaanalysis of six studies estimated that vaccine-derived immune protection to muv wanes about years post-vaccination ( ) . kennedy et al. ( ) also demonstrated a decrease of ∼ % in mumps neutralizing antibody titers over years. in contrast, other studies appear to contradict, these findings, showing no link between mumps protection and time elapsed following administration of mumps vaccine ( , , , , ) . lebaron et al. ( ) and gothefors et al. ( ) demonstrated that - % of individuals still had detectable anti-mumps antibodies ∼ years after initial vaccination. cohen et al. ( ) also demonstrated minimal antibody level decline after two mmr doses - years after second vaccination. neutralizing antibodies against the jl- vaccine strain has also been detected in ∼ % for age groups - years, % for age group - years; and % for age group + years ( ) . implementation of a third dose of the mmr vaccine has been shown to be effective as a stop gap measure in limiting disease spread in outbreak settings situations ( ) . individuals vaccinated for the third time had a % lower risk of contracting mumps, with a decreased attack rate of . vs. . cases per , when compared to those who received a second dose. more than % of those who received a third dose of the mmr vaccine showed a -fold increase in mumps antibody titers ( , , , ) . an increase in mumps igg humoral immunity was also observed post-vaccine administration. however, this immunity boost has been shown to be a transient effect, with mumps antibody titers returning to pre-third dose of mumps-vaccination levels year after vaccination. therefore, as waning immunity is thought to be an important factor facilitating mumps outbreaks, the emphasis placed on the quantity/quality of mumps-specific antibodies may need to be re-assessed. it is yet undetermined if the total loss of detectable antibodies correlates to a loss of clinical protection, as the minimal level of neutralizing antibody required for protection against mumps has not yet been defined ( ). antigenic variation and thus reduced cross-neutralization between the vaccine and circulating strains of different muv genotypes have been cited as possible explanations for mumps outbreaks in highly vaccinated populations ( , , ( ) ( ) ( ) . recent outbreaks in europe and northern america (including ireland) have shown the circulating muv during the current outbreaks to be genotype g ( , , , ) . this muv genotype was first identified in , and has demonstrated intra-genotype diversity of up to % (table ) ( , ) . the jl vaccine strain (genotype a), differs phylogenetically to the circulating muv (genotype g) ( ) . in vitro studies of the genotypic distribution and temporal shift of muv suggest that cross neutralization between wild type and vaccine genotypes may be approximately half the concentration measured against the vaccine strain ( ) . pre-infection neutralization titers in mumps positive cases were also significantly lower against genotype g vs. mumps vaccine strain, potentially due to amino acid differences in b-cell epitopes and/or n-linked glycosylation sites on the hn and also within the f protein ( ) . santak et al. ( , ) also demonstrated that conformational changes within the f protein may lead to immunological escape. despite the decline/scarcity of cross-neutralizing antibodies, different mumps vaccines used worldwide have been shown to prevent significant clinical mumps infection during outbreaks ( , ) . dependent on the strain, a - -fold variation of patient sample titers has been shown to be protective in in vitro plaque reduction neutralizations ( , , ) . although the sera of one of these studies, was collected only weeks after mmr vaccination, a time point that may not signify the concept of waning immunity and antigenic differences, several other groups have shown that the most divergent strains of muv can be neutralized in vitro with only slight variations in titers, supporting the concept that muv is serotypically monotypic ( , , , ) . epitopes of the muv that are presented to cd + t-cells have been shown to be present in not only the circulating strains of virus but also in a number of vaccine strains ( ) . in addition, lewnard et al. ( ) also found no evidence that recent mumps outbreaks were due to the emergence of muv strains escaping vaccine-driven immunological pressure. therefore, the limited data does not suggest that antigenic drift of the muv leading to diminished neutralization capacity of the vaccine strain could fully explain the recent outbreaks ( ) . further studies into the cross-neutralizing capacity of the mumps vaccine strain administered - years previously to the current circulating strain of muv in countries where outbreaks are being observed will allow better deductions to be made. it is possible that differences in the neutralization capacity of vaccine-induced antibodies against different muv strains may be more significant when levels of neutralizing antibody are low and become "overwhelmed" when the mumps viral load challenge is high ( ) . several prominent mmr/mumps vaccine studies were undertaken at a time when there was still a high prevalence of circulating wild type virus, which enabled sub-clinical boosting to occur in an individual. such natural boosting is illustrated in belarus, where a subpopulation of vaccinated individuals only had a small amount of their overall mumps igg antibody levels specific to the vaccine-strain ( ) . neutralization antibodies against iowa-g/usa (the circulating wild type virus) were also present in pre-infection plasma of all mumps cases during a recent outbreak in the us ( ) . this indicates that the mumps vaccine alone is not solely responsible for the high levels of mumps antibodies ( ) , and that longterm antibody persistence or protective efficacy data of the vaccines used may not truly reflect the current circumstance of viral transmission/circulating within a highly vaccinated population ( ) . herd immunity increases the chance for natural mumps boosting for an individual is at a minimum, reducing the potential of the frequency of mumps outbreaks ( , , ) . with less opportunity for subclinical boosting (asymptomatic response to the circulating virus), the impact of other elements of waning immunity may play an increasingly critical role in the re-emergence of mumps outbreaks ( , ) . additionally, as the heterogeneous uptake of vaccines in this modern era is leading to susceptible individuals within the community, future work will need to encompass genotyping of circulating muv to examine how impactful subclinical boosting was on early measures of vaccine efficacy in current populations. why do we consider antibodies to be the best measurement of vaccine efficacy? the evolution of an individual's immune response differs between natural infection and vaccination, in particular the difference in the affinity and specificity of an immunological marker such as antibodies ( ) . true correlates of mumps immunity after vaccination have been poorly characterized; to date, there are no reliable correlates of protection from either symptomatic mumps infection (clinical immunity), or individuals previously exposed to muv ( ) . therefore, a serological surrogate/ substitute is used ( ). mumps vaccine efficacy is quantified by a single measure, igg which may not suffice to evaluate the magnitude of the actual humoral response. borgmann et al. ( ) proposed an increase in mumps-specific igg titer in sera as a diagnostic criteria of mumps reinfection ( ) . it has been suggested that vaccinated individuals have modified b-cell responses to muv that allow for the rapid generation of igg antibodies and a blunted or absent igm response ( , ) . in addition, emerging data in simian immunodeficiency virus studies suggests that not all antibody responses are equal, and qualitative features of antibodies may be key to defining protective immune profiles ( ) . despite its use, the correlation to mumps-specific igg concentrations and neutralization titers against the jl virus is poor, suggesting that igg concentrations do not adequately represent a sufficient surrogate correlate of protection ( ) . this is demonstrated in finland; only % of vaccinees had no detectable mumps antibodies after years ( , ) . data from the european sero-epidemiology network (esen ) project in reported that mmr immunization uptake in ireland in was % ( ), however it was also suggested that only - % of -to -year-olds in ireland had detectable antibodies to muv by either natural immunity or immunization ( ) . in , vaccine coverage of medical students in germany was reported to be . % ( ) . in children between the ages of - years, where . % had been vaccinated with the mmr vaccine at least once, only . % showed prevalence of antibodies ( ) . however, . % showed a prevalence of antibodies to measles and rubella in the absence of mumps-specific antibodies. therefore, previous measurement of anti-mumps-specific igg that represented immunity induced by the mumps vaccine appears to be overestimated ( , ) . antibody levels of other components of the mmr vaccine have seen similar trends. waning rubella antibody titers have been observed, despite the number of acute rubella and congenital rubella syndrome cases not increasing. it has also been shown that college students who received rubella vaccination during childhood and had low/no antibody response were able to mount a secondary response when challenged with rubella indicating that an individual's low antibody levels are not always indicative of susceptibility to infection ( ) . measles antibodies can also be detected for up to a decade post-vaccination, with > % of individuals still measles igg positive at - years of age ( , ) . however, as with mumps and rubella, waning measles antibody titers have been observed ( , ) . despite this, a recent longitudinal study of up to years demonstrates how effective the mmr vaccine has been in preventing diagnosed measles cases during the 's/ 's ( ) . similarly, three doses of the hepatitis b (hbv) vaccine in a cohort of alaskan natives showed > % seroconversion in children and young adult post-vaccination and provided long term and durable protection against chronic hbv infection. although no increase of hbv prevalence were observed % individuals had low to undetectable antibody levels after years. these observations suggest that an individual's antibody levels do not indicate susceptibility to infection, that either an antibody titer lower than recommended guidelines is still protective, or/and is an ineffective surrogate of protection. this is emphasized in a study by amanna et al.; ( ) responses to non-replicating protein antigens (tetanus and diphtheria) were shown to have approximate antibody half-lives of - years. in comparison, antibodies following wild type infection were shown to have half-lives of years or more which was thought until recently to confer a more prolonged lifelong protection ( , , ) . however, reinfections observed in individuals that were previously naturally infected have demonstrated that the quantitative measurement of antibodies do not indicate sterile immunity ( ) . it is also important to stress that seroconversion rates due to immunization/natural infection only reflects a change of antibody status from negative to positive, but not necessarily the intensity of antibody response. in addition, there is no consistency in the timing of sample collected post-vaccination to test vaccine efficacy, and between the serological tests utilized for detecting mumps antibodies. as a result, documented seroconversion rates of the mumps vaccines used vary widely (jl: - %, rit strain: - %, urabe am : - %, rubini: - %). this highlights that the assays used to detect immunity to muv may not always detect an adequate post-vaccination response. only a small number of serological commercial assays such as the detection of hepatitis b surface antibody (anti-hbs) ( ) and rubella igg ( ) have been designed using who reference material as a standard for quantification. however, even utilizing this reference standard demonstrates significant differences in the determined quantification of either anti-hbs or rubella igg depending on the assays used; although a value for anti-hbs of iu/ml is regarded as protective against significant hbv infection, the detection of this anti-hbs is significantly influenced by which anti-hbs assays is used ( ) ( ) ( ) ( ) ( ) . therefore, it is possible that the current assays/tests mechanisms utilized to measure mumps antibodies are too insensitive/inappropriate/crude to identify nuances in the immune response which could correlate with immunity against mumps. in addition, variation within neutralization epitopes i.e., the quality of the antibody present could be a more important correlate than quantity ( , ) . though labor-intensive, neutralizing antibodies are considered to be a better correlate of mumps immunity. antibodies against the haemagglutinin-neuraminidase protein (hn) and nucleoprotein (np) have been shown to neutralize muv, however, repeated attempts to define a titer that provides a protective threshold titer have been inconclusive ( , ) . in older studies, during field evaluations of the jl vaccine, neutralizing antibody titers of : - : in unvaccinated individuals was considered seropositive and protective from mumps infection ( , , ) . using a more contemporary wild-type isolate (iowa-g/usa ), a : neutralizing titer cut off was defined between case patients and exposed patients, despite the fact that no cut-off could fully discern between the two groups ( ) . however, that these results are dependent on the challenge virus strain used in the assay. rasheed et al. demonstrated a fold lower neutralization titer to the g-genotype when compared to the jl vaccine strain in - year olds ( ) . this has also been seen between mumps vaccine strains vs. circulating strains in india and china ( , ) . despite studies in more highly vaccinated populations demonstrating that hn-inhibiting titers after natural disease were : compared to : post-vaccination, neither appeared to prevent reinfection ( , ( ) ( ) ( ) ) . there is increasing evidence that the mumps-specific antibody response is broader than neutralization alone ( ) . avidity testing for virus-specific igg has been proposed ( , , ) . individuals who lack measurable mumps-specific antibody levels may be susceptible to infection but protected from significant illness as they may be protected by cell-mediated immune memory. prolonged t-cell responses are reported after other vaccinations; - years after a single dose of the rubella vaccine ra / , a t-cell proliferative response to neutralizing antibodyinducing peptides suggest t helper and b-cell interactions. this indicates that full vaccine effectiveness could be dependent on mounting both an antibody and cell-mediated immune response ( ) . although cell mediated immunity has not been as wellassessed in mumps infection, a lymphoproliferative response was induced in infants vaccinated at , , or months of age was induced ( ) with antigen-specific t-cells reported to appear within month of infection ( ) . lymphoproliferative responses to measles and mumps vaccine viruses were shown to persist in two thirds of the population at least years after immunization ( ), with t-and b-cell immunity persisting for years post-immunization ( ) . low levels of mumps-specific memory b-cells have also been documented suggesting that mumps infection or vaccination may not generate a robust b-cell memory ( , ) . two principal mechanisms for maintaining long-term humoral immunity have been proposed and reviewed by amanna et al. ( ) : associations between memory b-cell levels and antibody may reflect an epiphenomenon in which serum antibody levels and memory b-cells are equally stable but independently maintained. if memory b-cells and plasma cells are independently regulated, then multiple re-exposures to antigens may cause divergence between memory b-cell levels and antibody levels ( ) . antigens with the highest rates of boosting through vaccination or latent viral infection coincidentally showed the weakest association between memory b-cell titers and antibody titers ( ). although the role and efficacy of t-cell immunity to mumps infection is unclear, there is a possibility that certain muv strains may be capable of escaping vaccine induced t-cell responses, which may not be considered of significance until b-cell waning immunity comes into play ( ) . in individuals who did not respond to vaccination (i.e., had a ≤ -fold of mumps antibody titers days post-vaccination), several genes including those implicated in antigen presenting, processing, t-cell response and function showed significantly increased expression, with mhc class ii hla-drb and hla-dra, and cd induced when compared to responders day post-mmr vaccination. this may indicate that the stimulation of a rapid adaptive immune response limits antigenic presentation and hence prevent the differentiation of memory b-cells to antibody-producing plasma cells ( ) . differences in predicted b-cell and t-cell epitopes between jl vaccine strain and other vaccine strains may also be implicated in the outbreaks witnessed ( ) . although, it has also been shown that natural mumps infection or vaccination do not always induce both cellular and humoral immunity. de wit et al. ( , , ) has shown the presence of th -type cd + t-cells recognizing a muv epitope in a hlr-dr restricted manner. in addition, the response of ifn-γ and tnf producing cd + t-cells specific to muv epitopes are lower in vaccinated individuals when compared to individuals who were naturally infected ( , , ( ) ( ) ( ) . utilizing current knowledge and new technologies may help define a better surrogate correlate of protection and potentially determine a cut-off between the immunity of a vaccinated individual and a secondary mumps infection. this may potentially move the diagnostic preference from serological tests to more comprehensive functional assays. despite the large resurgence of mumps outbreaks, there is insurmountable evidence highlighting the benefit of the mumps vaccine ( table ) . routine childhood mmr vaccination has resulted in a dramatic decrease in the incidence of mumps cases, and has shifted the peak age-specific attack rates from a young children (manifesting between and years) to one that affects young adults, in particular those who have close interaction with other young adults ( - years) ( , ) . additionally, clinical manifestations and severity of disease in vaccinated vs. unvaccinated individuals differ ( , ) . although muv can be clinically asymptomatic in about - % of those who become infected, the vaccine against mumps confers protection in a dose response manner; unvaccinated individuals saw an attack rate of based on the reduction seen upon the introduction of a mumps vaccine, it has been proposed that mmr vaccination also prevents the transmission of the virus. there is limited knowledge regarding the shedding and transmission of muv, but it is thought that close contact and transmission of a certain viral load may induce clinical symptoms ( , , ) . modeling data suggests that infectious muv shedding decreases rapidly after the onset of symptoms, however - % are patients are thought to still be virally shedding days after the onset of symptoms ( ) . this could be the reason why the transmission of muv can be exacerbated by close social situations within a heterogeneously vaccinated population. outbreaks generally occur in situations of intense contact such as college dormitories, boarding schools, and youth summer camps ( ) , with up to a third reporting some contact with a mumps case ( ) . evidence of lower levels of viral replication also suggests a clinical benefit of the vaccine ( , ) . viral load and presence of the mumps vaccine genome in areas of viral replication was lower in vaccinated individuals vs. unvaccinated individuals ( ) . in addition, patients who contracted mumps but had two doses of mmr have been shown to shed less muv in their urine, with fewer experiencing bilateral parotitis or orchitis than unvaccinated individuals ( ), this suggests that immunity induced by mmr vaccination limits virus transmission and complications ( , ) . it should be noted also that individuals who received two doses of mmr, and had a positive correlation between viremia, salivary viral loads and systematic clinical mumps infection may have an increased risk of transmitting virus. these individuals also lacked mature functional responses, with low neutralizing antibody titers and avidity indexes ( ) . overall, evidence demonstrates a clinical advantage to receiving a mumps vaccine ( table ) . currently no global consensus exists for the measurement of mumps antibodies, mumps avidity or neutralizing titers that correlate to vaccine response and protection in healthy individuals. if a biomarker is discovered, it could be utilized as an international diagnostic reference standard to allow global harmonization and evaluation of the relative effectiveness of the different vaccination programs worldwide. such an attempt was conducted by andrews et al. ( ) , who reported on the european sero-epidemiology network project which was established to harmonize the seroepidemiology of five vaccine preventable infections including measles, mumps, and rubella in eight european countries. the study concluded that the development of an international standard for mumps would help in the standardization and comparability of mumps antibodies in the different enzyme immunoassays used in laboratories. however, to date, no international reference standard for mumps has been established. in response to infection, the human immune system launches a series of immunological responses with the goal of controlling or eliminating the pathogen. if the pathogen circumvents the frontline defense of the innate immune system, an adaptive immune response specific for the pathogen will become activated to respond, with the intention to generate humoral-and cell-mediated immunity. humoral immunity, represented by antibodies secreted by b-cells are not effective against pathogens that invade host cells. therefore, cell-mediated immunity instructed by the vaccination aims to stimulate the host immunological process and formation of cell-mediated immunological memory via the use of live-attenuated or of inactivated/subunit vaccine components to promote a cell-mediated immune response. extensive knowledge gaps significantly hinder improvements to the mumps vaccine and prospects for mumps eradication and maintaining proficient population immunity ( , , ) . few studies have collected data that examines different aspects of mumps immunity and are limited in their predictive value for future outbreaks ( ) . for example, the importance of t and b-cell responses in protective mumps immunity and how memory/plasma cell numbers are homeostatically maintained post-infection or vaccination is relatively unknown ( ) . it should be acknowledged that the mechanism of protection of infection may not be the same mechanism of recovery from infection, which may make the identification of a common correlate of protection and recovery difficult ( ) . therefore, if a correlate or surrogate correlate is unobtainable to define an individual's protection to mumps, should we re-consider and re-focus efforts on optimizing the vaccine using available historical clinical and trial data? it has been suggested that wild-type infection could confer a "better quality, " broader and prolonged immuno-activation than vaccine-induced immunity. this is reflected in mean neutralizing antibody titers detected post-mumps vaccination, which were over five times lower than those detected following wild type infection. similarly, hemagglutination-inhibiting titers after natural disease were : compared to : post-vaccination ( , , ) . the use of a live-attenuated virus vaccine is intended to mimic immunological reactions and responses between the host and wild type virus ( ) . the current liveattenuated mmr vaccine is intramuscularly injected, a route that significantly differs from the natural infection mode of transmission. however, emphasized by differing immunological kinetics between immunized and naturally infected individuals when subjected to wild type pathogens, injectable vaccines are considered not to be the best inducer of antigen-specific mucosal immune responses for mucosal pathogens, especially if the mode of administration is not the natural route (the respiratory tract) ( , ) . improvements on a broader range of antigen delivery systems will improve vaccination strategies and potentially prolong the effect of a vaccination by producing a localized immunological response in the relevant tissues ( , ) . mucosal vaccines such as intra-nasal vaccination have advantages over traditional injectable vaccines as they can induce an effective, more robust immune response without any physical discomfort and more closely replicate the natural route of infection for mumps ( , ) . b-cells induced by the mucosal response are also capable of secreting iga class of antibodies in the lumen, where the interaction and neutralization of specific antigens form iga-antigen complexes are easily able to be entrapped in the mucus and eliminated by cilial epithelial cells ( ) . activated mucosal lymphocytes can also reach other mucosal sites via the lymphatic system and have the capability to transfer immunity ( ) . such an example is the intranasal immunization of inactivated influenza. with a - % similar efficacy between the injectable and intranasal influenza in healthy individuals this intranasal vaccine can elicit the secretion of haemagglutinin and neuraminidase specific iga antibodies in the upper respiratory tract, and corresponding igg antibodies ( ) . live, cold adapted attenuated nasal influenza vaccine has been routinely used in russia for over years ( ) . other liquid live-attenuated intranasal vaccines are available; "nasovac r " in india, and "flumist r " in the us, uk and new zealand ( , , ) . inactivated vaccines consisting of heat/chemical or liveattenuating monovalent or multivalent pathogens in animals/cell lines were developed to protect against disease causing microorganisms ( ) . less emphasis was placed on understanding the mechanisms related to conferring immunological memory; the focus lay on the availability, mass production and administration of the vaccine to introduce herd immunity into populations ( ) . currently, the least expensive and time effective method to licensure is the comparison of serologic responses of the new vaccine to an existing licensed vaccine, which can lead to a bias on the development of novel vaccines ( ) . this methodology also does not account for the fact that each vaccine developed elicits its own immunological signature and may need to be considered on an individual basis ( ) . raymond et al. ( ) has suggested that embryonated chicken egg-based vaccines may induce antibodies that are more preferential to egg adapted strains better than wild type virus. amino acid substitutions/differences in key antigenic targets due to the passage of the growing virus within this environment may optimize the growth of the virus, but could lead to differences over time that could affect the immunogenicity or potency of the vaccine ( , , ) . the jl vaccine contains two isolates of the jl strain (jl and jl ) and whilst no immunological differences have been documented, jl grows to higher titers than jl in embryonic eggs and also demonstrates significant sequence variability ( , ) . zost et al. ( ) also demonstrated that an egg selected mutation within a glycosylation site in the - influenza vaccine strain led to the production of poorer neutralizing antibodies to the vaccine strain compared to wild type influenza virus. vaccine rit strain derived from one of the two distinct virus subtypes of the jl vaccine (jl ) showed comparable seroconversion rates despite inducing a significantly lower geometric mean antibody titer when compared to recipients of the jl vaccine, but does not have any longitudinal trials investigating its efficacy, even though there are populations who are currently receiving it ( , ) . the significant time gap between pathogen emergence and vaccine licensure, could potentially lead to antigenic drift. there is potential that modern biotechnologies could be utilized to design novel vaccine platforms ( , , ). clinically derived recombinant muv lacking the expression of the immunomodulatory v or sh protein are currently being investigated ( ) . in china, a vaccine consisting of the prevalent wildtype virus genotype (f) has recently been produced and is currently undergoing trials ( ) . in addition, despite being extremely pleomorphic, utilizing mhc epitopes as potential b-cell and t-cell vaccine candidates are also being investigated ( , , ) . vaccine design has involved the utilization and templating of epitopes that previously induced a b-or t-cell response during natural disease that are considered to be immunogenic enough to induce similar responses if administered in a vaccine. however, the appropriate b-cell and t-cell epitope/peptide candidates to induce a protective immunological response can be difficult to correctly identify and synthesize, as it may differ to the immunodominant epitope and host presentation of that antigen ( , ). prediction of mhc-peptide binding and cleavage has demonstrated mismatches in both vaccine tcell and b-cell epitopes in vaccinated individuals highlighting small number of distinguishing amino acid changes of the jl major strain ( ) . the importance of understanding tand b-cell responses and how antigen-specific memory cells numbers are homeostatically maintained post-infection is crucial to understand to ensure successful vaccine development ( , ) . since the 's, significant progress has also been made in developing flexible, amplifiable, scalable, inexpensive, and cold-chain free rna vaccines, such as synthetic mrna molecules encoding only the antigen of interest and selfamplifying rna (sa-rna) ( ) . such examples include an experimental mrna vaccine candidate (mrna- ) which encodes a stable form of the sars-cov- spike protein and has been accepted as a trial candidate for clinical trials in healthy male and female individuals ( , ) . in addition, sa-rna viruses as gene delivery and vaccine vectors have also demonstrated therapeutic efficacy in a number of preclinical studies. in the context of influenza, sa-rna vaccines have shown comparable results of protection at lower doses than mrna vaccines ( , , ) . exponential developments in the "omic" area has enabled further vaccine development and understanding of the immunological response and challenges surrounding this area ( ) . systems vaccinology, which includes immunoformatics, dna/rnaseq, microarrays, mass spectrometry proteomics, transcriptomics, and metabolomics have all shown huge potential in elucidating differences in vaccine strains, vaccine growth and individual response in depth and on an epigenetic level allowing the identification of new vaccine antigens with increased speed and sensitivity ( , , ( ) ( ) ( ) . adjuvants, a group of biological and chemical compounds could also be considered to enhance and improve the longevity of the immune response of a vaccine such as the mmr. adjuvants have been successful in significantly reducing overall antigen dose in vaccine formulations as well as alter and broaden the host response through epitope spreading and qualitatively shaping the effector function of antibodies through subclass selection ( , ) . the re-purposing of live-attenuated vaccines as tibv are also being investigated. trained immunity based vaccines (tibv) elicit heterologous protective effects by inducing a broader, lasting priming of innate immune cells, in addition to the intended specific immunological response and memory of conventional vaccines [reviewed in ( ) ]. mmr and bcg vaccines have been considered as potential tibv in the context of the current coronavirus disease (covid- ) pandemic ( ) , however further research is needed. the mumps component of a vaccine is an unpurified product whose potency is measured through a biological assay for the substance rather than through evaluation of integrity of physical form (quantitative pcr after cell culture) ( ) . a monovalent mumps vaccine lot is used to characterize the performance of the mumps potency assay with international reference standards. degradation products are neither identified nor quantified ( ) . currently, the minimum potency of the mumps vaccine used varies between brands used [summarized by su et al. ( ) ] ( ) . however, this potency measurement differs to other mmr vaccines strains previously used [reviewed in ( ) ]. in addition, the maximum required potency is not usually specified. atrasheuskaya et al. ( ) demonstrated that the four out of lots of vaccine associated with six cases of viral transmission postvaccination to previously vaccinated contacts were in fact twice as potent as the lots that were not associated with viral transmission post-vaccination ( , ) . this may impact the use and efficacy of specific vaccines. due to their neurovirulence and increased incidence of aseptic meningitis and mumps cases, the urabe am and rubini mumps vaccine strains were discontinued in many countries ( , , ) . comparing alternative culturing technologies and defining a viral potency range for vaccines could help reduce variability within the mmr vaccine ( ) . ensuring the use of a reference sample that had similar replication rate and composition as the virus to be tested will allow accurate determination of the quantity of virus present per lot of vaccine. investigating novel vaccine candidates shown to induce a similar quantity but qualitatively different antibodies will help segregate and reveal potential correlates of protection ( ) . incorporating more modern technologies such as microarray technology or antibody pattern/profiling (rather than single antibody measures) to investigate biomarkers of neutralizing antibody response and/or correlates of protective immunity, in addition to incorporating what has been accomplished in finland will allow further understanding of mumps immunity ( , , , , , ) . the efficacy of a vaccine is defined by disease prevention (sterile immunity, establishment of primary infection and shedding of mature virus particle), or complications associated with infection (orchitis, neurological issues etc.) ( ) . despite the well-documented success of the global immunization programs demonstrating how vaccines significantly attenuate disease and onward transmission of infection, they are rarely totally efficacious (demonstrated in pre-licensure clinical trials) or effective (determined by practical use) ( , , ) . therefore, does "immunity" refer to sterile immunity or solely to protection from symptomatic infection? what defines an effective vaccine, or what constitutes vaccine failure? does the medical profession and the "pro-vaccine" message contribute to the public skepticism regarding immunization? is it time to shift the medical and public perception paradigm from "protection of infection following vaccination" to "protection from serious clinical mumps manifestation"? the lack of definition leads to misinterpretation by health professionals and media of what is truly occurring. such an example is currently observed with influenza; individuals who have recently being vaccinated against influenza and subsequently become infected with influenza, assume that the vaccine has "failed" even though there is a reduction in symptoms. the current assertion that vaccines "protect against" or "eliminate" the risk of infection may contribute to the misperception about what level of protection a vaccine actually provides (vaccination efficacy) perpetuated by the witnessing of visible clinical disease and outbreaks despite vaccination ( , , ) . therefore, definition and consensus of what is termed a true "vaccine failure" is required to inform both the clinical and public perception of what the function of a vaccine is. deciding what the clinical endpoint of a vaccine is i.e., infection with mild clinical symptoms vs. natural infection/disease with its associated complications and assessing the impact of the vaccine in a heterogeneously vaccinated population will allow a better consensus of what is required. a paradigm shift in what is considered to be a good vaccine i.e. one that provides protection against serious clinical sequalae, in addition to identifying a reliable laboratory marker for this protection is required ( ) . by focusing on, and acknowledging that vaccines may not prevent infection but will attenuate the clinical complications/consequences that arise from infection in addition to reducing onward transmission will provide a more realistic view of the benefits of vaccination ( ) . immunity is therefore beneficial but does not necessarily mean protection. if we can decide whether the end point of a vaccine is either the prevention of infection or protection against serious sequalae of infection, its efficacy and impact can be determined and will have enormous implications on how vaccine failure can be studied, quantified and interpreted. this teasing out of the immunological response to muv will ultimately provide potential correlates with robust predictive power, suggest directions for further vaccine improvement, and enable the discovery of potential biomarkers to help create a more efficient diagnostic assay that can discern between different infectious diseases and vaccination vs. disease status. the identification and incorporation of a correlate into diagnostic protocols which can be widely accessible may potentially allow global harmonization of criteria defining immunological protection against mumps. the medical and scientific field needs to inform the public more accurately about what a good vaccine consists of, which may result in a more positive attitude toward vaccines. in the majority of individuals, a vaccine can prevent serious clinical sequalae and associated complications following wild type infections, but also significantly reduce onwards transmission in particular to the cohorts who are not vaccinated due to a contraindication to vaccination. this is the positive and realistic view of vaccination which should be presented rather than the current flawed message of "get the vaccine and be protected from infection." the public deserves, and will appreciate, a more accurate and informed message. ac, jc, and jh contributed to the conception and design of the review. ac wrote the first draft of the manuscript. jc, tl, and jh contributed to manuscript revision. all authors have read and approved the submitted version. this work was funded by the national children's research centre, children's health ireland, dublin, ireland with grant number c/ / awarded to jh. mumps virus analysis of mumps vaccine failure by means of avidity testing for mumps virus-specific immunoglobulin g infectiousness of communicable diseases in the household (measles, chickenpox, and mumps) hearing loss due to mumps molecular epidemiological evaluation of the recent resurgence in mumps virus infections in ireland isolation of virus during the incubation period of mumps infection function of small hydrophobic proteins of paramyxovirus proposed criteria for classification of new genotypes of mumps virus mumps in the vaccination age: global epidemiology and the situation in germany measles resurgence in argentina: - outbreak available online at triple viral/double viral immunization: coverage data of mmr and mmr national vaccination calender everything you need to know about the new vaccination law in argentina molecular identification of mumps virus genotypes from clinical samples: standardized method of analysis genomic diversity of mumps virus and global distribution of the genotypes world health organization. mumps reported cases (as of austrailian government department of health. . mumps (last updated mumps laboratory case definitnion austrailian institute of health and welfare parental opinions towards the "no jab, no pay a protracted mumps outbreak in western australia despite high vaccine coverage: a population-based surveillance study immunogenicity and safety of the combined vaccine for measles, mumps, and rubella isolated or combined with the varicella component administered at -month intervals: randomised study calendários de vacinação sbim vacina sarampo, caxumba, rubéola e varicela (atenuada) outbreak of aseptic meningitis associated with mass vaccination with a urabe-containing measles-mumps-rubella vaccine: implications for immunization programs outbreak of aseptic meningitis and mumps after mass vaccination with mmr vaccine using the leningrad-zagreb mumps strain detection of a new mumps virus genotype during parotitis epidemic of - in the state of sao paulo, brazil reemergence of mumps in sao paulo, brazil-the urgent need for booster shot campaign to prevent a serious infectious disease guidelines for the prevention and control of mumps outbreaks in canada (archived) guidelines for the prevention and control of mumps outbreaks in canada. mumps-containing vaccine and immunization programs in canada immunization coverage report for school pupils in ontario. - school year. toronto, on: queen's printer for ontario investigation and management of a large community mumps outbreak among young adults in toronto guidelines: mumps in canada assessment of onedose mumps-containing vaccine effectiveness on wild-type genotype f mumps viruses circulating in mainland china mumps epidemiology and mumps virus genotypes circulating in mainland china during - importation of mumps virus genotype k to china from vietnam waning immunity against mumps in vaccinated young adults pediatric vaccines: global brands and country availability available online at information sheet observed rate of vaccine reactions. measles, mumps and rubella vaccines routine immunization: regional and country profiles summary of routine immunization and vaccine-preventable diseases surveillance data, based primarily on data for submitted through the who/unicef joint reporting form on immunization measles elimination efforts and - outbreak progress toward measles elimination in germany immunogenicity of mumps virus vaccine candidates matching circulating genotypes in the united states and china routine immunization: regional and country profiles; germany. summary of routine immunization and vaccine-preventable diseases surveillance data, based primarily on data for submitted through the who/unicef joint reporting form on immunization list of the names, pharmaceutical forms, strengths of the medicinal products, routes of administration, marketing authorisation holders in the member states (annex , article ) mumps and mumps vaccine: a global review live attenuated measles mumps and rubella vaccines: an over view the epidemiology of mumps in italy pediatric sentinel surveillance of vaccinepreventable diseases in italy available online at the law on compulsory vaccination in italy: an update years after the introduction mmr vaccination and autism european centre for disease prevention and control. : annual epidemiological report for ; mumps measles in mexico, - : interruption of endemic transmission and lessons learned detection of mumps virus genotype h in two previously vaccinated patients from mexico city missed opportunities for measles, mumps, and rubella (mmr) immunization in mesoamerica: potential impact on coverage and days at risk el programa nacional de vacunacion: orgullo de mexico progress toward measles elimination in the russian federation routine immunization: regional and country profiles; russian federation. summary of routine immunization and vaccine-preventable diseases surveillance data, based primarily on data for submitted through the who/unicef joint reporting form on immunization mumps vaccine failure investigation in safety evaluation of mmr vaccine during a primary school campaign in saudi arabia measles in saudi arabia: from control to elimination measles immunization in saudi arabia: the need for change ministry of health saudi arabia. ministries of health and education start a vaccination campaign against measles, mumps and rubella reemergence of mumps genetic characteristics of mumps viruses isolated in korea from to increasing mumps incidence rates among children and adolescents in the republic of korea: age-period-cohort analysis compulsory vaccines to be applied to baby after birth in turkey the national vaccination schedule in previously healthy children: the practical recommendations about additional vaccines routine immunization: regional and country profiles; turkey. summary of routine immunization and vaccine-preventable diseases surveillance data, based primarily on data for submitted through the who/unicef joint reporting form on immunization genotyping of mumps virus circulating in turkey in the - winter season risks of convulsion and aseptic meningitis following measles-mumps-rubella vaccination in the united kingdom nhs vaccinations and when to have them routine immunization: regional and country profiles; united kingdom of great britain and northern ireland. summary of routine immunization and vaccine-preventable diseases surveillance data, based primarily on data for submitted through the who/unicef joint reporting form on immunization proteomics for development of vaccine viral mumps: increasing occurrences in the vaccinated population. oral surg oral med oral pathol oral radiol centre for disease control and prevention. recommended child and adolescent immunization schedule for ages years or younger, united states vaccination coverage for selected vaccines and exemption rates among children in kindergarten -united states, - school year vaccination coverage among children aged - months -united states the molecular epidemiology of mumps virus the immunological basis for immunization series module : mumps. world health organization vaccination of human beings against mumps; vaccine administered at the start of an epidemic. i. incidence and severity of mumps in vaccinated and control groups preparation of mumps vaccines and immunization of monkeys against experimental mumps infection european centre for disease prevention and control. mumps: vaccine scheduler available online at: https://vaccineschedule.ecdc.europa.eu/scheduler/bydisease? live attenuated mumps virus vaccine. . vaccine development increased mumps incidence in the netherlands: review on the possible role of vaccine strain and genotype molecular differences between two jeryl lynn mumps virus vaccine component strains, jl and jl the jeryl lynn vaccine strain of mumps virus is a mixture of two distinct isolates health protection surveillance centre. definition of an outbreak estimation of the efficacy of three strains of mumps vaccines during an epidemic of mumps in the geneva canton (switzerland) comparative efficacy of rubini, jeryl-lynn and urabe mumps vaccine in an asian population estimates of mumps seroprevalence may be influenced by antibody specificity and serologic method mumps outbreak in a highly vaccinated student population mumps outbreak, england. emerg infect dis mumps outbreak in the republic of moldova mumps outbreak in jerusalem affecting mainly male adolescents ongoing mumps outbreak among adolescents and young adults mumps outbreak in a highly vaccinated university-affiliated setting before and after a measles-mumps-rubella vaccination campaign-iowa mumps outbreaks at four universities-indiana current status of mumps virus infection: epidemiology, pathogenesis, and vaccine mumps: an update on outbreaks, vaccine efficacy, and genomic diversity a report on the status of vaccination in europe mumps resurgences in the united states: a historical perspective on unexpected elements failure to vaccinate and vaccine failure the burden of disease and the changing task of medicine the politics of prevention: anti-vaccinationism and public health in nineteenth-century england a population-based cohort study of undervaccination in managed care organizations across the united states world health organization. meeting of the strategic advisory group of experts on immunization misinformation lingers in memory: failure of three pro-vaccination strategies delaying vaccination is not a safer choice reactogenicity and immunogenicity of a new live attenuated combined measles, mumps and rubella vaccine in healthy children measles, mumps, rubella vaccination and autism: a nationwide cohort study measles, mumps and rubella (mmr) vaccination has no effect on cognitive development in children-the results of the polish prospective cohort study available online at sustained transmission of mumps in a highly vaccinated population: assessment of primary vaccine failure and waning vaccine-induced immunity rapid effect on endemic measles, mumps, and rubella of nationwide vaccination programme in finland measles, mumps, and rubella in finland: years of a nationwide elimination programme knowledge gaps persist and hinder progress in eliminating mumps recent resurgence of mumps in the united states brief report: update: mumps activity-united states an outbreak of mumps in sweden mumps outbreaks in canada and the united states: time for new thinking on mumps vaccines dynamics of the serologic response in vaccinated and unvaccinated mumps cases during an epidemic challenges in interpretation of diagnostic test results in a mumps outbreak in a highly vaccinated population laboratory-based investigation of suspected mumps cases submitted to the german national reference centre for measles, mumps, and rubella comparison of the sensitivity of laboratory diagnostic methods from a wellcharacterized outbreak of mumps in new york city in enzyme-linked immunospot assay detection of mumps-specific antibodysecreting b cells as an alternative method of laboratory diagnosis mumps outbreak in a highly vaccinated school population: assessment of secondary vaccine failure using igg avidity measurements seroepidemiology of the recent mumps virus outbreaks in ireland laboratory testing and phylogenetic analysis during a mumps outbreak in ontario \sim:text=rt% dpcr% and % viral% culture,aid% in% diagnosing% mumps% infection diagnosis of acute mumps infection during an outbreak in a highly vaccinated population: mumps rna or mumps igm detection? monitoring viral genetic variation as a tool to improve molecular diagnostics for mumps virus persistence of mumps antibodies after doses of measles-mumps-rubella vaccine persistence of measles, mumps, and rubella antibodies in an mmr-vaccinated cohort: a -year follow-up mumps vaccine performance among university students during a mumps outbreak emerging mumps infection epidemiology of a mumps outbreak in a highly vaccinated island population and use of a third dose of measles-mumps-rubella vaccine for outbreak control-guam long-term follow-up for immunity after monovalent or combined live measles, mumps, and rubella virus vaccines persistence of antibody in human subjects for to years following administration of combined live attenuated measles, mumps, and rubella virus vaccines studies on live attenuated mumps vaccine. i. comparative field trials with two different live vaccines live attenuated mumps-virus vaccine. iv. protective efficacy as measured in a field evaluation live attenuated mumps-virus vaccine. . clinical and serologic aspects in a field evaluation experiences with jeryl lynn strain live attenuated mumps virus vaccine in a pediatric outpatient clinic genomic signature of early t-cell response is associated with lower antibody titer threshold for sterilizing immunity the effectiveness of the mumps component of the mmr vaccine: a case control study measles, mumps, rubella vaccine (priorix; gsk-mmr): a review of its use in the prevention of measles, mumps and rubella immunogenicity and safety of a measles-mumps-rubella vaccine administered as a first dose to children aged to months: a phase iii, randomized, noninferiority, lot-to-lot consistency study a new measles mumps rubella (mmr) vaccine: a randomized comparative trial for assessing the reactogenicity and immunogenicity of three consecutive production lots and comparison with a widely used mmr vaccine in measles primed children immunogenicity and safety of measles-mumps-rubella-varicella (mmrv) vaccine followed by one dose of varicella vaccine in children aged months- years or - years primed with measles-mumps-rubella (mmr) vaccine similar immunogenicity of measles-mumps-rubella (mmr) vaccine administrated at months versus months age in children immune response to the mumps component of the mmr vaccine in the routine of immunisation services in the brazilian national immunisation program immunogenicity and safety of measles-mumpsrubella vaccine delivered by disposable-syringe jet injector in india: a randomized, parallel group, non-inferiority trial safety and immunogenicity of human serum albumin-free mmr vaccine in us children aged - months immunogenicity and safety of early vaccination with two doses of a combined measles-mumps-rubella-varicella vaccine in healthy indian children from months of age: a phase iii, randomised, non-inferiority trial duration of the immune response to mmr vaccine in children of two age-different groups antibody persistence for years following two doses of tetravalent measlesmumps-rubella-varicella vaccine in healthy children a combined measles, mumps, rubella and varicella vaccine (priorix-tetra): immunogenicity and safety profile centers for disease control and prevention. prevention of measles, rubella, congenital rubella syndrome, and mumps, : summary recommendations of the advisory committee on immunization practices (acip) primary vaccine failure to routine vaccines: why and what to do? evaluation in young children of the urabe am strain of live attenuated mumps vaccine in comparison with the jeryl lynn strain safety and characterization of the immune response engendered by two combined measles, mumps and rubella vaccines horizontal transmission of the leningrad- live attenuated mumps vaccine virus mumps antibody levels among students before a mumps outbreak: in search of a correlate of immunity primary vaccine failure after dose of varicella vaccine in healthy children outbreak of mumps in a vaccinated child population: a question of vaccine failure? measles, mumps, and rubella-vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the advisory committee on immunization practices (acip) antibodies to measles, mumps and rubella in uk children years after vaccination with different mmr vaccines vaccine-induced measles virus antibodies after two doses of combined measles, mumps and rubella vaccine: a -year follow-up in two cohorts evaluation of cellular immunity to mumps in vaccinated individuals with or without circulating antibodies up to years after their last vaccination longterm persistence of mumps antibody after receipt of measles-mumpsrubella (mmr) vaccinations and antibody response after a third mmr vaccination among a university population immunity to mumps before and after mmr vaccination at years of age in the first generation offered the two-dose immunization programme vaccine waning and mumps reemergence in the united states differential durability of immune responses to measles and mumps following mmr vaccination antibody induced by immunization with the jeryl lynn mumps vaccine strain effectively neutralizes a heterologous wild-type mumps virus associated with a large outbreak mumps outbreaks in a highly vaccinated population: investigation of a neutralization titre against the current circulating wildtype genotype g mumps virus immunogenicity and reactogenicity of a new measles, mumps and rubella vaccine when administered as a second dose at y of age sera from different age cohorts in belgium show limited crossneutralization between the mumps vaccine and outbreak strains effectiveness of a third dose of mmr vaccine for mumps outbreak control antigenic relationships between six genotypes of the small hydrophobic protein gene of mumps virus serological and phylogenetic evidence of monotypic immune responses to different mumps virus strains remembering mumps phylogenetic analysis of clinical mumps virus isolates from vaccinated and non-vaccinated patients with mumps during an outbreak rt-pcr based diagnosis and molecular characterisation of mumps viruses derived from clinical specimens collected during the mumps outbreak in portugal mumps-specific cross-neutralization by mmr vaccine-induced antibodies predicts protection against mumps virus infection antigenic differences between vaccine and circulating wild-type mumps viruses decreases neutralization capacity of vaccine-induced antibodies identification of conformational neutralization sites on the fusion protein of mumps virus cross-neutralization between three mumps viruses & mapping of haemagglutininneuraminidase (hn) epitopes recent mumps outbreaks in vaccinated populations: no evidence of immune escape identification of naturally processed mumps virus epitopes by mass spectrometry: confirmation of multiple cd + t-cell responses in mumps patients seroprevalence of mumps in the netherlands: dynamics over a decade with high vaccination coverage and recent outbreaks investigation of mumps vaccine failures in minsk immune responses to mumps vaccine in adults who were vaccinated in childhood correlates of protection induced by vaccination correlations among measles virus-specific antibody, lymphoproliferation and th /th cytokine responses following measles-mumps-rubella-ii (mmr-ii) vaccination mumps virus infection in vaccinated patients can be detected by an increase in specific igg antibodies to high titres: a retrospective study laboratory diagnosis of mumps in a partially immunized population: the nova scotia experience mumps outbreak and laboratory diagnosis antibody fab-fc properties outperform titer in predictive models of siv vaccine-induced protection increase in mumps in ireland in late assessment of mumps virus-specific antibodies by different serological assays: which test correlates best with mumps immunity? seroprevalence of measles-, mumpsand rubella-specific igg antibodies in german children and adolescents and predictors for seronegativity cellular and humoral immunity after vaccination or natural mumps infection rubella specific cell-mediated and humoral immunity following vaccination in college students with low antibody titers measles, mumps, and rubella antibody patterns of persistence and rate of decline following the second dose of the mmr vaccine development and durability of measles antigen-specific lymphoproliferative response after mmr vaccination childhood mmr vaccination and the incidence rate of measles infection: a ten year longitudinal cohort study of american children born in the s duration of humoral immunity to common viral and vaccine antigens mumps outbreaks in vaccinated populations: are available mumps vaccines effective enough to prevent outbreaks? symptomatic mumps virus reinfections complete genome sequence of the who international standard for hepatitis b virus dna the establishment of surrogates and correlates of protection: useful tools for the licensure of effective influenza vaccines? duration of immunogenicity and efficacy of hepatitis b vaccine in a yupik eskimo population a longitudinal hepatitis b vaccine cohort demonstrates long-lasting hepatitis b virus (hbv) cellular immunity despite loss of antibody against hbv surface antigen antibody levels and protection after hepatitis b vaccine: results of a -year follow-up study and response to a booster dose protection provided by hepatitis b vaccine in a yupik eskimo population. seven-year results long-term efficacy of active postexposure immunization of infants for prevention of hepatitis b virus infection. united states-people's republic of china study group on hepatitis b mumps virus-specific antibody titers from pre-vaccine era sera: comparison of the plaque reduction neutralization assay and enzyme immunoassays decreased humoral immunity to mumps in young adults immunized with mmr vaccine in childhood mumps virus neutralizing antibodies do not protect against reinfection with a heterologous mumps virus genotype immune responses to measles and mumps vaccination of infants at , , and months correlates of lymphoproliferative responses to measles, mumps, and rubella (mmr) virus vaccines following mmr-ii vaccination in healthy children detection of mumps virus-specific memory b cells by transfer of peripheral blood mononuclear cells into immune-deficient mice are cases of mumps in vaccinated patients attributable to mismatches in both vaccine t-cell and b-cell epitopes?: an immunoinformatic analysis the human cd (+) t cell response against mumps virus targets a broadly recognized nucleoprotein epitope mumps infection but not childhood vaccination induces persistent polyfunctional cd (+) t-cell memory cellular immunity to mumps virus in young adults years after measles-mumps-rubella vaccination severity of mumps disease is related to mmr vaccination status and viral shedding mumps vaccination coverage and vaccine effectiveness in a large outbreak among college students-iowa characteristics of a large mumps outbreak: clinical severity, complications and association with vaccination status of mumps outbreak cases transmission of mumps virus from mumps-vaccinated individuals to close contacts the duration of mumps virus shedding after the onset of symptoms detection of rna of mumps virus during an outbreak in a population with a high level of measles, mumps, and rubella vaccine coverage notes from the field: absence of asymptomatic mumps virus shedding among vaccinated college students during a mumps outbreak-washington guidance for isolation precautions for mumps in the united states: a review of the scientific basis for policy change mumps clinical diagnostic uncertainty two major mumps genotype g variants dominated recent mumps outbreaks in the netherlands the european sero-epidemiology network: standardizing the enzyme immunoassay results for measles, mumps and rubella from vaccines to memory and back systematic review of measles and rubella serology studies how to determine protective immunity in the post-vaccine era challenges in mucosal vaccines for the control of infectious diseases correlates, surrogates, and vaccines aerosolized mmr vaccine: evaluating potential transmission of components to vaccine administrators and contacts of vaccinees vaccines against mucosal infections intranasal immunization with dry powder vaccines mucosal immunity and vaccines live attenuated pandemic influenza vaccine: clinical studies on a/ /california/ / (h n ) and licensing of the russian-developed technology to who for pandemic influenza preparedness in developing countries live attenuated influenza vaccine (flumist(r); fluenz): a review of its use in the prevention of seasonal influenza in children and adults proteomic contributions to our understanding of vaccine and immune responses advances in mrna vaccines for infectious diseases molecular signatures of antibody responses derived from a systems biology study of five human vaccines influenza immunization elicits antibodies specific for an egg-adapted vaccine strain influenza vaccine failure: failure to protect or failure to understand? sequence diversity of jeryl lynn strain of mumps virus: quantitative mutant analysis for vaccine quality control contemporary h n influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains stobart cc, moore ml. development of next-generation respiratory virus vaccines through targeted modifications to viral immunomodulatory genes self-amplifying rna vaccines give equivalent protection against influenza to mrna vaccines but at much lower doses immunogenicity of novel mumps vaccine candidates generated by genetic modification discovering protective cd t cell epitopes-no single immunologic property predicts it! characterization of peptides bound to the class i mhc molecule hla-a . by mass spectrometry identifying epitopes of hiv- that induce protective antibodies contrasting b celland t cell-based protective vaccines preclinical and clinical demonstration of immunogenicity by mrna vaccines against h n and h n influenza viruses safety and immunogenicity study of -ncov vaccine (mrna- ) for prophylaxis of sars-cov- infection (covid- ) kunjin virus replicons: an rnabased, non-cytopathic viral vector system for protein production, vaccine and gene therapy applications rna viruses as tools in gene therapy and vaccine development vaccinomics: current findings, challenges and novel approaches for vaccine development vaccines for the st century the role of systems biology approaches in determining molecular signatures for the development of more effective vaccines adjuvants and alternative routes of administration towards the development of the ideal influenza vaccine trained immunity-based vaccines: a new paradigm for the development of broad-spectrum anti-infectious formulations could an unrelated live attenuated vaccine serve as a preventive measure to dampen septic inflammation associated with covid- infection? mbio potency estimation of measles, mumps and rubella trivalent vaccines with quantitative pcr infectivity assay evaluation of medicines for human use quality of biotechnological products: viral safety evaluation of biotechnology products from cell lines of human or animal origin a framework for research on vaccine effectiveness the urabe am mumps vaccine is a mixture of viruses differing at amino acid of the hemagglutininneuraminidase gene with one form associated with disease studies on live mumps virus vaccine. v. development of a new mumps vaccine "am " by plaque cloning highly parallel characterization of igg fc binding interactions the concept of vaccination failure effective messages in vaccine promotion: a randomized trial it's not all about autism: the emerging landscape of anti-vaccination sentiment on facebook key: cord- -p cc xa authors: to, kin-wang; lee, sing; chan, tat-on; lee, shui-shan title: exploring determinants of acceptance of the pandemic influenza a (h n ) vaccination in nurses date: - - journal: am j infect control doi: . /j.ajic. . . sha: doc_id: cord_uid: p cc xa this study investigated the anticipated vaccination rate against pandemic human influenza a (h n ) in the health care setting. self-administered questionnaires were used to assess nurses' acceptance of vaccination against seasonal flu and h n . they were sent to nurses by post through various nurses' unions before initiation of the vaccination program. only . % of the respondents planned to receive the h n vaccine, compared with . % for the seasonal influenza vaccine. vaccination against seasonal influenza in the preceding season strongly predicted the likelihood of h n vaccination. the main reason cited for h n vaccination was self-protection, and reasons for rejecting vaccination included possible side effects, ineffectiveness of the vaccine, and the mild nature of the disease. personal contact with patients with h n or severe acute respiratory syndrome at work did not significantly increase the likelihood of receiving the h n vaccine. more than % of the respondents were undecided at the time of the survey. the promotion of vaccination against seasonal influenza may play a role in improving h n vaccination coverage. efforts are needed to address concerns about vaccination risk and to incorporate h n vaccination in standard infection control practice with policy support. vaccination against influenza protects health care workers (hcws) and patients from contracting influenza by reducing virus transmission in health service settings. vaccination of hcws is an important strategy, because infected hcws can be a source of infection to patients. reducing hcws' risk of acquiring infection protects patients indirectly. because it is easier to target hcws for vaccination than the general public, vaccinating hcws is a sound strategy to protect patients. however, vaccination coverage in hcws has been notoriously unsatisfactory, with rates ranging from about % to % in different countries. [ ] [ ] [ ] [ ] major barriers to vaccination include misconceptions about the rationale for vaccination, perceived ineffectiveness of the vaccine, perceived unlikelihood of contracting influenza, potential side effects, fear of injection, and lack of time. [ ] [ ] [ ] the recent emergence of pandemic human influenza a (h n ) in is stressing the health care system because of the lack of immunity in the public and the associated mortality and morbidity. , the possibility of genetic reassortment between different subtypes of influenza giving rise to more resistant genotype is another concern, which may potentially lead to new pandemics. [ ] [ ] [ ] [ ] vaccination is a timehonored strategy for preventing h n , which can predictably reduce mortality and morbidity. whereas there are abundant data on factors affecting the acceptance of seasonal influenza vaccine, those on h n vaccination are scarce. in many countries, the first wave of pandemic h n has come and gone. to enhance our preparedness for the impending second wave, which has yet to arrive in some countries in the northern hemisphere, we conducted a survey to estimate the acceptance rate of h n vaccination in a group of nurses, and to explore factors that might be associated with vaccination uptake. nurses registered as members of the hong kong nurses general union, the nurses branch, and the enrolled nurses branch of the hong kong chinese civil servants association were invited to participate in a self-administered anonymous questionnaire survey on infection control practices relating to influenza prevention that has been conducted every - years since . , the questionnaire, constructed in chinese, together with an introductory letter explaining the purpose and nature of the study, was delivered to each individual member's postal address. the content was developed after discussions with nurses in the field, followed by pilot testing before administration. approval was obtained from the survey and behavioral research ethics committee of the chinese university of hong kong. the questionnaire was divided into parts. part a assessed the respondent's vaccination status in terms of seasonal influenza in the preceding year and his or her willingness to receive vaccination against seasonal influenza and h n in the coming season. the reasons for receiving or rejecting vaccination (eg, perceptions regarding protection of themselves, relatives, and patients, mandatory requirement, circumstances of the outbreak) were also assessed. the respondent was asked to select and rank reasons that might have affected the decision for vaccination using a scale of (most important) to (least important). part b assessed the respondent's exposure to h n in the workplace or family. part c assessed the respondent's agreement with government policies for preventing h n and the perceived severity of h n compared with h n (avian) or seasonal influenza. the responses were evaluated on a likert scale ranging from (most disagreed) to (most agreed). part d consisted of questions on demographics and work nature in terms of clinical exposure. data entry was performed using microsoft excel (microsoft, redmond, wa). statistical analysis was performed with spss version . (spss inc, chicago, il). nonparametric tests were used to analyze ordinal data. dichotomous data were further analyzed by binary logistic regression analysis for odds ratio (or) calculation, with statistical significance defined as p , . . a total of questionnaires were sent out over a -week period in july and august . of these, were returned, for a response rate of . %. the majority ( ; . %) of the respondents were female registered nurses who had received formal -year training, versus enrolled nurses with a shorter ( year) training and lower entry requirements. of the respondents, ( %) were between and years old, and a high proportion ( ; %) had practiced nursing for . years. regarding clinical exposure, % ( ) reported having frequent direct contact with patients. concerning part a of the questionnaire, about % ( ) had received seasonal influenza vaccination in the preceding year. for the coming flu season, . % ( ) were planning to receive seasonal influenza vaccine, . % ( ) rejected vaccination, and . % ( ) were undecided. only . % ( ) of the respondents were considering vaccination against h n , with . % ( ) rejecting vaccination and . % ( ) undecided. age, experience, and frequency of patient contacts were divided into several strata for further analysis. the smaller proportion of nurses accepting h n vaccination was consistent across each stratum regardless of age, experience, or frequency of patient contacts. the nature of nursing practice and frequency of patient contact were not significantly associated with the decision for vaccination (or, . ; % confidence interval [ci], . - . ). for those who either had been vaccinated in the preceding influenza season or were planning to receive seasonal influenza vaccine, the majority (. %) believed that vaccination could protect against infection. work requirements and protecting others in the workplace from infection were less commonly cited reasons, reported by only about % of the respondents. for nurses who had not received vaccination in the previous year or declined vaccination in the coming year, the most frequent reason for doing was concern about side effects of the vaccine ( %- %). this reason was cited more frequently by those who declined h n vaccination ( . %). other reasons for declining the vaccination included the perceived mild nature of influenza ( . %- . %) and the belief that the vaccine could not prevent infection ( . %- . %). the latter reason was less common among those who declined h n vaccination. the findings are summarized in table . only ( . %) of the respondents were planning to receive h n vaccination when it became available. figure shows the relative importance of factors in the decision for considering h n vaccination. the number (percentage) of nurses choosing the most important factors were vaccine effectiveness ( ; . %), potential side effects ( ; . %), and illness severity ( ; %). government policy and professional opinions were of little importance. a small proportion was concerned about the inconvenience of vaccination procedures, for example, the need to be vaccinated separately from seasonal influenza vaccine, or if doses were needed. nurses that had received or were planning to receive seasonal flu vaccine had a significantly higher tendency to receive h n vaccine (or, . ; % ci, . - . vs or, . ; % ci, . - . , respectively). the or of the factors for h n vaccination was determined when each was taken as ''most important'' versus the rest. in such instance, the most significant factor was government and hospital guidelines, with an or for vaccination of . ( % ci, . - . ). frequent contact with patients, the global and hong kong risk of h n , vaccination schedule, severity of the disease, and professional opinion all tended to increase the or for vaccination, although these increases were not statistically significant ( table ) . regarding the respondents' personal experience with h n (part b of the questionnaire) ( %) of those accepting h n vaccination had never come into contact with any patients with the infection. a minority ( ; %) needed to manage h n patients at work, whereas ( %) reported that their workplace handled h n patients, but no contact was required. contact with h n patients did not increase the or of receiving vaccination (or, . ; % ci, . - . ). there were only ( %) suspected and ( . %) confirmed h n cases in the study population; of these cases, ( . %) were work-related. a family history of h n infection was associated with a higher tendency to accept vaccination (or, . ; % ci, . - . ) ( table ). figure graphically presents the respondents' attitudes toward h n (part c of the questionnaire). nurses who declined h n vaccination tended to be less worried about becoming infected and were less inclined to perceive h n as a severe infectious disease, although they basically agreed that it was highly infectious. overall, many ( ; . %) considered seasonal influenza and h n to be of similar severity, and most agreed that h n ( ; . %) and severe acute respiratory syndrome (sars) ( ; . %) were more serious than h n . regardless of their attitudes, most of the nurses agreed with government policies for controlling the h n epidemic. based on our results, we anticipated a low uptake rate for h n vaccination in nurses in hong kong. the proportion of nurses planning to receive the h n vaccine was much lower in that that for the seasonal influenza vaccine ( . % vs . %), despite the similarities of the two diseases in transmissibility and clinical outcomes as reported through clinical and epidemiologic observations. because influenza vaccination is not a mandatory requirement for hcws, vaccination coverage naturally hinges on the individual's willingness to get vaccinated, which in turn is dependent on the perceived risks and benefits of vaccination. our study suggests that self-protection was the main reason for receiving vaccination against both h n and seasonal influenza. surprisingly, past experience with respiratory infection did not increase the likelihood of receiving h n vaccination. nurses who had come into contact with patients infected with h n were not more likely to receive h n vaccination (or, . ). more nurses who had been in contact with h n patients at work ( / ; . %) believed that h n is a minor disease compared with those who had not been in contact h n patients at work ( / ; . %). moreover, many nurses considered seasonal influenza and h n to be less serious than h n or sars. personal exposure to the infection was not an important factor, although the number of respondents might be too small to allow meaningful interpretation. nonetheless, our earlier studies had demonstrated a positive impact of this factor on nurses' preparedness against avian flu outbreaks. , we explored a whole range of factors that might be associated with nonacceptance of h n vaccination ( table ) . unlike other studies on seasonal influenza vaccination, many of these potential factors did not have sufficiently strong statistical power to predict vaccination behavior against h n in our nurses. those rejecting h n vaccination had major concerns, perceived ineffectiveness and potential adverse effects of the vaccine, cited by . % of the respondents, consistent with previous studies. , , , about one-third of those declining vaccination considered either form of influenza to be a mild disease. misconceptions about seasonal influenza vaccination are common among nurses, even after education programs, as reported by raftopoulos and ofstead et al. in particular, the purpose of vaccination to protect an at-risk population, rather than as self-protection, was hardly recognized. the factors associated with a declining h n vaccination rate might well be similar to those for seasonal influenza vaccination, because many nurses considered the diseases to be of similar severity. it can be argued that the perceived benefit of vaccination is easily offset by the possible, yet uncertain side effects of the h n vaccine. we did not explore the cost of the vaccine as a factor in our study, because vaccination is free to all nursing staff in hong kong. an estimated % of the h n cases in the united states are acquired in health care settings. high vaccination coverage is crucial to preventing transmission of the infection. given that . % of our survey respondents were undecided about receiving the h n vaccination, the final vaccination coverage will depend on external factors that might affect their major concerns, rather than on promotion of vaccination as an effective tool to prevent infection transmission. interestingly, acceptance of seasonal influenza vaccination was a very strong predictor for acceptance of h n vaccination. similar findings from an internet survey of us adults was reported by maurer et al. vaccination against seasonal influenza in the preceding year was associated with an or of for receiving the h n vaccine in the coming season. this finding is in agreement with previous studies of seasonal influenza vaccination in hcws. [ ] [ ] [ ] thus, it has been speculated that efforts to increase seasonal influenza vaccination coverage will lead to increased h n vaccination coverage. in our study, . % of the nurses had received seasonal influenza vaccination in the previous year; however, the estimated vaccination rate for the coming flu season had dropped to . %, though some % of the respondents were undecided at the time of the survey. if all undecided nurses subsequently received vaccination, then the proportions vaccinated against h n and seasonal influenza would be quite similar, reaching $ % of the total cohort. how can vaccination coverage be improved? first, vaccination policy for hcws should be developed separately from that for the general public, given the differing concerns and priorities in the populations. currently, hcws are a priority category for receiving h n vaccination in hong kong, a practice also adopted in the united states and other parts of the world. such an approach could be counterproductive, however, because so many hcws do not consider themselves at risk of infection. in our study, nurses demonstrated positive attitudes toward government policies on controlling the epidemic irrespective of their degree of acceptance of h n vaccination. ironically, professional advice and official guidelines were relatively unimportant factors for those who rejected vaccination, a finding similar to that in a recent local study. this discrepancy has arisen because policy guidelines addressing the specific needs of hcws have yet to be developed. second, vaccination as an important measure to protect vulnerable populations should be emphasized in infection control training. currently, priority populations for h n vaccination include elderly persons, pregnant women, and persons with chronic disease. the purpose of offering vaccination to these latter groups is to prevent disease and reduce morbidity and mortality. theoretically, vaccination of hcws could serve a dual purpose of occupational safety and infection control, the latter to reduce the incidence of nosocomial infection. in our study, those accepting vaccinations perceived h n or seasonal influenza vaccination not as an infection control measure, but simply as a means of self-protection. rectifying this prevailing attitude should be considered through policy and educational strategies. third, combining the human h n and seasonal influenza vaccines in a single vaccination program may help improve the uptake rate. admittedly, the coverage of seasonal influenza vaccination has remained suboptimal, even though the percentage of nurses accepting the vaccination is much higher than that for h n vaccination. incorporating the h n vaccine in the seasonal influenza regimen, as advocated for the southern hemisphere in the coming year, could boost the coverage to that for the seasonal influenza vaccine. however, this would still not be good enough if the objective of vaccinating hcws is to control transmission, for which a near- % coverage is the goal. our study has some limitations. first, only a small number of nurses were represented in the survey. the total number of registered nurses and enrolled nurses in hong kong was , as of december . for practical reasons, it was impossible to include all nurses due to limited resources and the lack of a uniform survey platform. second, some % of the nurses in our cohort did not have frequent patient contact, a factor that should be noted when extrapolating results to the health care profession at large. we have not been able to categorize the population according to the nature of the workplace. it would be interesting to compare the responses in nurses with different jobs, such as those in outpatient clinics, hospitals, and nonclinical settings. third, most of the responding nurses were mature and highly experienced, characteristic of members of the nursing associations surveyed. younger nurses and those with less experience might not have been captured. moreover, the use of a mailin survey might have caused some bias in the responses. it could be argued that those who took time to return the questionnaire were probably more ready to express their thought and opinions. finally, nursing culture varies across countries, and so our results might not be applicable to other places. self-reported influenza vaccination rates among health care workers in a large health system influenza vaccination among primary healthcare workers influenzavaccination coverage among hospital personnel over three consecutivevaccination campaigns influenza vaccination of healthcare workers in the united states influenza vaccination of healthcare workers: a literature review of attitudes and beliefs nurses' attitudes and beliefs about influenza and the influenza vaccine: a summary of focus groups in alabama and michigan barriers to influenza vaccine acceptance: a survey of physicians and nurses pneumonia and respiratory failure from swine-origin influenza a (h n ) in mexico severe respiratory disease concurrent with the circulation of h n influenza emergence and pandemic potential of swine-origin h n influenza virus emergence of a novel swine-origin influenza a virus (s-oiv) h n virus in humans the h n influenza outbreak in its historical context triplereassortant swine influenza a (h ) in humans in the united states impact of sars on avian influenza preparedness in healthcare workers impact of severe acute respiratory syndrome and the perceived avian influenza epidemic on the increased rate of influenza vaccination among nurses in hong kong which determinants should be targeted to increase influenza vaccination uptake among health care workers in nursing homes? willingness of hong kong healthcare workers to accept prepandemic influenza vaccination at different who alert levels: two questionnaire surveys attitudes of nurses in greece towards influenza vaccination influenza vaccination among registered nurses: information receipt, knowledge, and decision making at an institution with a multifaceted educational program novel influenza a (h n ) virus infections among health-care personnel-united states does receipt of seasonal influenza vaccine predict intention to receive novel h n vaccine: evidence from a nationally representative survey of us adults healthcare workers should get top priority for vaccination against a/h n flu, who says responding to the renewed h n pandemic we thank cecilia so, hong kong nurses general union, nurses branch, and enrolled nurses branch of the hong kong chinese civil servants association, and all members of the associations who participated in this survey. the results presented in this article do not reflect the views of the associations that facilitated the administration of the research. we also thank david sorrell for general advice. key: cord- -sig h authors: yeung, may ps; ng, stephen kam-cheung; tong, edmond tak fai; chan, stephen sek-kam; coker, richard title: factors associated with uptake of influenza vaccine in people aged to years in hong kong: a case–control study date: - - journal: bmc public health doi: . /s - - - sha: doc_id: cord_uid: sig h background: in hong kong, people aged – years were added as a recommended priority group (recommended group) for influenza vaccination by the department of health (dh) starting from / onwards. the coverage rate of influenza vaccination for this age group was suboptimal at . % in / . this study investigates the factors associated with the uptake of influenza vaccination among adults in hong kong aged – years. methods: a case–control study was conducted in communities by street intercept interviews from july to august . cases were adults aged – years who had received the influenza vaccine in / or / , while controls were the same as the cases, except they had not received the influenza vaccine in / or / . multiple logistic regression analysis was performed on the data to explore the associations between vaccination status and the variables. results: six hundred and four respondents in total were interviewed and included in the analysis. there were cases (vaccinated) and controls (non-vaccinated), with a case-to-control ratio of : . . the following were strongly associated with vaccination compared to other factors: ‘eligible for free government vaccine’ (or . , % ci, . - . , p < . ); ‘willing to receive flu vaccination for free’ (or . , % ci, . - . , p < . ); ‘perceived having severe or moderate symptoms when contracting flu’ (or . , % ci, . - . , p = . ), and ‘convenient to reach a vaccination location’ (or . , % ci, . - . , p = . ). the majority of the cases ( . %) and controls ( . %) were not aware that they belonged to a recommended group for influenza vaccination and most (> %) were willing to be vaccinated if it was free. conclusions: factors related to free and convenient vaccination, the perception of the severity of symptoms when contracting influenza had a comparatively strong association with influenza vaccination uptake amongst – year olds, compared to other factors. seasonal influenza vaccination (referred to as 'influenza vaccination' , 'vaccination' or 'vaccine' , below) remains an effective measure to protect individuals and communities from severe morbidity and mortality induced by influenza. to mitigate the disease burden of influenza, many developed countries recommend vaccination for high-risk groups. some exceptions are the united states (us), austria and estonia, which have universally recommended people aged months or above to receive influenza vaccination [ ] [ ] [ ] . few european countries, such as belgium and ireland, included those aged - years in their recommended groups [ ] . although the vaccine did not provide an overall economic benefit in some communities, it yielded significant health benefits by reducing severe complications from influenza [ , , ] . meta-analysis and literature reviews demonstrated that the influenza vaccine had a moderate effect in reducing the clinical symptoms of influenza in healthy people from to years [ , ] . many middle-aged adults have undiagnosed medical conditions, such as diabetes mellitus, and are at higher risk of severe influenza-related complications [ , ] . in hong kong, people aged - years were added as a recommended priority group (recommended group) for influenza vaccination by the department of health (dh) starting from / [ ] . the major driver behind this inititiative was a real increase in influenzaattributed intensive care unit (icu) admissions and deaths among the middle-aged group in / , [ ] plus an anticipated increase in the years to come when the influenza a(h n )pdm strain was predicted to circulate in the population. after this new vaccination policy was launched, however, the vaccine was not well received and the vaccination coverage in this new target group was very low at . % [ ] . no free or subsidised influenza vaccination service was provided by the government to this group, except those who already belonged to the other free or subsidised recommended high-risk groups and those with financial difficulties, i.e., comprehensive social security assistance (cssa) recipients. healthy - year olds, without other risk indicators, had to pay if they wanted to be vaccinated. this study aimed to find out which factors were associated with the low uptake of influenza vaccination among people aged - years in hong kong. a survey was conducted in a community setting in hong kong from july to august , following which a case-control analysis was used to investigate the study hypothesis. street intercept interviews were undertaken in districts (out of a total of in the territory). cases were (i) those who received the influenza vaccine in / or / , i.e., from september to august ; (ii) aged - years in - ; and (iii) citizens who were resident in hong kong. controls were the same as the cases in (ii) and (iii), except they had not received the influenza vaccine in / or / influenza seasons. some controls had received the influenza vaccine before september . they were classified as control because they were not included as the recommended group in / and before. the sample size was calculated with a significance level of . (two-sided) and a power level of . . the calculation of the sample size was done by the fleiss formula for unmatched case-control studies with dichotomous exposure variables. a minimum sample size of was required with a case-to-control ratio of : [ ] . the interviewers were assigned a random time slot, covering weekdays, weekends, office and non-office hours. the questionnaire was conducted in summer before the next influenza vaccination season, which usually begins in september of each year. primary data were collected by four trained research interviewers who were fluent in chinese and english. the interviewers were stationed in areas of high pedestrian traffic, such as near underground train stations and shopping malls, during the assigned random time slot. this research had been approved by the human subjects ethics sub-committee of the hong kong polytechnic university and the ethics committee of the london school of hygiene and tropical medicine. before each interview, the interviewer would inform the respondent about the nature and purpose of the study and invited their voluntary participation. interviewees were asked to respond only after informed consent was obtained. no incentive was given. the hypothesis of this study was there were differences in associated factors (variables) between those hong kong residents aged - years who received the influenza vaccine in / and / , and those who did not. the null hypothesis assumes no such association. the questionnaire was designed with reference to past vaccination questionnaires from health authorities [ , ] and relevant studies [ ] [ ] [ ] . the draft questionnaire was then sent for comment to a multi-disciplinary team, comprised of an infectious disease specialist, an epidemiologist and general practitioners. the questionnaire was in chinese and english and had questions including on demographic data and covering the factors (variables) to be examined. statistical analyses were performed using the software sas . . categorical demographic data and variables were compared using the pearson chi-square test, crude and adjusted odds ratios (ors) with corresponding % confidence intervals (cis) and p-values. multiple logistic regression analysis was performed. any variables with p values < . and those with important associations demonstrated in the literature were selected for regression analysis (backward stepwise regression algorithms). the regression model is a built-in formula in the sas software. all statistical tests were two-tailed and variables were considered significant at a significance level of . . the study included cases (vaccinated) and controls (non-vaccinated), with a case to control ratio of : . . this sample size reached the required range in the sample size calculation. the average interview time was min (standard deviation ± min) for each questionnaire, and the response rate was . %. during street intercept interviews, there were more non-vaccinated individuals (controls) than vaccinated ones (cases). after the required number of non-vaccinated was recruited, the excess approached by the interviewers were counted as non-responders. in total man-hours were spent on the interviews. the differences between baseline demographic data of cases and controls were statistically insignificant regarding sex, ethics, education level, employment status, personal monthly income, current smoking and drinking status. the demography of cases and controls are shown in table . there was no apparent discrepancy in the sample and the target population. one exception was in the sampled respondents; there were proportionally higher numbers of females than males (m:f = : . ), while the overall ratio in the target community was : . other demographic parameters of the sampled population, such as the age proportion between groups, education level, ethnicity, and the percentage of those in employment, were comparable to the target population (i.e., hong kong general population aged - years). the majority of the respondents were chinese, and there were more female than male respondents ( . % vs . %). most ( . %) of those who were in employment were aged years or below. overall, half of the respondents ( . %) had no income. one in four ( . %) was a housewife and one fifth ( . %) was retired. the majority of them ( . %) had received at least years of education up to secondary level. the majority of all the cases ( . %) and controls ( . %) were not aware that the health authority had recommended vaccination against influenza. however, the cases were more aware of the recommendation for influenza vaccination than the controls, (or . , % ci . - . , p = . ). there were health knowledge differences between the cases and controls in all the questions asked on knowledge, including government vaccination services, vaccine reduction in influenzarelated hospital admission, and vaccine protection for healthy adults. however, these associations were statistically insignificant after the or was adjusted ( table ) . when compared to the controls, more of the cases had chronic diseases; more frequently 'visited doctors in the past months' and 'lived with children below years or elders above years'. however, none of these associations was statistically significant after the or was adjusted. there was no association between vaccination and smoking/drinking. most cases ( . %) stated that they were likely or very likely to receive the vaccine in / , compared to only . % among the controls. this implies those who had previous vaccinations in / and / would choose to be vaccinated again in the future. in general, more cases perceived there to be a higher risk of contracting influenza in the next months and/ or having severe influenza or moderate symptoms when there were no associations between differences in response to the government telephone reminder service for vaccination, if there was one. in respect of vaccination, the cases were more heavily influenced by others' opinions and actions than were the controls. when compared, more cases would 'accept advice from health professionals' (or . , % ci . - among the controls (i.e., never received vaccination or received vaccine on or before / ), . % of them had previously received the vaccine. the following were common reasons given by the controls for not receiving a vaccine: considered vaccination unnecessary ( . %); believed they were not in a high-risk group ( . %); and concerns about side effects of vaccination ( . %). of the controls that had previously been vaccinated, % had received the vaccine at a public clinic. a subgroup analysis was performed on those who received influenza vaccination but did not know they were recommended group by the department of health (dh). there were cases (who were vaccinated) and among them answered yes to "knowing oneself to be in the recommended group for flu vaccine" and answered no. in these people the five commonest reasons for vaccination were: advice from healthcare professionals ( . %), vaccine was useful in protect oneself against flu ( . %), flu shot had additional benefits, e.g. protect family member ( . %), perception of not having very good or good health ( . %) and eligible for free government vaccine ( . %). more than half ( %) of these people received their influenza vaccine at government public clinics, and most of the remaining ( %) at private general practitioners. this is a case-control study with vaccination status as the 'outcome' and personal or external environmental factors as 'exposures'. a case-control study design was chosen because of a low prevalence of eligible cases. a street intercept interview method enabled the interviewers to screen and approach a larger number of people, according to the outward appearance of their age. this probably lowered the rejection rate and enabled a greater control in completing the questionnaire. it was estimated that a larger number of people would have had to be approached should a telephone or postage survey been used. the low response rate ( . %) was attributable to the difficulty in finding cases, as the excess controls approached by the interviewers were counted as non-responders. moreover, the interviews were conducted in summer time when the street temperature was > °c, the streets were crowded and no incentive was offered. multi-dimensional factors have contributed to people's choice of whether or not to receive vaccination. these factors comprise of social, environmental and economic dynamics in a specific context. the factors were put in a multiple logistic regression model and statistically adjusted for age, employment status, in receipt of social security, and all independent variables. before statistical adjustment, most of these factors had statistically significant crude odds ratios. the variables affected each other and many became non-significant after adjustment. there would be a confounding effect between variables. the majority of the cases ( . %) and controls ( . %) were not aware that they were in a group recommended by the health authority to receive influenza vaccination. among the controls, a higher percentage ( %) deemed vaccination to be 'unnecessary'. this revealed a failure of dh and health professionals in communicating the message that 'vaccination is recommended' to this age group. given that there was an association between 'knowing oneself to be in the recommended group for flu vaccine' and vaccination, better communication of the risks might have improved the vaccination rate. a health promotion strategy on empowerment and enhancement of knowledge on this issue needs to be planned and supported by health-care policy. studies suggested that previous influenza vaccination was a predictor for subsequent vaccination (or . - . ) [ ] [ ] [ ] [ ] . however, past behaviour does not provide an insight into the reasons why a person chooses to be vaccinated. the vaccination coverage rate is price sensitive. this was demonstrated in this study and in countries which provided vaccine reimbursements to users [ , ] . to receive influenza vaccination, most ( %) people aged - years in the general hong kong population had to pay out-of-pocket. in this study, the odds of the cases being 'eligible for free government vaccine' were . times the controls. among the cases, half ( %) of them attended a private clinic or hospital and paid the vaccination fee. many study cases and controls expressed they were willing to receive the vaccine if it was free or subsidised. such a vaccination service could possibly increase the vaccination rate. there was only a mild association between chronic disease(s) and vaccination and the association was insignificant after the or was adjusted (or . , % ci . - . , p = . ). this result contradicted the findings of many studies that indicated that the presence of chronic diseases was one of the most persistent factors associated with vaccination [ , , [ ] [ ] [ ] [ ] [ ] [ ] . ' accept advice by health professional' was moderately associated with vaccination (or . , % ci . - . , p = . ). several other studies have shown that doctors' and health professionals' advice was associated with influenza vaccination [ , ] . health professionals had a duty to recommend vaccination to high-risk groups in order to protect them from influenza and severe complications. 'had family member received flu vaccine' was associated with people's uptake of the vaccination, but 'accept advice from relatives and friends' was not. in japan, advice from health professionals, family and/or close friends was strongly associated [ ] . in the usa and other western countries, advice from family and/or close friends was not a significant factor in acceptance of influenza vaccination [ , ] . this could possibly be due to the differences in cultural backgrounds between individuals in these countries. this study showed no association between vaccination and smoking and drinking. it is uncertain whether people were consistent in their health behaviours. studies have proven that smoking is not associated with vaccination [ , ] . no data was found on other health behaviours, such as drinking or frequent exercise, having a link to vaccination. given past experiences of infectious disease epidemics in hong kong, people may be more inclined to receive vaccination to protect themselves in anticipation of the occurrence of a disease epidemic such as sars or swine influenza. previous research has suggested that newly issued recommendations are not quickly embraced by the majority of citizens. in the us, government national health interview survey data did not show a marked increase in vaccination rates among adults aged - and - years after the us advisory committee on immunization practices expanded its recommendations to these subgroups in and , respectively [ , ] . this vaccination policy limited the government vaccination free service to those suffering economic hardship and chronic diseases among - year-olds. although the price of receiving an influenza vaccination constitutes a minute percentage of monthly income, this does not necessarily mean socio-economically deprived groups who are ineligible for free vaccination would be willing to pay for the vaccine. subsidised vaccination would attract those who are willing to pay at a discounted price. health providers could be engaged, with or without incentives, to promote the benefit of vaccination. in addition, dh should consider health promotion messages addressing factors with strong associations to encourage payment by the individual. these factors included 'the perception of having severe or moderate symptoms when contracting flu' , 'knowledge of being in the recommended group for flu vaccine' and 'good vaccine protection for healthy adults'. a case-control design enabled the measurement of many different exposures at once and for the combined effects of exposures to be examined. in addition, data were collected within a short time-frame. one of the important limitations of this case-control was the temporal sequence and reverse causality. it is difficult to interpret the time sequence of the exposures and the outcomes. for example, it is uncertain whether perception of the safety of the influenza vaccine was a cause or a consequence of vaccination. other limitations of this casecontrol include the information and recall bias of the respondents, and the inability to estimate the coverage of vaccination in this age band. one limitation of using the street-intercept method would be the possibility that the interviewers approached those who looked - years and, potentially missed a number of younger and older looking individuals; the extent of this bias is difficult to assess. another bias would be due to the sampling of respondents from different locations, e.g., on public and private estates, in train stations and shopping malls. a comparison of the demographic characteristics of the samples collected in different locations, and those of the relevant population, would be useful to identify potential bias. the study results have important implications for the general population aged - years in hong kong. there would be considerable differences between cultures, beliefs, norms and external environments -such as health systems and service provision -which have to be taken into consideration when applying the results to other populations. further studies on the local vaccination policy and the views of health professionals would provide a comprehensive account of the low vaccination coverage in this age group. factors related to free and convenient vaccination, perception of the severity of symptoms when contracting influenza had a comparatively strong association with influenza vaccination uptake among - year olds, compared to other factors. differences in national influenza vaccination policies across the european union, norway and iceland risk groups and other target groups -preliminary ecdc guidance for developing influenza vaccination recommendations for the season - prevention and control of seasonal influenza with vaccines. recommendations of the advisory committee on immunization practices-united states influenza vaccination in austria from to : a country resistant to influenza prevention and control the effectiveness of vaccination against influenza in healthy, working adults effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial vaccines for preventing influenza in healthy adults efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis undiagnosed diabetes-data from the english longitudinal study of ageing seasonal influenza (flu) specific groups: people at high risk ofdeveloping flu-related complications scientific committee on vaccine preventable diseases. recommendations on seasonal influenza vaccination for the seasonal influenza vaccination coverage survey for the / season statistical methods for rates and proportions seasonal influenza vaccination survey in eu/eea, influenza season - . venice ii consortium department of health. evaluation of the publicity of human swine influenza vaccination programme development of a survey to identify vaccine-hesitant parents: the parent attitudes about childhood vaccines survey influence of family on acceptance of influenza vaccination among japanese patients survey on hong kong citizens' knowledge and opinion of influenza vaccination hong kong prevalence of influenza vaccination and correlates of intention to be vaccinated among hong kong chinese comparison of different risk perception measures in predicting seasonal influenza vaccination among healthy chinese adults in hong kong: a prospective longitudinal study influenza vaccination uptake among the working age population of japan: results from a national cross-sectional survey predictors of influenza vaccine acceptance among healthy adults influenza vaccination in europe: an inventory of strategies to reach target populations and optimise vaccination uptake seasonal influenza vaccination coverage rates in countries in africa vaccination coverage rates in eleven european countries during two consecutive influenza seasons influenza vaccination uptake and socioeconomic determinants in european countries patient's perceptions and information provided by the public health service are predictors for influenza vaccine uptake factors influencing acceptance of influenza vaccination given in an ed predictors of flu vaccination among urban hispanic children and adults influenza vaccination coverage against seasonal and pandemic influenza and their determinants in france: a cross-sectional survey healthy young and middle age adults: what will it take to vaccinate them for influenza? vaccine patient acceptance of influenza vaccination compliance with influenza vaccination. its relation with epidemiologic and sociopsychological factors no intention to comply with influenza and pneumococcal vaccination: behavioural determinants among smokers and non-smokers behavior and beliefs about influenza vaccine among adults aged - years we would like to thank the interviewers from the hong kong rehabilitation power; cathel hutchison for providing the language editing service; and ss lee, nguyen-van-tam and mark jit for their invaluable expert opinions. authors' contributions mpsy was the principal investigator and generated the research framework and methods, collected, analysed, interpreted the data and drafted the manuscript. skcn and etft contributed to the study methodology, analysis and revision of the manuscript. sskc contributed to the questionnaire design and statistical analysis. rc contributed to the conception, design, analysis and interpretation of the study, and critically revised the manuscript. all authors read and approved the final manuscript. key: cord- -guciupc authors: hajj hussein, inaya; chams, nour; chams, sana; el sayegh, skye; badran, reina; raad, mohamad; gerges-geagea, alice; leone, angelo; jurjus, abdo title: vaccines through centuries: major cornerstones of global health date: - - journal: front public health doi: . /fpubh. . sha: doc_id: cord_uid: guciupc multiple cornerstones have shaped the history of vaccines, which may contain live-attenuated viruses, inactivated organisms/viruses, inactivated toxins, or merely segments of the pathogen that could elicit an immune response. the story began with hippocrates b.c. with his description of mumps and diphtheria. no further discoveries were recorded until a.d. when the smallpox vaccine was described. during the eighteenth century, vaccines for cholera and yellow fever were reported and edward jenner, the father of vaccination and immunology, published his work on smallpox. the nineteenth century was a major landmark, with the “germ theory of disease” of louis pasteur, the discovery of the germ tubercle bacillus for tuberculosis by robert koch, and the isolation of pneumococcus organism by george miller sternberg. another landmark was the discovery of diphtheria toxin by emile roux and its serological treatment by emil von behring and paul ehrlih. in addition, pasteur was able to generate the first live-attenuated viral vaccine against rabies. typhoid vaccines were then developed, followed by the plague vaccine of yersin. at the beginning of world war i, the tetanus toxoid was introduced, followed in by the pertussis vaccine. in , the expanded program of immunization was established within the who for bacille calmette–guerin, polio, dtp, measles, yellow fever, and hepatitis b. the year witnessed the launching of the international aids vaccine initiative. in , the who passed a resolution to eradicate polio by the year and in ; the first vaccine to prevent cervical cancer was developed. in , “the decade of vaccines” was launched, and on april st , the united nations launched the “shot@life” campaign. in brief, the armamentarium of vaccines continues to grow with more emphasis on safety, availability, and accessibility. this mini review highlights the major historical events and pioneers in the course of development of vaccines, which have eradicated so many life-threatening diseases, despite the vaccination attitudes and waves appearing through history. vaccines constitute one of the greatest success stories within the health sector. they form part of a multifaceted public health response to the emergence of pandemics. this review is general in nature. it highlights the major historical cornerstones in the development and progress of various types of vaccines since the beginning and through the ages until today. it recognizes the major pioneers whose work has made a difference in the advancement of this vital health field, despite all the anti-vaccination movements that appeared through the ages. multiple reviews were encountered during our literature search; however, each of those reviews dealt with a specific aspect of vaccination like effectiveness of a particular vaccine, or side effects of another or even attitudes toward vaccines. consequently, this work tried to put together the major achievements through history stressing the importance, continuous vital role, and the need for immunization for health prevention and protection as well as its impact on human experience. the physiological mechanisms behind vaccination are well established. vaccination activates the immune system and induces both innate and adaptive immune responses thus leading to the production of antibodies, in the case of a humoral response, or to the generation of memory cells that will recognize the same antigen, if there is a later exposure. periodic repeat injections can improve the efficacy and effectiveness of inoculations ( ) . the approval of a vaccine abides by a set of well-established international rules and regulations. prior to their approval by the respective health authorities, scientists test vaccines extensively in order to ensure their efficacy, safety, and effectiveness. next to antibiotics, vaccines are the best defense that we have to date against infectious diseases; however, no vaccine is actually % safe or effective for everyone. this is attributed to the fact that each body reacts to vaccines differently ( ) ( ) ( ) . significant progress has been made over the years to monitor side effects and conduct research relevant to vaccine safety. in addition, vaccine licensing is a lengthy process that may take years or longer. the food and drug administration (fda) and the national institute of health (nih) require that vaccines undergo the required phases of clinical trials on human subjects prior to any use in the general public. this process is becoming more complex as more caution and care is being allocated to the quality of the market product. furthermore, vaccines can be divided into different categories depending on the way that they are prepared including liveattenuated vaccines, inactivated vaccines, subunit vaccines, conjugate vaccines, and toxoids. live-attenuated vaccines are used more frequently for viruses rather than bacteria, since the former contain a lesser amount of genes and can be controlled more easily ( ) . the most common method in formulating live-attenuated vaccines involves passing the virus through successions of cell cultures to weaken it. this will produce a form of the virus that is no longer able to replicate in human cells. however, it will still be recognized by the human immune system, hence protecting the body from future invasions. examples of such vaccines are measles, rubella, mumps, varicella (more commonly known as chickenpox), and influenza. the disadvantage of using this technique is that the virus may transform into a more virulent form due to a certain mutation and cause illness once injected into the body. although this rarely occurs, it must always be taken into consideration ( ) . by using heat, radiation, or certain chemicals, one can inactivate a microbe. the microbe will no longer cause illness but can still be recognized by the immune system. poliovirus and hepatitis a are common examples of inactivated vaccines. this type of vaccine has the disadvantage of being effective for a shorter period of time than live-attenuated vaccines. multiple boosters of the vaccine are sometimes required to improve effectiveness and sustainability ( ) . a subunit vaccine contains only portions of the microbe that can be presented as antigens to the human immune system instead of the microbe as a whole. the antigens or the microbe portions that best activate the immune response are usually selected. an influenza vaccine in the form of shots is an example. in addition, a recombinant subunit vaccine has been made for the hepatitis b virus. hepatitis b genes are injected into maker cells in culture. once these cells reproduce, the desired antigens of the virus are produced as well, and these can be purified for use in vaccines ( ) . conjugate vaccines are designed from parts of the bacterial coat. however, these parts may not produce an effective immune response when presented alone. hence, they are combined with a carrier protein. these carrier proteins are chemically linked to the bacterial coat derivatives. together, they generate a more potent response and can protect the body against future infections. vaccines against pneumococcal bacteria used in children are an example of conjugate vaccines ( ) . some bacteria release harmful toxins that cause illness in infected individuals. vaccinations against such types of bacteria are prepared by inactivating or weakening the toxin using heat or certain chemicals. this will help prepare the immune system against future invasion. the vaccine against tetanus caused by the neurotoxin of clostridium tetani is a good example of a toxoid ( ) . the generation of vaccine-mediated protection is a complex challenge. effective early protection is conferred primarily by the induction of antigen-specific antibodies. the quality of such antibody responses has been identified as a determining factor of efficacy. efficacy requires long-term protection, namely, the persistence of vaccine antibodies and/or the generation of immune memory cells capable of rapid and effective reactivation upon subsequent microbial exposure ( ) . the exponential development of new vaccines raises many questions about their impact on the immune system. such questions related to immunological safety of vaccines as well as triggering conditions such as allergy, autoimmunity, or even premature death ( ) . such issues were always looked for and monitored and some vaccines were even stopped because of these issues. recent vaccine models rely on both a cell-mediated response and a humoral immune response with highly specific antibodies and have shown an adequate amount of success. this, however, has not been the case for a few diseases such as tuberculosis where the humoral immunity mounted by the bacille calmette-guerin (bcg), the only currently used human vaccine, is inefficient in conferring proper immunization ( ) . however, t cells do take part indirectly in the production of antibodies and of secreted biological molecules (e.g., interferon) for protection. it seems that a proper mounted immunity is better achieved by vaccineinduced antibodies, whereas a t cell immune response is needed for disease attenuation. hence, a robust understanding of b and t cell function is needed for proper immunization ( ) . multiple determinants modulate the primary vaccine antibody response in healthy individuals; they include the vaccine type, live versus inactivated, protein versus polysaccharide, and use of adjuvants ( ) . they also include the nature of the antigen and its intrinsic immunogenicity ( ) , the dose of the antigen, the route of administration, the vaccine schedule, and the age at administration ( ) . in addition, genes play a direct role in the body's response to vaccination even in healthy individuals ( , ) . for each of the above determinants, there might be a particular mechanism involved and is further influenced by other factors including extremes of life, acute or chronic diseases, immunosuppression, and nutrition status ( ) . early life immune responses are limited by ( ) limited magnitude of antibody responses to polysaccharides and proteins, ( ) short persistence of antibody responses to protein, ( ) influence of maternal antibodies, and ( ) limited cd + t cell and interferongamma responses. such factors are difficult to study in human infants due to neonatal immune immaturity and the inhibitory influence of maternal antibodies, which increase with gestational age and wane a few months post-natal ( ) . on the other hand, in elderly persons, the immune system undergoes characteristic changes, termed immunosenescence, which leads to increased incidence and severity of infectious diseases and to insufficient protection following vaccination ( ) . vaccines induce both innate (non-specific) and adaptive (specific) immune responses, which decline substantially with age thus leading to the decreased efficacy of vaccines in elderly persons. in the elderly, the innate immune response will witness a reduced phagocytic capacity of neutrophils and macrophages, a decrease in their oxidative burst, and impairment in the up-regulation of mhc class ii expression among other parameters ( ) . in addition, persistent inflammatory processes occur with increasing age and may reduce the capacity to recognize stimuli induced by pathogens or vaccines. for the elderly, improved special antigen delivery systems are needed to overcome these limitations ( ) . furthermore, the adaptive immune response is functionally defective in the elderly. the involution of the thymus with aging leads to a decrease in content and in output of mature naïve t cells into the periphery, which hampers the induction of adaptive immune responses to neoantigens. in the context of primary vaccination, this causes reduced response rate ( ) ( ) ( ) ( ) ( ) ( ) . b cells also undergo age-related changes that aggravate the functionality of b cells colonies. as effector b cells accumulate, naïve b cells decrease in number and this leads to a reduction in the diversity of antibody responses. in brief, vaccines tailored to the needs of the elderly will have to be developed, taking into consideration these limitations in order to improve protection in this population. in , weinberg and szilagyl eloquently approached the issues of efficacy and effectiveness clarifying the road to correctly answer the relevant but complex question: "how well does the candidate vaccine prevent the disease for which it was developed?" they highlighted clearly the distinction between efficacy (individual level) and effectiveness (population level), which are often confused terms that fit well into the new paradigm of translational research ( ) . at about the same time, curns et al. elaborated on the distinction between the epidemiologic concepts of vaccine efficacy and effectiveness within the context of translational research ( ) . such concepts were also addressed earlier, but slightly differently, by clemens and co-workers in two separate publications in and , and also by orenstein et al. in ( - ) . accordingly, vaccine efficacy is measured as the proportionate reduction in disease attack rate when comparing vaccinated and unvaccinated populations. vaccine efficacy studies always have rigorous control for biases through randomized prospective studies and vigilant monitoring for attack rates ( ) . in addition to proportionate reduction in attack rates, these studies can furthermore assess outcomes through hospitalization rates, medical visits, and costs. despite the complexity and expenses that arise from the initial trials, they are needed to establish vaccine efficacy ( ) . on the other hand, the related but distinct concept of vaccine effectiveness has always been compared to a "real world" view of how a vaccine reduces disease in a population. as such, it can evaluate risks versus benefits behind a vaccination program under more natural field conditions rather than in a controlled clinical trial. vaccination program efficiency is proportional to vaccine potency or efficacy in addition to the degree and success of immunization of the target groups in the population. in brief, it is influenced by other non-vaccine-related factors that could influence the outcome. the "real world" picture provided by vaccine effectiveness data is desirable in planning public health initiatives, an advantage that makes these studies attractive. translating research data into real public health application are a process that has been reengineered by the nih as part of a road map for future research. consequently, a new expanded definition of translational research, consisting of four steps was proposed, which fits nicely within the continuum of vaccine research ( ) . in this new process of phase i to phase iv clinical trials, safety, immunogenicity, efficacy, and post-licensure effectiveness of a particular vaccine are assessed ending up in phase iv with the burden of the disease ( ) . vaccines stood the test of time and many techniques have been introduced into the world of vaccination. practitioners used to write articles about their vaccinating instruments and techniques. according to john kirkup, vaccinators and physicians used various instruments and techniques to inject the vaccinating material into the human body. more than different vaccinating instruments have been recorded in british, american, german, and french catalogs between the years and ; most of them are out of use nowadays ( ) . there are multiple major landmarks in the history of vaccines. it was reported that the origin goes as far back as hippocrates, the father of modern medicine, b.c. he described mumps, diphtheria, and epidemic jaundice among other conditions ( ) . the earliest methods of immunization and protection against smallpox date back to about a.d., and are attributed to the chinese. it has been said that the son of a chinese statesman was inoculated against smallpox by blowing powdered smallpox sores into his nostrils ( ) . another method used for inoculation was the removal of fluid from the pustules of an infected individual and subsequently rubbing it into a skin scratch of a healthy individual. this procedure was later introduced into turkey around , long before reaching europe ( ) . it took six centuries for variolation to be introduced to great britain, in ( ) . the eighteenth century was marked by several major events that started with the spread of variolation from turkey and china to england and america, followed, in the late eighteenth century, by edward jenner's breakthrough of vaccination. variolation, derived from the latin word varus, meaning "mark on the skin, " or inoculation, derived from the latin word inoculare, meaning "to graft, " are two words that were used interchangeably in describing the aforementioned immunization process. by , variolation was introduced to england after the pursuit of an english aristocrat, lady mary wortley montague, who had been personally inflicted with an episode of smallpox. after being informed of the method of variolation, she made the embassy surgeon, charles maitland, perform the procedure on her year-old son in in turkey. in , dr. charles maitland performed the first english variolation on lady montague's year-old daughter after their return to london ( ) . lady montague became a great proponent of the procedure and worked thoroughly on advocating this process for its ability to protect against the spread of smallpox. data from the u.s. national library of medicine and the nih showed that - % of those variolated died as compared to % of those who contracted the disease naturally. correspondingly, rev. cotton mather and dr. zabdiel boylston introduced variolation in america and were also great advocates of this procedure especially since, in the same year, there was a smallpox epidemic in boston that killed hundreds ( ) . however, lady montague, rev. mather, and dr. boylston faced great opposition regarding their promotion of variolation even with the presentation of the comparative analysis of fatality rates, which reached % for those variolated compared to % for the naturally occurring disease ( ) . despite some variolation-related deaths, the word of inoculation kept spreading along with data suggesting that variolation was still the safeguard against the spread of smallpox. in addition, benjamin franklin, who lost his son in , wrote: "i long regretted that i had not given it to him by inoculation, which i mention for the sake of parents who omit that operation on the supposition that they should never forgive themselves if a child died under it; my example showing that the regret may be the same either way, and that therefore the safer should be chosen" ( ) . in , dr. william heberden, at his own expense and with the support of benjamin franklin, wrote a pamphlet entitled "some account of the success of inoculation for the small-pox in england and america: together with plain instructions by which any person may be enabled to perform the operation and conduct the patient through the distemper" ( ) . toward the late eighteenth century came jenner's breakthrough in finding a safer immunizing technique than variolation, which is vaccination. the method of variolation had low yet significant death rates; therefore, physicians were on the quest of finding a new and more secure method of immunization with minimal or no death rates. on this basis, an english physician named edward jenner ( - ) searched for a cure for smallpox, a debilitating disease that rendered the world helpless. jenner became interested in certain individuals who were immune to smallpox because they had contracted cowpox in the past. he personally witnessed this when he learned of a dairymaid that was immune to smallpox due to her previous infection with the cowpox virus, usually transmitted from infected cattle. during that time, an english farmer named benjamin jesty personally took charge of inoculating his wife and children with fresh matter from a cowpox lesion in one of his cows out of fear of having his wife and children become victims of the smallpox epidemic. he applied this method after having contracted cowpox himself and believing he was immune to smallpox. he never published his results even though his wife and children did not show symptoms after being exposed to smallpox ( ) . during these years, there were still outbreaks of smallpox. george washington, after surviving smallpox, ordered mandatory inoculation for his troops in ( ) . after many speculations on the role of cowpox and its immunizing effect against smallpox, jenner, in , inoculated an -year-old boy named james phipps using matter from a fresh cowpox lesion on the hands of a dairymaid named sarah nelms who caught them from her infected cattle. after several days, jenner inoculated the boy again but this time with fresh matter from a smallpox lesion and noted that the boy did not acquire the disease proving that he was completely protected ( ) . a few years later, word of his success circulated among the public, and jenner wrote "an inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western counties of england, particularly gloucestershire and known by the name of cowpox, " after adding several cases to his initial achievement with the boy phipps. at first, his publication and achievement did not stir any interest in his community, but with time, word of jenner's breakthrough began spreading ( ) . the late eighteenth century was characterized by the implementation of the new process of immunization, vaccination, which required the inoculation of fresh matter from cowpox lesions into the skin of healthy individuals. the nineteenth century was a major landmark in the history of vaccines since it witnessed discoveries made by louis pasteur, the father of microbiology, and robert koch, the scientist who discovered the germ responsible for tuberculosis ( ) . in the beginning of the nineteenth century, the term "vaccination" was introduced by richard dunning from the latin word for cow "vacca. " after becoming aware of the fact that vaccination was more secure than variolation, several physicians initiated movements against the use of variolation and advocated for its eradication. dr. jean de carro, for example, aided in the elimination of variolation and its substitution with vaccination. some of the major efforts implemented in america were initiated by dr. benjamin waterhouse, who received the vaccine from edward jenner and vaccinated his own family. he later proved that they acquired immunity when they remained asymptomatic after he infected them with smallpox. waterhouse worked effectively on making vaccination universal in the u.s. unfortunately, like any other medical breakthrough, problems arose both because waterhouse aimed at making profit and the public was not ready to implement these procedures. however, after breaking his initial monopoly, waterhouse accepted to share his vaccines and made the supplies available to other physicians ( ) . despite all these efforts, smallpox epidemics continued to occur and jenner stated in a pamphlet that he wrote, "the annihilation of the small pox, the most dreadful scourge of the human species, must be the final result of this practice. " eradication was finally achieved years later. the time it took could be attributed to the fact that jenner did not think of the necessity of revaccination nor of the instability of vaccines, which made them unable to handle different environmental conditions, including countries other than england ( ) . the late nineteenth century was distinguished by pasteur's achievements that made him the father of vaccines after creating the first laboratory vaccine. louis pasteur ( - ), a french chemist and microbiologist, was the first to propose the "germ theory" of disease in addition to discovering the foundations of vaccination ( ) . he studied chicken cholera and received strains of bacteria causing anthrax and septic vibrio. pasteur started his experiments by intentionally infecting chickens by feeding them cholera-polluted meals and then recording the fatal progression of the illness. at first, pasteur was using fresh cultures of the bacteria to inoculate the chickens, most of which did not survive. during that time, pasteur had to go on a holiday, so he placed his assistant in charge of injecting the chickens with fresh cultures. however, his assistant accidentally forgot to perform the injections, and the bacterial cultures were left in a medium that was exposed to room air for about a month. later, the attendant injected the chickens with the now "attenuated" strain of bacteria resulting in mild, nonfatal symptoms. pasteur later re-injected these chickens, but this time with fresh bacteria. to his surprise, they did not get ill. ultimately, pasteur reasoned that what made the bacteria less deadly was exposure to air, mainly oxygen. pasteur used the french verb "vacciner" during the years and to describe how he was able to provide total body immunity through vaccination by inoculation of an attenuated virulence which was the first vaccine made by a human in the laboratory ( ) . pasteur also developed the anthrax vaccine in his laboratory, not long after performing his studies on chicken cholera. in , pasteur used his own anthrax vaccine, which contained attenuated live bacterial cultures in addition to carbolic acid, and demonstrated that all vaccinated animals survived while the control group died ( ) . during the same year, louis pasteur in france and george miller sternberg in the u.s. almost simultaneously and independently isolated and grew the pneumococcus organism. later in , pasteur successfully fought rabies that was endangering the european livestock by using his attenuated rabies vaccine obtained from desiccated brain tissue inactivated with formaldehyde, which provided immunity to dogs against rabies in his experiments ( ) . he reported his success to the academy of sciences in france, and a year later, he applied his original vaccine h after a -year-old boy was bitten several times by a rabid dog. the boy survived after being first inoculated with the most attenuated organisms, then subsequently with less attenuated organisms each day for days ( ) . in , the pasteur institute was established as a rabies treatment center as well as an infectious diseases research and training institute. after pasteur's successful live vaccines, a new type of vaccine was introduced in the last few years of the nineteenth century. these were killed vaccines, which were directed against three chief bacterial causes of human morbidity: cholera, typhoid, and the plague. the first cholera vaccine used to immunize humans was actually a live vaccine developed by jaime ferran ( - ), which provided a high level of protection during the epidemic in spain. however, the first killed vaccine for cholera was developed in by wilhelm kolle ( - ) and was used in japan in with over % efficiency. the credit for developing the killed typhoid vaccine during the s goes to both richard pfeiffer and almroth wright who made great contributions. wright was later credited for carrying out the "first large-scale vaccination using a killed typhoid vaccine" ( ) . finally, the killed vaccine for plague was first developed in by haffkine, who was one of pasteur's followers, when an epidemic struck bombay. during this period, vaccine production was taken over by factorytype laboratories, which formed the precursors of the biological products supply houses. many types were produced. paul ehrlich ( - ), a german physician and scientist who worked under a contractual collaboration with behring, noted the existence of toxoids in the late s. he also promoted enrichment and standardization protocols. these protocols enabled the exact determination of quality of the diphtheria antitoxins. in , it was demonstrated that toxoids could be used to durably immunize guinea pigs. it is crucial to briefly address the historical background of the bacterial infections that led to some of the earliest and most successful use of toxoids, inactivated forms of bacterial toxins, for the purpose of immunization. until the twentieth century, diphtheria, tetanus, and pertussis proved to be significant causes of illness and death with no effective treatments or prevention in sight. fortunately, advances in improved the prognosis of numerous future patients ( ) . at the end of the nineteenth century, especially in and , the cholera and typhoid vaccines were developed, followed by the introduction of the plague vaccine. the latter was preceded by the preparation of anti plague horse serum at the pasteur institute by alexandre yersin. yersin demonstrated disease protection in animals. later, he went to china to try his vaccine on humans during a plague epidemic ( ) . diphtheria is a potentially fatal disease that primarily involves tissues of the upper respiratory tract and kills its victims slowly by suffocation. in , a german physician, edwin klebs ( - ), was able to successfully isolate the bacteria that proved to be the etiological agent of the disease. it was later proved that toxin production is initiated only after the bacteria are themselves infected by a specific virus or a bacteriophage carrying the toxin's genetic instructions ( ) . in france, during the year , emile roux discovered the diphtheria toxin. his discovery led to the development of passive serum therapies through the scientific contributions of many, including emil von behring and paul ehrlich ( ) . similarly, the etiological agent of pertussis, commonly known as the "whooping cough, " was found to be a bacterium isolated from infected patient tissues in ( ) . tetanus was similarly a significant cause of mortality usually resulting from dysfunction of the autonomic nervous system or the respiratory muscles ( ) . in , another german scientist, arthur nicolaier ( - ), correlated tetanus with an anaerobic soil bacterium found in wounds. a few years later, the japanese investigator shibasaburo kitasato ( - ) was able to isolate this bacterium ( ) . at the beginning of world war i in , the tetanus toxoid was introduced following the development of an effective therapeutic serum against tetanus by emil von behring and shibasaburo kitasato. the rabies and typhoid vaccines were then licensed in the u.s. as the etiology of these destructive diseases was slowly being uncovered, by shibasaburo kitasato along with emil von behring ( ) . they discovered that the serum of animals that had been exposed to sub-lethal doses of the bacteria involved in tetanus and diphtheria was protective against the lethal effects associated with these pathogens by having an antitoxin effect when injected into another animal. additionally, this discovery, which earned behring the inaugural nobel prize for physiology and medicine in , was the concept of passive transfer in addition to serum therapy. he proved that serum could be acquired from immune animals and transferred to others as protection ( ) . once this concept made its way to clinical practice in , technical problems were faced while developing the right antitoxin concentration and potency. as a result, in the early twentieth century, the u.s. congress enacted the biologics control act legislation "to regulate the sale of viruses, serums, toxins, and similar products" to ensure medication quality control. nevertheless, with the increasing use and popularity of antitoxins derived from animal serum, scientists began to observe a syndrome now called serum sickness, or a reaction to immune-complexes formed from combining high concentrations of antigens with antibodies. this eventually led to the use of human rather than animal serum in order to decrease the frequency of adverse events; still, serum therapy was not perfect in preventing disease due to the frequency of adverse events and its brief duration of action. later on, combining diphtheria toxin and antitoxin in the same syringe proved much more effective in decreasing mortality rate. this combination became commercially available in . this was the first step in the shift from passive to active immunization ( ) . in , gaston ramon ( - ), a french veterinarian working at the pasteur institute, used a diphtheria toxoid produced by formalin and heat inactivation without the use of antitoxin to safely induce active immunity in humans. this product, termed anatoxine, was the basis for the novel and clinically effective toxoid vaccine against diphtheria. experiments followed to improve the durability of the protective response of the vaccine, and in , the importance of aluminum salts as an adjuvant added to the vaccine to augment the immune response to the antigen, became apparent ( ) . this was discovered by alexander thomas glenny ( - ) who proved that toxoid alone produced a lower level of antibody and immunity than desired, whereas better immunity was achieved when an inflammatory reaction was triggered. with these significant improvements, tetanus and diphtheria toxoids became routinely used across america and europe in the s and s ( ) . since then, refinements have been made to these vaccines to yield higher purity and reduce the number of booster doses. nowadays, widespread childhood vaccination is reducing the burden of these diseases. while this is a huge advantage, vaccines may potentially produce adverse effects that can discourage their acceptance by some populations. this has led to numerous safety movements which culminated in the congressionally legislated national childhood vaccine injury act in the s created to compensate families for selected adverse events potentially related to mandatory childhood vaccinations ( ) . nevertheless, global recommendations continue to call for routine immunization of children against diphtheria, tetanus, and pertussis with the combined dtp vaccine to sustain immunity in childhood and adolescence. dtp has, therefore, become one of the most widely used vaccines to achieve widespread immunity across age groups ( ) . tuberculosis, otherwise known as the "great white plague, " is another disease that started spreading as an epidemic once industrialization began. this disease caused approximately % of deaths in the eighteenth and nineteenth centuries across all socioeconomic groups ( ) . a french physician named jean antoine villemin ( - ) demonstrated that the mode of transmission of disease is through the respiratory system. robert koch ( - ) , known as the founder of modern bacteriology, revealed in that the causative agent of the disease is mycobacterium tuberculosis, which later became known as koch's bacillus ( ) . following this discovery, koch created what later came to be known as koch's postulates, which listed the criteria necessary for proof of bacterial causality: "the organism must be present in diseased tissues; it must be isolated and grown in pure culture; and the cultured organisms must induce the disease when inoculated into healthy experimental animals" ( ) . in , two bacteriologists working in the pasteur institute in lille, albert calmette ( - ) and camile guerin ( - ), announced their discovery of mycobacterium bovis, which is a strain of tubercle bacilli that could be used to create a vaccine against tuberculosis. this occurred after it became evident that different forms of the bacterium were required to prevent or treat tuberculosis, including non-pathogenic, attenuated, or killed tubercle bacilli from different sources, including human, bovine, and equine. this strain had an attenuated virulence while maintaining its antigenicity and became known as bcg ( ) . bacille calmette-guerin vaccinations proved to be successful in animal studies in and were soon used as an oral vaccine to immunize humans against tuberculosis. in , the bcg vaccine, constituted by the live-attenuated m. bovis, was first used in newborns. it has become the most widely administered of all vaccines in the who expanded program for immunization, but has been estimated to prevent only % of all potentially vaccinepreventable deaths due to tuberculosis ( ) . despite its imperfections, bcg remains the only effective vaccination for protection against human tuberculosis ( ) . yellow fever is a highly fatal infection caused by a small, enveloped, single-stranded rna virus and results in renal, hepatic, and myocardial injury, along with hemorrhage and shock ( ) . unlike previously mentioned diseases, the history of yellow fever is highly uncertain and filled with misconceptions. early work on immunization against the disease began with carlos finlay in the s and s when koch's postulates were becoming increasingly accepted. finlay proposed that mosquitos carried the yellow fever "germ. " he attempted to prove it by feeding mosquitos that had fed on yellow fever patients. however, it was later revealed that his process failed due to the lack of an incubation period within the mosquito, which is a transmission requirement that finlay was unaware of ( ). since , significant advances have been made in creating a vaccine by the yellow fever commission, which was originally led by walter reed ( - ) along with jesse lazear, aristedes agramonte, and james carroll. reed's experiments took finlay's discovery one step further by adding an incubation period of approximately weeks and achieved the same positive results. when mosquitos bite non-immune individuals after feeding on individuals who had yellow fever, none of the non-immune subjects died and very few suffered disease. this led the commission of investigators to a major discovery, namely, the identification of the asibi strain, which is the parent strain of the present d vaccine, obtained via continuous indirect passage through the aegypti mosquitos and direct passage through monkeys. in addition to identifying the etiological agent of the disease, the commission also identified rhesus monkeys as susceptible hosts, hence providing a means for testing future vaccine attempts. this paved the way for max theiler and other rockefeller foundation scientists to develop a successful live-attenuated vaccine for yellow fever in . "the most important experimental passage seriesdesignated d -used a virus that had been subcultured eighteen times in whole mouse embryos, followed by passages in wholeminced chick embryo cultures, after which the virus was passed in minced chick embryo depleted of nervous tissue. " theiler himself was actually one of the first individuals to be successfully vaccinated. the vaccine was quickly implemented, and alternative vaccines shown to be more dangerous were discontinued ( ) . influenza has proved to be very difficult to trace back in history due to its non-specific symptoms and features. it was not until the early twentieth century that influenza outbreaks began to be systematically studied due to well-documented clinical descriptions and epidemiological data. in , the "spanish flu" influenza pandemic was responsible for - million deaths worldwide and more than one-half million in the u.s. this virus was unusual because it spread so quickly, was so deadly ( ) . richard e. shope ( - ) , a physician who conducted his research in the department of animal pathology at the rockefeller institute in princeton, was the first to isolate influenza virus; a member of the orthomyxovirus family, from a mammalian host in ( ) . he was able to induce the syndrome of swine influenza in pigs by applying respiratory secretions intranasally. he also isolated a bacterium from the respiratory tract of infected pigs called haemophilus influenzae suis. when this bacterium was combined with a filterable agent and inoculated, the pigs developed the clinical manifestations of swine influenza. these two agents seemed to act synergistically with the virus to damage the respiratory tract hence creating the suitable environment needed for the virus to exercise its pathological effects. in , scientists from the british national institute for medical research including christopher andrews, wilson smith, and patrick laidlaw successfully isolated and transmitted the influenza virus from humans. throughout this year, "burnet has successfully cultivated the organism in chick embryos; other influenza types had been recognized; neutralizing antibodies had been identified and quantitated; and viral surface glycoproteins, h and n had been described" ( ) . these discoveries led scientists to introduce the inactivated vaccine in the mid- s that is still used to this day ( ) . the influenza a/b vaccine was initially presented to the armed forces epidemiological board in . it was licensed following the war and used for civilians in in the u.s. starting , a series of vaccines were licensed for haemophilus influenza type b (hib) polysaccharide vaccines. these vaccines are recommended routinely for children at and months of age. the vaccine was, however, not consistently immunogenic in children < months of age. in , the protein-conjugated hib vaccine was licensed and in the next years, it became available. during , a combined vaccine hib conjugate and hepatitis b was licensed. later on, in , the first nasally administered influenza vaccine was licensed. this live influenza a and b virus vaccine was indicated for healthy, non-pregnant persons ages - years. the contracts to develop vaccine against the h n avian influenza virus were awarded to aventis pasteur and to chiron in . during the following year, an inactivated, injectable influenza vaccine was licensed. it was indicated for adults years of age and older. during the same year, the fda approved afluria, a new inactivated influenza vaccine, for use in people aged years and older. two years later in , the department of health and human services, supported the building of a facility to manufacture cellbased influenza vaccine. it also directed toward development of a vaccine for novel influenza a (h n ). during the same year, the fda approved four vaccines against the h n influenza virus high-dose inactivated influenza vaccine (fluzone high-dose) for people aged years and older. in , the fda approved several vaccines: hibmency a new combination of meningococcal and hib vaccine for infants; flucelvax, which is the first seasonal influenza vaccine, manufactured using cell culture technology and a quadrivalent formulation of fluarix ( ) . unfortunately, one of the difficulties in dealing with influenza is the continuous mutability of the viral genome necessitating annual reassessments and reformulations of the vaccine. this has led to a suboptimal effectiveness of influenza vaccines, which are only successful against strains included in the vaccine formulation or strains of homogenous subtype. several pandemics were caused by the influenza virus: during the years - , the "asian" influenza pandemic caused by h n influenza virus resulted in an estimated , deaths in the u.s. alone and in the years - , the "hong kong" influenza pandemic caused by an h n influenza virus induced roughly , deaths in the u.s. ( ) . future studies should focus on producing vaccines protective against variant strains and creating surveillance systems to detect novel strains in time to formulate the proper vaccines. poliomyelitis, or polio, is an intestinal infection spread between humans through the fecal-oral route. it is a disease of the developed nations striking younger individuals most frequently in warmer weather. one of the most famous polio victims, president franklin d. roosevelt, founded the national foundation for infantile paralysis in , later known as the march of dimes ( ) . it is well established that better hygiene decreases childhood exposure to the disease, when infection would usually be milder since protective maternal antibodies are present ( ) . in , the nobel prize in medicine was awarded to john enders, thomas weller, and fredrick robbins for their discovery of the ability of poliomyelitis viruses to grow in tissue cultures ( ) . two major lifelong competitors were involved in the race for the polio vaccine, jonas salk and albert sabin . salk took a more traditional route using a killed-virus approach, which did not involve natural infection in acquiring immunity. instead, his approach involved a fully inactivated virus that still had the ability to induce protective antibodies. sabin, on the other hand, set out to create a live-virus vaccine based on the belief that this would trigger natural immunity and provide a lasting protection. salk had speed, simplicity, and safety on his side since a killedvirus did not have the ability to revert to virulence, whereas the live-virus vaccine could be given orally, establish longer lasting immunity, and offer passive vaccination through the excreted weakened virus potentially immunizing a large portion of nonvaccinated communities ( ) . not surprisingly, salk's vaccine was the first to make it to the population. following successful clinical trials in , six companies began mass production of the vaccine. unfortunately, salk's vaccines were soon suspended and recalled when contaminated samples were found in the market due to poor monitoring and control in some laboratories leading to serious health consequences and national panic. the first cutter polio vaccine incident was reported on april , with more cases reported just a day later with the number eventually rising to of those vaccinated and in of their close contacts. on april , the laboratory of biologics control requested that cutter laboratories recall all vaccines and the company did so immediately. on may , the surgeon general recommended that all polio vaccinations be suspended pending inspection of each manufacturing facility and thorough review of the procedures for testing vaccine safety. the investigation found that live polio virus had survived in two batches of vaccines produced by cutter laboratories. large-scale polio vaccinations resumed in the fall of ( ) . at the same time, sabin had been making great advances with his live-virus vaccine since . after successful clinical trials conducted in the soviet union that left polio virtually wiped out with no safety issues, it soon became the vaccine of choice in the west. the polio vaccination assistance act was enacted by congress and was the first federal involvement in immunization activities. it allowed congress to appropriate funds to the communicable diseases center [later the centers for disease control and prevention (cdc)] to help states and local communities acquire and administer vaccines. at the beginning of the s, the oral polio vaccine types , , and as well as the trivalent product were licensed in the u.s. the first were developed by sabin and grown in monkey kidney cell culture, while the trivalent oral polio was developed to improve upon the killed salk vaccine ( ) . as a result, in the late s, the cdc recommended switching back to salk's killedvirus polio vaccine, while the who also advocated the switch for polio-free nations and the continued use of the favored live-virus vaccine for routine immunization ( ) . the last two cases of wild type polio were reported in an unvaccinated amish in and in a -year-old boy from peru in ( ) . in , the enhanced-potency inactivated poliovirus vaccine was licensed. following successful developments in the polio vaccine, attention soon shifted to three other common viral diseases of childhood: measles, mumps, and rubella. the measles virus is an rna virus from the genus morbillivirus belonging to the paramyxooviridae family. it causes an acute illness that includes fever, cough, malaise, coryza, and conjunctivitis, in addition to a maculopapular rash. in general, measles is a mild disease but, like many others, has the potential to cause serious complications. in addition, measles is known to be one of the most contagious human diseases causing major outbreaks to occur very often. until the year , measles was still the leading cause of vaccine-preventable childhood deaths worldwide ( ) . john enders ( enders ( - , known as the "father of modern vaccines" had a particular interest in revealing the virus responsible for measles. he isolated the edmonston strain of the virus in , which was named after the child from whom it was isolated. a formalin-inactivated measles virus vaccine derived from this strain was subsequently licensed in the u.s. in . however, following the discontinuation of this vaccine in due to short-lived and incomplete immunity, over further attenuated vaccines were developed and used throughout the world, most of which were also derived from the edmonston strain ( ) . the first live-virus measles vaccine, rubeovax, was licensed in . other live-attenuated virus measles vaccines were eventually licensed in the u.s. in . the recommended age for routine administration was changed from to months of age. the first national measles vaccine campaign was launched in . the world recorded a % decreased incidence compared to the pre-vaccination years. in , a second live, further attenuated measles virus vaccine was also licensed. in , both the advisory committee on immunization practices (acip) and the american academy of pediatrics (aap) issued recommendations for a routine second dose of the measles vaccine. during the midto-late s, a high proportion of reported measles cases were in school-aged children ( - years) who had been appropriately vaccinated. these vaccine failures led to new national recommendations of a second dose of measles-containing vaccine ( ) . mumps is another acute viral illness. it is the only virus known to cause epidemic parotiditis in humans accompanied by fever, anorexia, headache, and malaise. k. habel and john enders isolated the virus in ( ) , and trials of formalin-inactivated mumps vaccine in humans began the same year by joseph stokes and colleagues and by enders. this approach was abandoned in the s due to short-lived immunity, and work began to develop live-attenuated mumps vaccines in by the vaccinologist maurice hilleman ( hilleman ( - and colleagues ( ) . hilleman isolated the wild type virus from his daughter, jeryl lynn, who contracted the virus at the age of and was recovering from it. it became known as the jeryl lynn strain of mumps virus. the mumps livevirus vaccine was licensed in december , ( ) . trials with this attenuated virus resulted in % protective efficacy and the vaccine was licensed in the u.s. in . this strain is still used to produce mumps vaccines until this day. it is given as part of the measles, mumps, and rubella (mmr) vaccine ( ) . rubella is a rash disease in children and adolescents caused by a filterable virus. it poses a severe threat to pregnant women and their children by potentially causing congenital deafness and cataracts. in , a rubella epidemic swept the u.s. resulting in . million cases of rubella infection, with an estimated , newborns having congenital rubella syndrome (crs), along with fetal and neonatal deaths in the thousands ( ) . the rubella virus was detected and isolated by two groups of scientists, thomas weller and franklin neva at harvard medical school, in addition to paul parkman and colleagues at the walter reed army institute of research (wrair). similar to measles and mumps, inactivated whole virus vaccines proved ineffective, so efforts turned to discovering a live-attenuated vaccine ( ) . in , paul parkman left wrair and joined harry meyer jr. at the nih division of biological standards, and the pair developed the first live-attenuated rubella vaccine in , hpv- , which was subsequently included in the initial mmr vaccine used in the u.s. in the s ( ) . maurice hilleman discovered the superior ra / vaccine that became the only vaccine used outside of japan starting in the late s. this vaccine maintained its preference due to many factors including increased durability and harmlessness to fetuses of inadvertently vaccinated pregnant women ( ) . in , three rubella virus strains were licensed in the u.s.: hpv- strain grown in dog-kidney culture, hpv- grown in duck-embryo culture, and cendehill strain grown in rabbit-kidney culture. a decade later, in , the ra / (human diploid fibroblast) strain of rubella vaccine (meruvax ii) by merck was licensed. all other strains were discontinued. merck's combined trivalent mmr as well as the combined measles and rubella vaccine (m-rvax) developed by maurice hilleman and colleagues, was licensed by the u.s. government in ( ) , and is still in use today. moreover, the age for routine vaccination with mmr vaccine was changed from to months in the year of . the next vaccine that combined measles, mumps, rubella, and varicella antigens (proquad) was licensed in . it was indicated for use in children months to years. in response to the association of this vaccine with autism, in , the eighth and final report of the immunization safety review committee was issued by the institute of medicine concluded that the body of epidemiological evidence favors rejection of a causal relationship between the mmr vaccine and autism ( ) . combination vaccines hold many advantages including reduced need for several injections, therefore, reducing the incidence of vaccination site reaction ( ) . the etiological agent of clinical hepatitis, identified by its distinguishing yellow jaundice, was found to be infectious in the early s. the different hepatitis strains, a and b, were first differentiated in ( ) . in the mid- s, blumberg and coworkers and prince discovered hepatitis b surface antigen in the circulating blood of carriers of the infection. deinhardt et al. soon followed this discovery with that of the hepatitis a virus ( ) . provost et al. successfully prepared a killed hepatitis a vaccine in , which proved to be safe and highly effective in extensive clinical trials. the first inactivated hepatitis a vaccine (havrix) was licensed in . the following year, a second inactivated vaccine (vaqta) also became available ( ) . hepatitis b, on the other hand, rarely causes any severe risk as a primary infection. however, those who develop a chronic persistent infection may continue to have severe disease for the rest of their lives. this may even lead to cirrhotic destruction of the liver due to host immune response to the virus. the discovery of the surface antigen particles of the hepatitis b virus by blumberg and colleagues in the plasma of human carriers was followed by attempts to create a vaccine. in , a killed hepatitis b vaccine was developed and clinical trials began in proving the safety and efficacy of the vaccine. merck and pasteur institute subsequently independently licensed the plasma-derived vaccine in ( ). on july rd , the recombinant hepatitis b vaccine (recombivax hb) was licensed. using recombinant dna technology, merck scientists developed a hepatitis b surface antigen subunit vaccine. three years later, on august th , the recombinant hepatitis b vaccine (engerix-b) was licensed. a decade later in , the fda approved a two-dose schedule of hepatitis b vaccination for adolescents - years of age using recombivax hb (by merck) with the -μg (adult) dose at and - months later. at the beginning of the new millennium, in , a combined hepatitis a inactivated and hepatitis b (recombinant) vaccine, twinrix was licensed. the following year, a vaccine combining diphtheria, tetanus, acellular pertussis, inactivated polio, and hepatitis b antigens (pediarix) was licensed ( ) . in conclusion, fortunately, both hepatitis a and b are now preventable due to the discovery of these highly effective vaccines that proved to maintain long-term immunity in vaccinated individuals ( ) . in , the world health assembly called for global smallpox eradication, which was launched the following year. during the first year of the program , cases of polio were reported in countries that were endemic to smallpox. four years later, the cdc recommended discontinuation of routine vaccination for smallpox in the u.s. following a greatly reduced risk of disease ( ) . during the s, especially in , the expanded program on immunization was created within who, in response to poor immunization levels in developing countries (< % of children in ). the following vaccines were used by the expanded program on immunization: bcg, polio, dtp, measles (often mmr vaccine), yellow fever (in endemic countries), and hepatitis b. three years later, in october , the last case of naturally acquired smallpox occurred in the merca district of somalia. in the same year, the first pneumococcal vaccine was licensed, containing serotypes (of the known serological groups) that composed % of all bacteremic pneumococcal infections in the u.s. ( ) . on may , the world health assembly declared the world free of naturally occurring smallpox. on the other hand, in july , two enhanced pneumococcal polysaccharide vaccines (pneumovax and pnu-imune ) were certified. these vaccines included purified capsular polysaccharide antigens of streptococcus pneumoniae and replaced the -valent polysaccharide vaccine licensed in . a few years later, in , the world health assembly passed a resolution to eradicate polio by the year ( ) . later on, in , the japanese encephalitis (je) inactivated virus vaccine (je-vax) was licensed. during the year , the expanded program for vaccine development and the vaccine supply and quality program were merged creating the global program for vaccines and immunization. during the same year, the western hemisphere was finally labeled as "polio-free" by the international commission for the certification of polio-eradication. the was another monumental year with the launching of the international aids vaccine initiative (iavi) that called for the speedy development of a human immunodeficiency virus (hiv) vaccine for use worldwide. this in turn led to the introduction of the scientific blueprint for aids vaccine development. iavi was funded by several ngos and foundations. it is a collaborating center of the joint united nations program on hiv/aids (unaids) whose efforts led finally lead to the first possible vaccine against hiv (aidsvax) which reached phase iii trials, the largest recorded human hiv vaccine trial at that time. the trial involved volunteers from the u.s., canada, and the netherlands, the majority of whom were men who have sex with men ( ) . preliminary results from the trial of aids vax (vaxgen) vaccine were reported in early . while the vaccine was shown to be protective amongst non-caucasian populations, especially african-americans, the same effect was not reproducible in caucasians ( ) . during the same year, the children's vaccine program was established at who's program for appropriate technology in health (path). the program's goal was to provide vaccines to children in the developing world and to accelerate research and development of new vaccines. the first vaccines purchased were hib, hepatitis b, rotavirus, and pneumococcal, which were not commonly used in the developing world ( ) . at the beginning of the new millennium, the western pacific region of the world was certified as polio-free. during the next years, the european region also became certified as polio-free. in , the fda licensed the first vaccine developed to prevent cervical cancer (gardesil), precancerous genital lesions and genital warts due to human papillomavirus (hpv) types , , , and . the first smallpox vaccine for certain immune-compromised populations was delivered under project bioshield on july th . the following year , the who declared the "decade of vaccines" and in , the united nations foundation launched shot@life campaign ( ) . varicella ("chickenpox") is caused by the varicella zoster virus (vzv). michiaki takahashi, professor of virology at the research institute for microbial diseases at osaka university, successfully produced the oka vaccine strain of live, attenuated varicella vaccine in the s. takahashi was able to make this remarkable advance at a time when very few viruses had been attenuated to produce efficacious live-virus vaccines including yellow fever, polio, measles, mumps, and rubella as previously mentioned. the vzv vaccine is the first and only licensed live, attenuated herpesvirus vaccine in the world. numerous trials in the early s continued to prove the safety and efficacy of the vaccine in both healthy and immunocompromised, high-risk individuals. as a result of these successful trials, the live varicella virus vaccine (varivax) was licensed in for the active immunization of persons months of age and older ( ) . about years later, in , varizig, a new immune globulin product for post-exposure prophylaxis of varicella, became available under an investigational new drug application expanded access protocol ( ) . as a herpesvirus, vzv possesses the unique ability to establish latent infection subsequent to primary infection. zoster results from reactivation of latent vzv that spreads through nerves to the skin. therefore, one fear associated with this vaccination was the possibility that it could increase the incidence and/or severity of zoster when compared to natural disease. conversely, it was actually shown that following vaccination, zoster is less common than after natural infection ( ) . in , the fda licensed a new vaccine to reduce the risk of shingles in the elderly. the vaccine, zostavax was approved for use in people aged years of age and older ( ) . rotavirus is the leading cause of severe diarrhea and vomiting (severe acute gastroenteritis) among young infants and children worldwide. no significant difference was found in the incidence of rotavirus in industrialized and developing countries, suggesting that vaccination may be the only way to control the impact of this severe disease. dr. ruth bishop and colleagues were the first to describe rotavirus in humans in . it was clear, early on, that a naturally acquired first infection, whether symptomatic or asymptomatic, was the most effective defense against severe reinfection, and subsequent infections progressively created greater protection. therefore, the goal was to create a vaccination that mimicked the effectiveness of naturally acquired immunity following infection. the development of live, attenuated, oral, safe, and effective rotavirus vaccines was then attempted starting in the mid- s. dr. albert kapikian and colleagues, at the nih, developed the rrv strain that was subsequently used to develop the rrv-tv, or the rotashield, live oral, and tetravalent vaccine licensed in to be used in infants at , , and months of age ( ) . however, due to several reported cases of vaccine-associated intestinal intussusception, rotashield was pulled off the market in the u.s. months after its introduction on the th of october, . in , the national institute of allergy and infectious diseases (niaid), part of the nih, awarded a new license agreement for rotashield to biovirx, inc. of minneapolis, mn, usa, which planned its global commercialization. in , history of intussusception was added as a contraindication for rotavirus vaccination ( ) . clark, offit, and plotkin then produced the rotateq vaccine by merck based on their bovine strain wc in , which was licensed in by the u.s. fda. this vaccine, live oral and pentavalent, is destined for use in infants ages - weeks ( ) . another vaccine, rotarix, was also licensed in . it is a liquid given in a two-dose series to infants from to weeks of age. before being licensed, both vaccines were shown to be safe and effective in rigorous clinical trials ( ) . during the past two decades, improvements in environmental health have contributed tremendously to disease vector control. however, substantial challenges remain in dealing with the newly emerging diseases such as severe acute respiratory syndrome (sars), h n , h n , and h n influenza, middle east respiratory syndrome (mers-cov), rotavirus, ebola virus, and a variety of other viral, bacterial, and protozoal diseases ( ) . the role of vaccines in the control and protection from the above mentioned emerging diseases cannot be overemphasized. actually, the importance of inducing protective immunity through vaccination came out to be the most powerful tool and effective strategy to prevent the spread of emerging viruses among populations, in particular, among people that are immunologically naïve and susceptible hosts. such emerging diseases represent a major public health concern; they affect livestock and humans thus threatening the world's economy and public health. vaccine strategies for emerging pathologies are limited by sudden appearance of the pathogen and the delayed time consuming traditional vaccine development process. novel methods to rapidly develop vaccine are being experimented, whereby investigators are working to achieve a better understanding of the nature of the interactions between the immune system and a panel of novel harmful microbes. on this basis several novel strategies have been developed and applied. such strategies included the use of ( ) recombinant proteins, or nanoparticles like in sars-cov and mers-cov, ( ) synthetic peptides like the case of influenza virus, in managing or even in preventing the emergence of new infectious diseases, a plan should be developed to strengthen surveillance and promote a multi-partners response within local, national, and global programs. with the high burden of emerging infectious diseases (eid) it becomes an essential part to find an effective method of either preventing or controlling their spread, that is where the role of vaccines prevails. it is significant to mention that the average case fatality rate for ebola is around % and outbreaks are affecting both developed and developing countries. another emerging disease, mers-cov, has caused the death of around % of people reported to have contracted the disease. another disease with high health and economic burden would be rotavirus which was estimated to have annual direct and indirect costs of around $ billion with "more than , physician visits, more than , emergency department (ed) visits, , to , hospitalizations, and to deaths each year in children younger than years" (cdc, ) . these are few of the facts regarding the affliction of eid most of which have no approved vaccine yet. on the other hand, the influenza virus which was estimated to cause an average of , deaths annually with a $ billion cost of an epidemic, showed that with the introduction of its vaccine, studies proved it to be % effective in preventing death ( ) . these figures have managed to influence many governmental and non-profit organizations to intervene either through governmental funding of vaccines where the congress provides yearly international eid funding to several u.s. governmental agencies or through international non-profit organizations which are the leaders in global health innovation ( ). vaccines remain among the most reliable and effective medical interventions in providing the means to fight debilitating and preventable diseases thus ensuring the continuity of mankind and saving lives. through reviewing the factsheets provided by the world health organization, which provide statistical data on the mortality and morbidity percentages before and after the introduction of the vaccines, one can comprehend the vital role vaccines have played up till this day. some of the figures that depict the impact of vaccines in decreasing mortality and morbidity include more than % decrease in polio cases since , with cases reaching , from over endemic countries down to cases as reported in with only endemic countries, measles vaccine has prevented the death of around . million children during - , in general vaccines prevent around million deaths annually worldwide ( ) . this success in providing better public health does not negate the economic burden of vaccination. vaccination programs require excessive funding to ensure proper handling and maintenance of vaccines, adequate staffing and ongoing provision over efficacy and safety of vaccines and the development of newer vaccines ( ) . nevertheless, the economic and social burden related to the expenses in hospitalizing affected unvaccinated people still outweighs the aforementioned burden. moreover, better health in the society would promote economic growth and productivity. consequently, public awareness and public efforts agree on the importance of vaccination and the implementation of policies regarding mandatory vaccinations as a way to decrease outbreaks of preventable diseases and improve global health and prosperity. as early as the introduction of vaccines, campaigns against vaccination were raging. as with any new medical intervention there are safety concerns that arise which might be deleterious to the public health. concerns regarding vaccines often follow a path that starts with the hypothesis of a potential adverse event that is impulsively announced to the public without having reproducible studies to confirm this hypothesis, and thus it would take the public several years to regain trust in the vaccine. a notable example in the recent history would be of the paper published by andrew wakefield in the british medical journal the lancet in , linking the mmr vaccine to autism. however, his research was discredited and the paper was retracted from the journal after it was proven that actually there is no link between mmr vaccine and autism as per the systemic review by the cochrane library ( ) . the battle against vaccines did not reach a halt, and there are still ongoing campaigns that come from religious, political, community-based, and even individual-based grounds raising even ethical issues regarding the mandatory vaccinations proposed by the government. according to the cdc, this year % of the children were vaccinated in the u.s., leaving % unvaccinated due to religious and philosophical exemptions or even parental refusal due to the fear of vaccine's side effects and concerns regarding autism from vaccines ( ); this is still a critical number since the unvaccinated would pose risk of outbreaks even among the immunized, which necessitates the need for additional awareness campaigns regarding the importance of vaccination since vaccines remain the only plausible measure of protection against preventable diseases. actually, a trend was reported in the health news lately, in the u.s., that pediatricians refuse to offer medical care for children whose parents declined their vaccination. vaccination has been of great importance throughout centuries (tables and ). people started with inoculation techniques dating back to a.d. with the chinese, turks, and asians. with every century and with every curious physician, inoculation techniques improved gradually giving rise to newer vaccination techniques with edward jenner and later on, louis pasteur and others. however, there is still plenty of room for improvement with the presence of ongoing epidemics and the spread of newly emerging diseases. one important goal is to strengthen the science base for vaccine development and for public health action and disease prevention. despite the common belief that infectious diseases were virtually eliminated by the middle of the twentieth century, new and reemerging infections are appearing along with drug resistant infections in the past two decades in the various parts of the world and whose incidence threatens to increase in the near future, due to changes in human demographics and behavior, immigration, and speed of international travel among other things ( ) ( ) ( ) . the importance of vaccine safety continued to grow throughout the twenty-first century, with the development and licensure of new vaccines added to the already robust immunization armamentarium. scientists also perfected new ways of administering immunizations including edible vaccines and needleless injections. however, formulated or delivered, vaccines will remain the most effective tool we possess for preventing disease and improving public health in the future. despite the antivaccination campaign and the association of vaccines with some side effects, vaccines continue to remain a cornerstone in global health. the distinctions between national and international health problems are losing ground and could be misleading, the "world is a village. " clinicians and public health workers need to interact on regular basis with veterinarians and veterinary public health. actually, good examples of the necessity of such collaboration is the emergence of sars-cov and mers-cov, it shows clearly how coronaviruses can spillover from animals into humans at any time, causing lethal diseases. foodborne diseases could lead to regional and international outbreaks which might constitute a threat to national and global security. centers for disease control and prevention. vaccines and immunizations: the basics epidemiology of vpds, vaccine safety the complicated task of monitoring vaccine safety vaccine safety: current and future challenges niaid. topics: vaccines the college of physicians of philadelphia. articles -different types of vaccines general aspects of vaccination the immune response to bcg vaccination of newborns the methodology for determining the efficacy of antibodymediated immunity aluminum hydroxide adjuvant induces macrophage differentiation towards a specialized antigen presenting cell type twin studies of immunogenicity-determining the genetic contribution to vaccine failure biology of immune responses to vaccines in elderly persons the influence of genetic factors on the immune response as judged by pneumococcal vaccination of mono-and dizygotic caucasian twins genetic regulation of immune responses to vaccines in early life vaccine epidemiology: efficacy, effectiveness, and the translational research roadmap the aging innate immune system reduction in acute gastroenteritis hospitalizations among us children after introduction of rotavirus vaccine: analysis of hospital discharge data from us states resolving the pneumococcal vaccine controversy: are there alternatives to randomized clinical trials? evaluating new vaccines for developing countries. efficacy or effectiveness? assessing vaccine efficacy in the field. further observations translational research and pediatrics the evolution of surgical instruments the history of pediatric infectious diseases the college of physicians of philadelphia. history of vaccines timelines. the college of physicians of philadelphia ( ) surgeons, smallpox, and the poor: a history of medicine and social conditions in nova scotia the immunization action coalition. vaccine timeline. the immunization action coalition jenner and the history of smallpox and vaccination experience in massachusetts and a few other places with smallpox and vaccination the medical side of benjamin franklin history of vaccine development (smallpox eradication: the vindication of jenner's prophesy chapter history of vaccine development. (pasteur and the birth of vaccines made in the laboratory chapter the history of anthrax vaccines: a biography (rabies) vaccines: a biography (killed vaccines: cholera, typhoid, and plague) vaccines: a biography (toxoid vaccines) historical review of pertussis and the classical vaccine preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the advisory committee on immunization practices (acip) a brief history of vaccines and vaccination vaccines: a biography (tuberculosis and bcg chapter the history of tuberculosis yellow fever: a disease that has yet to be conquered vaccines: a biography (yellow fever chapter a history of influenza vaccines: a biography (influenza chapter vaccines: a biography (polio chapter a brief history of polio vaccines vaccines: a biography (measles, mumps, and rubella chapter the history of vaccines and immunization: familiar patterns, new challenges vaccines in historic evolution and perspective: a narrative of vaccine discoveries history of vaccine development (three decades of hepatitis vaccinology in historic perspective. a paradigm of successful pursuits chapter vaccines: a biography (varicella and zoster chapter vaccines: a biography (rotavirus chapter pandemic preparedness and response -lessons from the h n influenza of emerging infectious diseases: a cdc perspective vaccination greatly reduces disease, disability, death and inequity worldwide historical comparisons of morbidity and mortality for vaccinepreventable diseases in the united states vaccines for measles, mumps and rubella in children vaccination coverage among children in kindergarten -united states historic dates and events related to vaccines and immunization ih is the first author. she provided the idea and followed along with aj the execution of the work and final editing. nc and sc did the literature search for the eighteenth and nineteenth century and the respective preliminary writing about this period. ss and rb did the literature search for the twenty-first century, and about general aspects of vaccination and the respective preliminary writing about this period.mr did the literature search regarding vaccine efficacy and effectiveness in the context of the transnational research map and regarding vaccination instruments and inoculating techniques. ag did the literature search and the preliminary writing for the early history of vaccination and wrote a draft of a manuscript about this period. al edited thoroughly and commented on the final manuscript. aj supervised the whole process from inception to the final submission and edited the whole manuscript. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -uazc lyg authors: hedrick, stephen m. title: the imperative to vaccinate date: - - journal: the journal of pediatrics doi: . /j.jpeds. . . sha: doc_id: cord_uid: uazc lyg nan stephen m. hedrick, phd the disease legacy of civilization h uman beings are almost certainly the most diseased species on earth. by one accounting, there are at least human pathogens, including bacteria, fungi, prions, protozoa, viruses, and worms, and of these, - appear capable of causing human epidemics. , even this is likely to be an underestimate, as new and sensitive sequencing techniques continue to uncover new viruses at a steady rate. we human beings are remarkable in many ways, but why are we remarkable for playing host to so many infectious agents? why is it that we must maintain high levels of vaccine coverage to prevent infectious agents from sickening or even killing large swaths of the population? the answers lie in the story of human disease epidemics, and it begins with human cultural and technological ascendance and what we now understand to be its inevitable consequences for pestilence and death. it is about our ingenuity, which has caused the retreat of many infectious diseases, but highlights a central tension in human existence-immediate self-interest vs long-term collective welfare. the concept is not just academic; there are realworld implications that we can resolve with an understanding of human disease ecology. the notion is that we are not only culturally connected or genetically connected through a common ancestry. rather, there is another fundamental concept that is, perhaps, not widely accepted or even understood. we are biologically connected, in the present, through our exchange of infectious agents and our common susceptibility to disease. to understand modern human disease prevalence, we have only to look to the most basic principles of epidemiology. a simplified version is that diffuse or small host populations cannot sustain an acutely infectious agent, meaning one in which infection is followed by clearance and long-term immunity. as the number of people with immunity increases, the density of susceptible hosts decreases, and with the corresponding decline in transmission, the infectious agent is not maintained in the population. this principle described our preagricultural ancestors-a few thousand individuals congregated in groups but spread out over an enormous area. small or low-density populations can only sustain a certain type of infectious agent, one that persists, usually for the life of the host. , once infected with herpes viruses, such as herpes simplex virus, cytomegalovirus, or epstein-barr virus, we are infected for life, and such viruses have infected us since even before we became human beings. [ ] [ ] [ ] [ ] to some extent, this was the primordial state of disease in diffuse bands of preagricultural hunter-gathers: persistent viruses, bacteria (eg, mycobacterium tuberculosis), intestinal protozoa, worms, and fleas. our paleolithic ancestors were not disease-free, but they almost certainly did not experience periodic and devastating epidemics. , conversely, large populations that live at high density, such as modern human beings, can sustain a much greater diversity of infectious agents, including those that the immune system is able to clear. transmission from person to person is rapid enough and continuous, such that there is little selective pressure for persistence. large and dense urban populations can maintain acutely infectious agents indefinitely due to a constant source of newly susceptible hosts in the form of immigration or births. these agents often share an ability to be transmitted by casual contact such as respiratory droplets produced by a cough or a sneeze, and as evidence of the success of this pathogen strategy, there are more than different viruses from at least different virus families (adenovirus, coronaviruses, influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinovirus) that cause "cold" symptoms: sneezing, coughing, and runny nose. the dawn of agriculture and the domestication of animals, especially herd animals, allowed the emergence of permanent human settlements and the growth of large situated communities. the world's population increased approximately -fold from the beginning of the agricultural revolution to the end of the th century, and most importantly, settlements eventually grew into a huge massing of humanity. simultaneously, we domesticated animals and ourselves, and we sampled all of the viruses and bacteria existing in cows, horses, pigs, sheep, goats, and birds. those that could replicate in human beings and spread from person to person by respiratory propulsion (or other means, such as fecal-oral) became established evermore in the human population. this is the answer to why we are the most diseased species on earth. we are the only species to so profoundly and rapidly change the way in which we interact with each other and other animals; in other words, we invented for ourselves an entirely new ecosystem. so, in addition to the endless parade of cold viruses that circulate among us, we acquired a great many deadly infectious agents, such as those that cause diphtheria, influenza, measles, meningitis, mumps, plague, rubella, smallpox, typhus, whooping cough, and others. each disease has its own history and severity, but all rely on large, high-density populations for continued propagation. these newly acquired infectious agents not only caused severe or deadly disease, they shaped the population. many are known as childhood diseases because they infect susceptible children who either recover from the disease and retain immunity or die. in a population in which a disease like measles existed, everyone contracted the virus exactly once, such that almost all surviving adults were immune. what does the world look like in the face of measles? from to , before the availability of a vaccine, an average of cases of measles were reported each year in the us, along with an average of measles-related deaths, encephalitis cases (often with permanent brain damage), and respiratory complications. the measles vaccine was licensed in and the measles, mumps, rubella (mmr) vaccine was licensed in . for the years between and , the number dropped to cases of measles in children younger than years of age; died, contracted encephalitis, and contracted pneumonia. since , there has been less than case per million population in the us. the global burden of measles in was an estimated deaths that were reduced through a world-wide vaccination campaign to an estimated deaths in . those who survive measles without lasting effects still have worries. one is that measles infection depresses the immune system for up to years, making children more susceptible to other infections, and a second is the possibility of developing subacute sclerosing panencephalitis, a usually fatal neurologic degenerative disease caused by reactivation of latent measles virus. the assessed risk is on the order of in measles cases and as much as -fold greater for children who contract measles before the age of months. for children who are immunocompromised, such as those being treated for leukemia, an actual measles infection is severe, extended, and often fatal. although measles is possibly the world's most infectious human virus, it was not the most devastating of the childhood infectious diseases. the smallpox death toll for just the th century has been estimated at upwards of million people, similar to the entire population of the present-day us. smallpox caused more deaths than all the wars in history. for centuries before vaccination, most urban families could count on losing multiple children to smallpox, diphtheria, scarlet fever, or whooping cough. with widespread vaccination, combined with targeted vaccination to insulate the last few cases, smallpox was eliminated as an infectious disease on earth. smallpox eradication was our first and thus far only complete victory over a human disease-causing agent, made possible by universal, global vaccination, and intensive surveillance. after tortuous millennia of epidemic disease and hundreds of millions dead, who would argue that this was not a most wonderful gift given by humankind to itself? but that gift was not without cost, and the cost was a tincture of personal independence and the acknowledgement that each of us is inextricably tied to the entire human community. it took the idea of community out of the realm of philosophy and placed it as a fundamental property of life. smallpox eradication itself was a physical enactment of the tension between personal freedom and the authority of society. in on liberty, in chapter iv, john stuart mill asks, "what then is the rightful limit to the sovereignty of the individual over himself? where does the authority of society begin? how much of human life should be assigned to individuality, and how much to society?" mill's inquiries can be answered by biology, but first consider the concept of community protection (often referred to as "herd immunity"). as the density of susceptible (unvaccinated or disease naïve) hosts declines, so does the incidence of disease. below a certain threshold, the incidence of disease (frequency of new infections), even in unimmunized people, approaches zero. this is community protection, and it follows directly from basic epidemiology. vaccination effectively reduces the number and density of the disease-susceptible people, making acutely infectious agents unsustainable in the population. conversely, because vaccine protection is sometimes imperfect, a vaccinated individual living within a diseasesusceptible population is at substantial risk. the risk of disease for any individual is thus most importantly dependent on the collective immunity of the population, especially those most susceptible to infection, usually the youngest children and oldest adults. in this regard, disease ecology does not equivocate; in the world as it exists today, our health and our very being depend on the immune status of the rest of humanity. the rightful limit to the sovereignty of the individual over him or herself stops at the boundary of disease immunity. as long as one case of smallpox could be found on earth, billions were at risk. even without considering the imperative of contagious disease, mill came to the same conclusion, "as soon as any part of a person's conduct affects prejudicially the interests of others, society has jurisdiction over it. . .." two centuries before on liberty and before the enlightenment, this was expressed after a fashion in john donne's meditation xvii, "now this bell tolling softly for another, says to me, thou must die," written while he was convalescing from a near-fatal disease, possibly typhus. although this meditation was ostensibly concerned with god as the author of every person and every death, we might equally apply it in a way that donne could not-we are each of a network, a medium for disease that transcends us as individuals. the death of one of us portends many more. we can rage against this injustice, but it is literally a fact of life. in this context, the famous line from meditation is relevant, "no man is an island, entire of itself." community protection is a fundamental concept with no strict definition. the threshold is sharp but varies with each infectious agent. it protects vaccinated and unvaccinated people alike. it is the most powerful force in disease prevention but exists only in the immunity status of the entire population network. considering the difficulty of this concept, it is no wonder that as a society and as a people we do not have a consensus the journal of pediatrics • www.jpeds.com volume • october concerning the responsibility of individuals to vaccinate their children. one way to understand vaccination decisions is as an exercise in game theory played out over the entire human population of the earth. in this case, each individual is defined narrowly in economic terms, acting as if he or she balances costs against benefits to maximize personal advantage. if most everyone cooperates (vaccinates), then everyone enjoys the benefits of being disease free. in contrast, the decision to cooperate may be perceived to have a cost, and individuals looking to maximize personal advantage will choose noncooperation at a certain probability. when no one is vaccinated and everyone is in danger, that probability is close to zero-everyone is incentivized to vaccinate or risk the possibility of deadly disease. this must have been the dominant sentiment in the time of smallpox. as universal vaccination is approached, danger diminishes with or without vaccination, and the probability of noncooperation increases. for measles, the threshold for community protection is calculated to be . %, that is, when . % of the population has received doses of mmr vaccine, the community is protected from disease. under such conditions, some parents may decide not to vaccinate and thus avoid even very rare adverse effects. the consequence of this is that the rate of vaccination drops below the threshold, and the community is no longer protected. in other words, as we proceed toward elimination of a disease by vaccination, as we are for poliomyelitis, the invisible hand of the market pulls defeat from the jaws of victory. from this reasoning, elimination of a disease on a purely voluntary basis has been proposed to be unlikely, and the thought is that compliance to protect the population or eradicate a disease can only be achieved by a mandatory vaccination policy. in the western hemisphere, we have all but eliminated measles and rubella, in one sense moving us backward in time to the pre-columbian rarity of acutely infectious diseases. however, should we lapse in our vaccination vigilance, within one generation we could replay the disease devastation of the th century that included death of more than one-half of the native inhabitants of the western hemisphere. we are part of, what watts and strogatz called, a small-world network -with no more than degrees of separation connecting the entire + billion human beings on earth. like the spread of middle east respiratory syndrome from the middle east to korea, we can consummate those connections, wherever they may be, with a day's travel. a glimpse of a future with poor vaccine adherence occurred not too long ago, with an outbreak of measles originating in anaheim, california. the infecting person (patient zero) almost certainly arrived from abroad, but most of the infected individuals were unvaccinated us residents. the decline in mmr vaccination compliance began with a medical report in the journal lancet. andrew wakefield and colleagues published an analysis of children claiming to show a connection between mmr vaccination and the onset of a newly described "pervasive developmental disorder" that they summarized as a "chronic enterocolitis in children that may be related to neuropsychiatric disorder." at face value, this is a tiny sample size with no controls. it linked common conditions with mmr vaccination based on parent's recollections. multiple large studies subsequently showed no such association, and the paper was retracted by of the authors and by the journal after a prolonged study by the general medical council in the united kingdom; however, it was not just a case of flawed science, it turned out to be fraud driven by avarice. in articles published by the british medical journal, the investigative journalist brian deer revealed how wakefield had been hired to attack the mmr vaccine by a lawyer, richard barr. wakefield and colleagues were paid to contrive the existence of a syndrome, he initially called, "autistic enterocolitis" for the express purpose of bringing a class action lawsuit against vaccine manufacturers; this occurred before initiation of the disgraced study. another apparent moneymaking scheme was ironically to market vaccines. in a press conference given after the publication of his lancet paper, wakefield said he could not support the triple mmr vaccination and called for vaccination to each disease separately. he had previously patented a single measles vaccine. the british general medical council revoked his license to practice medicine, and he was asked to leave the royal free hospital in london. the wakefield study has no basis in reality, but its publication corresponded to a substantial drop in mmr coverage in the united kingdom, europe, and the us. in response, some countries or states within the us have made vaccination a mandatory condition for entrance into schools. for example, california senate bill no. , signed into law june , requires vaccination for all children attending any public or private elementary or secondary school, childcare center, day nursery, nursery school, family daycare home, or development center. exemptions for described medical conditions are permitted, but those based on personal or religious beliefs were to be phased out. because california requires vaccination records for all schools, the effects of the bill could be tracked-and the effects were dramatic. in , more than % of school children lived in california counties with vaccination rates less than %, and % of children lived in counties with less than a % vaccination rate. interestingly, the counties with the lowest rates of vaccination were of types, rural counties largely located in the most northern part of the state and counties that include the tony urban communities surrounding san francisco and los angeles. by , more than % of children were from counties with greater than % vaccination. nonetheless, the law only requires vaccination records for students as they enter each grade span (kindergarten, seventh grade, etc), and it recognizes personal exemptions previously on file. as such, there are still schools in which a single case of measles could spark a local epidemic. contrast the vaccination rate in california, where comprehensive vaccination is required to attend school, with that of oregon, where exclusions based on personal beliefs are allowed with only a requirement for completing an informational module online. the proportion of the population in oregon counties with kindergarten vaccination rates greater than % has gone from almost % in to just % as of . in addition to community health, the notion of not vaccinating seems to deny short-term self-interest. even with a low disease incidence brought about by community protection, pertussis vaccination is a small price to pay for the prevention of whooping cough. beyond that, universal vaccination protects children with immunodeficiencies that arise either from congenital or acquired conditions and their treatments. it can eliminate a disease from the world for all time, saving all future generations, but at what cost? what is the safety of vaccination? each vaccine from each manufacturer is reviewed by the food and drug administration for safety before licensing, and after licensing, the centers for disease control and prevention and food and drug administration maintain a nationwide monitoring system, the vaccine adverse event reporting system, a signal detection system to identify rare events not found in prelicensing reviews. the program allows anyone to report an adverse reaction online, by fax, or by mail. the centers for disease control and prevention also operates the vaccine safety datalink in conjunction with us care organizations that track data from more than million people. these data provide the means to monitor the safety of current and recently introduced vaccines nearly in real-time as they are administered to people across the country. the data from the vaccine safety datalink are used to devise the vaccine regime for children and assess the frequency of complications as they arise. there also exists a national vaccine injury compensation program (vicp), run by the health resources and services administration. this program receives reports of adverse vaccine reactions, studies each claim, and makes of determinations: ( ) an adverse reaction occurred "more likely than not"; ( ) the individual is compensated, although the panel does not concede that there occurred a vaccine-related adverse reaction; and ( ) the case is adjudicated by a court within the us court of federal claims. because the vicp is the only avenue for vaccine-related compensation in this country, the number of filed cases is one measure of the number of adverse reactions severe enough to incite a claim. for the years of through , there were approximately . billion vaccine doses distributed in the us. the total number of cases brought before the vicp was , and the number ultimately compensated was . that is, about in a million vaccine doses was associated with some sort of adverse reaction severe enough to bring a patient to the vicp. importantly, this is but an average for all vaccines and all groups of people, but it highlights the overall rarity of vaccine-associated, severe adverse events. considering the benefit to the individual and to society, this would seem to be a reasonable risk. aside from sober risk assessment, sticking an infant with a needle to induce an immune reaction might feel unnatural. but it isn't so. the immune system is naturally engaged and constantly fighting many potential infections on a continuous basis. for example, in people with an acquired immunodeficiency, such as those low numbers of t lymphocytes, previously benign bacteria, fungi, and viruses become deadly: cytomegalovirus, candida, pneumocystis carinii (now pneumocystis jirovecii), toxoplasma, and other environmental agents can cause sickness or death. regardless of the presence of actual disease-causing agents, without the constant activity of our immune system, we perish. another concern is that multiple vaccinations might "overload" the immune system, causing children to be more susceptible to unvaccinated diseases. however, in a study of nonvaccine-targeted infections recorded from emergency department visits, there was no significant correlation with the number of vaccines given to children - months of age. medical studies are difficult to evaluate, even for professionals. the wisdom of one moment is often replaced in the next. a reasonable course of action with respect to new clinical findings is to wait and act conservatively. however, we now have a century's worth of experience in vaccinating billions of people. we have witnessed the regression or elimination of many infectious diseases in the face of vaccination. and we have studied the short-and long-term effects of vaccination. this is now established science. we can work to make vaccines even safer and more effective, but we cannot as a society regress to some past era in which we count hundreds of thousands of measles or polio cases per year. infectious diseases are a major, and almost certainly permanent, part of human existence. the growth of civilization with the addition of animal domestication made the appearance of epidemic diseases inevitable, but human inventiveness has allowed us to find countermeasures that relieve at least some of our collective misery. furthermore, the experience of humankind over the past several millennia has shown that we have no choice; our place in the network of hosts susceptible to human pathogens gives lie to our notions of complete personal independence. even the most atavistic society would not choose for their children a path of immune naiveté (at least not for long). perhaps this is an instructive irony. it takes deadly infectious diseases to see that we are all of a one species, biologically connected, and isolated on earth. ■ submitted for publication jan , ; last revision received jun , ; accepted jun , risk factors for human disease emergence ecological origins of novel human pathogens search strategy has influenced the discovery rate of human viruses the meaning of human existence network structure and the biology of populations measles endemicity in insular populations: critical community size and its evolutionary implication epidemiology meets evolutionary ecology molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses epstein-barr virus infection review of cytomegalovirus seroprevalence and demographic characteristics associated with infection evolutionary origins of human herpes simplex viruses and infectious diseases in primitive societies genomics, the origins of agriculture, and our changing microbe-scape: time to revisit some old tales and tell some new ones the common cold plagues and peoples historical comparisons of morbidity and mortality for vaccine-preventable diseases in the united states vaccines. long-term measles-induced immunomodulation increases overall childhood infectious disease mortality subacute sclerosing panencephalitis: the devastating measles complication that might be more common than previously estimated human immunology of measles virus infection smallpox and its eradication. geneva: world health organization vaccination and herd immunity to infectious diseases why does measles persist in europe vaccination and the theory of games : new revelations of the americas before collective dynamics of 'small-world' networks measles outbreak linked to disney theme parks reaches five states and mexico wakefield's "autistic enterocolitis" under the microscope how the case against the mmr vaccine was fixed after a debacle, how california became a role model on measles vaccination rate jumps in california after tougher inoculation law safety monitoring in the vaccine adverse event reporting system (vaers) the vaccine safety datalink: successes and challenges monitoring vaccine safety opportunistic infections in patients with and patients without acquired immunodeficiency syndrome association between estimated cumulative vaccine antigen exposure through the first months of life and non-vaccine-targeted infections from through months of age key: cord- -gevrlcvy authors: shewen, p.e.; carrasco-medina, l.; mcbey, b.a.; hodgins, d.c. title: challenges in mucosal vaccination of cattle date: - - journal: vet immunol immunopathol doi: . /j.vetimm. . . sha: doc_id: cord_uid: gevrlcvy recognition of the mucosal portal of entry for many infectious diseases and of the relevance of mucosal immune response to protection has encouraged the development of vaccines administered by mucosal routes, principally oral and intranasal, for stimulation of intestinal and nasopharyngeal lymphoid tissues respectively. the oral route is problematic in cattle and other ruminants where antigen degradation in the rumen is likely, prior to transit to the intestine. on the other hand, rumination can be exploited for exposure of nasopharyngeal tissues during cudding if vaccine antigen is expressed by a fibrous feed like alfalfa. an increase in anti-leukotoxin (lkt) iga was demonstrated in nasal secretions of calves following feeding of alfalfa expressing a truncated lkt from mannheimia haemolytica, and there is evidence suggesting that such vaccination may protect against experimentally induced pneumonia. intranasal vaccination is an alternative approach for use in pre-ruminating calves. intranasal administration of iscoms carrying soluble antigens of m. haemolytica, including native lkt, induced lkt specific iga in nasal secretions after vaccination at and weeks of age. subcutaneous (s.c.) administration of the same vaccine induced lkt specific igg in both serum and nasal secretions, whereas s.c. administration of a commercial m. haemolytica vaccine did not. regardless of the vaccination strategy employed it is difficult to assess the immunogenicity of mucosally administered vaccines because production of secreted antibodies tends to be transient, and they do not persist on the mucosal surface in the absence of ongoing antigenic stimulation. an additional challenge is demonstration of vaccine efficacy in response to experimental infection. protection of the mucosally vaccinated animal will most probably result from recall response, which may not amplify sufficiently to counter the effects of experimental pulmonary delivery of a large bolus of virulent bacteria, even though the response would suffice over the more prolonged and gradual infection that occurs in natural induction of pneumonia. the vast majority of infectious diseases in all species are initiated by colonization of, or entry across, mucosal surfaces of the respiratory, intestinal or urogenital tracts. there has, therefore, been a great deal of interest in immune response at these sites and in development of vaccines that target these portals of entry (hodgins et al., ) . the reality is that most current vaccines for such infections are delivered parenterally and act thorough induction of systemic rather than mucosal immunity. protection is typically mediated by ''spill-over'' of mediators onto mucosal surfaces or by blocking of infection once the mucosal surface is breached; examples include vaccines for influenza viruses, vibrio, salmonella, and veterinary immunology and immunopathology ( ) - a r t i c l e i n f o mucosal immunity vaccination mannheimia haemolytica cattle a b s t r a c t recognition of the mucosal portal of entry for many infectious diseases and of the relevance of mucosal immune response to protection has encouraged the development of vaccines administered by mucosal routes, principally oral and intranasal, for stimulation of intestinal and nasopharyngeal lymphoid tissues respectively. the oral route is problematic in cattle and other ruminants where antigen degradation in the rumen is likely, prior to transit to the intestine. on the other hand, rumination can be exploited for exposure of nasopharyngeal tissues during cudding if vaccine antigen is expressed by a fibrous feed like alfalfa. an increase in anti-leukotoxin (lkt) iga was demonstrated in nasal secretions of calves following feeding of alfalfa expressing a truncated lkt from mannheimia haemolytica, and there is evidence suggesting that such vaccination may protect against experimentally induced pneumonia. intranasal vaccination is an alternative approach for use in pre-ruminating calves. intranasal administration of iscoms carrying soluble antigens of m. haemolytica, including native lkt, induced lkt specific iga in nasal secretions after vaccination at and weeks of age. subcutaneous (s.c.) administration of the same vaccine induced lkt specific igg in both serum and nasal secretions, whereas s.c. administration of a commercial m. haemolytica vaccine did not. regardless of the vaccination strategy employed it is difficult to assess the immunogenicity of mucosally administered vaccines because production of secreted antibodies tends to be transient, and they do not persist on the mucosal surface in the absence of ongoing antigenic stimulation. an additional challenge is demonstration of vaccine efficacy in response to experimental infection. protection of the mucosally vaccinated animal will most probably result from recall response, which may not amplify sufficiently to counter the effects of experimental pulmonary delivery of a large bolus of virulent bacteria, even though the response would suffice over the more prolonged and gradual infection that occurs in natural induction of pneumonia. ß elsevier b.v. all rights reserved. (corbeil et al., ; wilkie and markham, ) . despite these successes, development of mucosally delivered vaccines remains an area of active investigation in many laboratories, for both human and veterinary pathogens. why vaccinate mucosally? immune mediators, both immunoglobulins and effector t cells generated by mucosal exposure to antigens differ from those generated by systemic immunization (boyaka et al., ) . certainly, where the goal is prevention of infection, the presence of mediators on the mucosal surface is needed. memory cells generated at mucosal sites and in draining lymph nodes, home preferentially to other mucosal locations providing a primed response at all potential portals of exposure (youngman et al., ) . there are also non-immunologlical reasons for seeking vaccines that are delivered without injection, including ease of delivery and the absence of injection site reactions. vaccination of food producing animals would be facilitated by mass delivery of vaccine in feed, water or by aerosol, meaning less labor cost for producers and reduced stress on the animals. additionally, carcass condemnation due to needle breakage or injection site reactions would be avoided (roeber et al., ) . increasing consumer pressure for organically produced food and a natural approach to disease management is more compatible with disease prevention using noninvasive methods of vaccine delivery. mucosal delivery of antigens triggers immune response in mucosa-associated lymphoid tissues including the peyer's patches of the small intestine, the tonsil and associated pharyngeal lymphoid tissues, the bronchus associated lymphoid tissues of the lung and diffuse lymphoid aggregates lining the urogential tract. induction sites for mucosal immunity have been most thoroughly described for the intestinal tract where antigens are delivered to underlying peyer's patches by specialized membranous non-ciliated epithelial cells, m cells, located in villous crypts, and by dendritic cells (dcs) that send processes to the surface between ciliated columnar epithelial cells of the villi. these dcs deliver antigen to peyer's patches and to draining mesenteric nodes (meeusen et al., ) . similar mechanisms for antigen acquisition exist at other mucosal sites, including in tonsilar crypts and in balt where both m cells and epithelial dcs have been identified (gebert and pabst, ; stanley et al., ) , and presumably also at genital sites (hodgins et al., ) . experimentally, calves have been immunized by the vulvovaginal and rectal routes (loehr et al., (loehr et al., , , but most mucosal vaccines deliver antigens by oral administration, which targets intestinal induction, or intranasally which targets pharyngeal and, depending on particle size, deeper respiratory tissues. there are many challenges inherent in mucosal antigen delivery. intranasal vaccines must be delivered in dosages sufficient to overcome innate clearance mechanisms and facilitate uptake in the pharynx. oral vaccines must be protected against degradation by digestive processes, mechanisms are needed to facilitate antigen adherence to the mucosal epithelium and avoid clearance with the mucociliary blanket coating the gut, and the potential for induction of tolerance rather than active immunity must be considered . in mouse models, oral delivery of auto-antigens may lead to oral tolerance and reversal or reduction of autoimmunity. however, oral tolerance has not yet been reported in studies where plant expressed antigens have been delivered as vaccines in mice or other monogastric animals (arntzen et al., ; rice et al., ) . successful oral vaccines exist; vaccines for polio and rabies are excellent examples. vaccines using avirulent live bacteria (e.g. salmonella, bordetella) or viruses (e.g. adenovirus, coronavirus, reovirus) have been shown to be quite effective in stimulating mucosal immune responses and in cases where the vaccine organism is at least minimally invasive, systemic responses as well. perhaps the greatest challenge for mucosal immunization lies in vaccination with non-replicating antigens. such preparations are difficult to protect against digestion, tend not to adhere to mucosal surfaces, and generally fail to trigger the danger signals needed to initiate appropriate cellular stimulation for active immune response. experimentally several strategies have been employed to overcome these inherent challenges. vaccine antigens have been enclosed within microspheres, linked to bacterial toxin subunits such as ct or lt, or administered with molecules that induce danger signals, like cpg motifs, or with cytokines to stimulate lymphocyte activation (holmgren et al., ) . ruminating animals pose a particular challenge for development of orally administered vaccines. encapsulation of antigens in polymer microparticles or microspheres that resist digestion in the rumen is one approach that shows promise for stimulation of mucosal immune response in peyer's patches by oral delivery (bowersock et al., ) . an alternative approach is to exploit the process of rumination for exposure of the pharyngeal lymphoid tissues including the tonsil during cudding. this could be a particularly valuable approach for vaccination against both respiratory and intestinal diseases, since it is recognized that memory cells produced in tonsilar lymphoid tissue migrate preferentially to the lung and intestine, priming these sites for subsequent natural exposure (brandtzaeg and johansen, ) . with this in mind, we hypothesized that delivery of protective antigens in a palatable fibrous feed, such as alfalfa, could lead to repeated exposure of pharyngeal lymphoid tissue by cudding during rumination. because of its relevance as an economically important disease of cattle, we selected bovine pneumonic pasteurellosis as the target disease for study. our extensive experience with immunity to the principal causative bacterium mannheimia haemolytica and its protective antigens made this both an appropriate and convenient model system to test both the immunogenicity and efficacy of edible vaccines comprised of transgenic alfalfa. the first antigen targeted in this research was the leukotoxin (lkt). many studies have demonstrated lkt's importance in pathogenesis and the correlation between the presence of anti-lkt antibodies in serum and protection against pneumonia; however, most suggest that an anti-lkt response is essential but not sufficient alone to provide immunity (shewen and wilkie, ; jeyaseelan et al., ) . the transgenic alfalfa used in these experiments expressed a truncated form of leukotoxin (lkt ) that contained the neutralizing epitope (lee et al., ) . the concentration of lkt was at least mg/g of dried plant material, estimated as a percentage of total soluble protein. posttranslational modification of proteins occurs in plants ( gomord and faye, ) , including both n-linked and olinked glycosylation, but plant glycosylation patterns can differ from those found in bacteria. since the extent of glycosylation and type of glycan added to proteins can alter their immunogenicity, an early step in this work was demonstration of the immunogenicity of plant expressed lkt following intramuscular inoculation of rabbits, and verification that antisera from immunized rabbits recognized both recombinant and native lkt (lee et al., ) . use of transgenic alfalfa as a vehicle provides an efficient means for delivery of antigen that also furnishes protection against immediate dilution and destruction in the rumen. the natural process of cudding means that the fibrous feed is regurgitated, chewed slowly and held as a cud in the posterior oral cavity. typically this activity occurs - times over a period of several days, spraying the pharyngeal lymphoid tissues with antigen during each cycle, before it is finally digested and passed on. with this system, concerns about delivery, avoidance of innate clearance mechanisms and antigen destruction are addressed, but at least two major challenges remain as barriers to vaccine development. the first is demonstration of immunogenicity when the anticipated response is predominately mucosal and therefore inherently both difficult to sample and transient in the absence of continual antigen stimulation. it is also quite possible that pharyngeal exposure will merely prime the lung for an anamnestic response on infection, rather than lead to production of mucosal antibodies in response to the levels of antigen delivered by vaccination. the second related challenge is demonstration of efficacy, given that protection is most likely derived from a recall response. such response should suffice during natural exposure since this is gradual and continual over a period of hours or days, but can easily be overwhelmed in experimental challenge where the successful challenge model uses intrabronchial delivery of a large number of organisms, sufficient to cause pneumonia, as a single bolus. to determine the extent of these challenges and to address related questions of dose and duration of feeding needed for immunization, we have conducted a series of pilot studies feeding transgenic alfalfa to small groups of calves, typically two vaccinates and two controls that receive an equal amount of wild type alfalfa in lieu of the transgenic feed. for initial studies we opted to use colostrum deprived animals, reared in an isolation facility, to avoid interference by passive maternal antibodies and to minimize commensal colonization by m. haemolytica that might confound demonstration of response to vaccination. the animals were not germfree, nor were they caesarian derived, thus there was a low level of colonization and a low baseline antibody titer in serum at the time of first feeding, typically about months of age. all experiments were conducted under approval of the university of guelph animal care committee and adhered to the canadian council of animal care guidelines for use of animals in research. growth, processing, storage and feeding of the transgenic alfalfa as well as disposal of animals and animal waste were as specified in letters of permission from the canadian food inspection agency, which is responsible for regulation of gmos and use of experimental vaccines. in early trials, calves were fed in two rounds, g of dried alfalfa, each day for days, at a -week interval. they were then challenged approximately weeks after the second feeding by intrabronchial administration of ml of m. haemolytica (atcc ) at approximately cfu/ ml. this dose was estimated to cause infection sufficient to elicit recall response, but not produce pneumonia in controls. calves were euthanized or days postchallenge and mononuclear cells were harvested from blood, tonsil, spleen, and retropharyngeal, bronchial and mesenteric lymph nodes. serum and nasal swabs were collected at various points throughout the trial, and the presence of antibodies was determined by an lkt specific elisa using either alfalfa expressed lkt or native leukotoxin, in log phase serum-free culture supernatant, as the antigen. the latter elisa was further adapted as an elispot assay for detection of antibody secreting cells in mononuclear cell preparations following incubation with native leukotoxin. mononuclear cell culture supernatants were also assayed for production of interferon gamma using a commercial kit (bovigam, pfizer). during these studies it was noted that feeding of transgenic lkt alfalfa led to an increase in lkt specific iga in nasal secretions week following the second feeding ( fig. ) . this increase was transient and by the time of challenge levels of specific nasal iga were similar in vaccinates and controls. no changes in serum antibodies were observed prior to challenge. low level intrabronchial challenge with m. haemolytica, < cfu/ml, resulted in an increase in both serum and nasal antibodies in all calves at days post-challenge. these observations illustrate the difficulty in demonstrating humoral immune response to mucosal vaccination. the response is likely to be local, not systemic, and transient. thus sampling site and timing become critical. a similar response to vaccination was recently observed in a larger scale feeding trial in colostrum sufficient calves ( vaccinates and controls) (fig. ) . baseline serum antibodies to lkt were higher in all calves than previously observed in colostrum deprived animals, and feeding did not result in a noticeable change in serum antibodies. several calves fed recombinant alfalfa maintained elevated nasal iga to lkt from week after the second feeding up to the day of challenge. that the response was sustained in these animals may be a characteristic of conventional calves, since continuous antigen stimulation due to natural exposure could help maintain the response that was enhanced by vaccination. in this experiment where the challenge, ml of m. haemolytica at . cfu/ml, was intended to induce pneumonia, a correlation between the level of anti-lkt nasal iga and protection against pneumonia was observed. however, there was also a correlation between the level of anti-lkt igg in serum and protection, even though we could not demonstrate an effect of vaccination on the circulating level of those antibodies. thus, despite the encouraging nasal antibody results, we cannot confidently associate protection with vaccination. during one pilot study the challenge dose, at cfu/ ml, was sufficient to induce pneumonia in the two control calves (lesion scores / for both, % and % pneumonic tissue). both calves fed alfalfa expressing lkt had no clinical signs of pneumonia and no lesions at necropsy. although caution must be exercised in interpreting this as evidence of vaccine efficacy, since calf numbers are small, several interesting observations were made with respect to the response of mononuclear cells in susceptible versus resistant calves. vaccinated calves had lkt specific antibody producing cells in and day old cultures of cells derived from blood and bronchial nodes harvested at necropsy and there was evidence of class switching since igg and iga producing cells were present as well as cells producing igm. each of the control calves had only a single blood cell ( in ) producing antibodies, one igm and one iga. there was no interferon gamma production by blood mononuclear cells of any calves, response in tonsil cells was very weak, and there was no differential between vaccinated and control calves in ifng response in bronchial node cells. spleen and retropharyngeal node cells from vaccinates produced ifng rapidly within h of incubation, whereas cells from control calves responded later or not at all. the most striking difference was observed on culture of cells from mesenteric nodes with lkt. cells from vaccinates responded by producing ifng, controls did not (fig. ) . this was especially interesting since the challenge was pulmonary, not intestinal; thus, one would not expect activation of lymphocytes in these nodes. does this confirm trafficking of antigen-specific memory cells following exposure of the nasopharynx to transgenic alfalfa or does this suggest that vaccine antigen survived rumination and sensitized galt by transport across the intestinal epithelium? these questions remain to be addressed but at least we have identified a tissue to target in ongoing investigations. is the edible format the future for veterinary vaccines in ruminanting animals? perhaps, but even if that approach succeeds it will not address the question of pneumonia in younger calves that are not yet ruminating. bacteria in the pasteurellaceae family are major contributors to enzootic pneumonia that occurs at - weeks of age in both veal calves and replacement dairy heifers (van donkersgoed et al., ) . mucosal delivery of vaccine is also a relevant goal in these neonates, in particular intranasal delivery has appeal for both logistical (ease of delivery) and immunological (targets nasopharyngeal lymphoid tissues) per- fig. . iga antibodies to leukotoxin (lkt) in nasal secretions, determined in an elisa assay using alfalfa expressed lkt as antigen. od = optical density against lkt alfalfa minus od using a mock antigen preparation derived from alfalfa expressing gfp. grids span feeding days, solid vertical bar indicates day of challenge, oval indicates increase in specific iga days after feeding in vaccinated calves ( vaccinates, control). group means for iga antibodies to leukotoxin in nasal swabs obtained from calves fed alfalfa expressing lkt and control calves fed wild-type. median sample to positive (s/p) ratios determined in an elisa assay using native lkt as antigen. grids span feeding days, solid vertical bar indicates day of challenge. spectives. the added difficulty in calves of this age is the potential for interference in active immune response by passive maternal antibodies. in fact, pneumonia, at - weeks of age, occurs precisely during the period when passive immunity has waned to the extent that it is no longer protective, but the effects of interference with active immune response have delayed generation of protective immunity (prado et al., ) . previously we demonstrated that calves do not produce leukotoxin neutralizing antibodies in response to parenteral vaccination with a commercial m. haemolytica culture supernatant vaccine (presponse, wyeth/fort dodge) prior to weeks of age (hodgins and shewen, ) . earlier induction of active immunity may be possible through selection of an appropriate adjuvant or delivery by a mucosal immune route. immune stimulating complexes (iscoms) are an antigen delivery and adjuvant system (morein et al., ) wherein many antigens can be incorporated within or on the surface of small ( - nm) cage like structures formed of cholesterol, saponin and phosphatidylcholine. antigens contained in multivalent subunit iscom vaccines are found both within the cytosol and endosomic vesicles of antigen presenting cells (villacres et al., ) . iscom vaccines have been shown to stimulate both humoral and cell mediated immune responses and are claimed to override the down-regulatory effects of passively acquired maternal antibodies (nordengrahn et al., ; hagglund et al., ) . iscoms, prepared using supernatants from log-phase cultures, were shown to contain native lkt, as the target antigen, as well as other soluble antigens of m. haemolytica. iscom vaccines were used to vaccinate groups (n = or per group) of colostrum fed dairy heifers at and weeks of age, by either the intranasal or subcutaneous routes. response to vaccination was compared to that in unvaccinated controls and a group of calves that received a commercial vaccine, presponse sq (wyeth/fort dodge) subcutaneously at and weeks. all vaccinated calves were challenged to assess recall response by subcutaneous vaccination with the commercial vaccine at weeks of age, an age where response to vaccination might normally be expected. all three vaccines were standardized by antigen capture elisa to contain concentrations of lkt equivalent to that present in the commercial vaccine. sera and nasal swabs were collected weekly from to weeks of age and antibody responses were determined by direct and indirect agglutination, for antibodies to bacterial surface antigens, and by elisa for isotypic response to lkt. antibody responses were expressed as the change in titer from that at week , the time of initial vaccination, to adjust for antibodies present due to passive transfer. subcutaneous vaccination with iscoms induced an increase in the direct agglutination titer in serum at week , one week after the second vaccination and the titer remained elevated for the duration of the study (data not shown). vaccination with the commercial s.c. vaccine had no effect on titer by any assay before weeks of age. the earlier i.m. formulation of the same vaccine had been shown previously to induce agglutinating antibodies and igm to capsular polysaccharide, but not lkt neutralizing responses, in calves vaccinated at and weeks of age (hodgins and shewen, ) . both iscom vaccines induced an increase in serum igg to lkt week following the second dose (fig. , top panel) . the rate of decline in titer, from week to , was less in calves receiving presponse compared to controls. titers in control calves rose by week , consistent with a naturally induced active immune response to commensal colonization. as hoped, intranasal vaccination induced a significant change in lkt specific iga in nasal secretions week following first vaccination at week , the earliest age at which we have succeeded in inducing active immunity to lkt to date. this may be particularly important given the correlation between nasal iga to lkt and protection, recently demonstrated in our edible vaccine trial (above). by weeks of age nasal iga titers had begun to increase in all groups (fig. , middle panel) . interestingly, subcutaneous vaccination with iscom vaccine induced an increase in lkt specific igg in nasal secretion, which could relate to spillover from systemic response, but may reflect homing of memory cells to the nasopharynx permitting enhanced response to natural exposure locally (fig. , lower panel) . thus iscom vaccines, but not the commercial vaccine, induced immune response to lkt in serum and nasal secretions following vaccination at and weeks of age. this preceded responses arising from natural exposure that were evident at weeks of age. the hope would be that this earlier response would protect should the calves receive a challenge sufficient to induce pneumonia in the - week old period, but that was not assessed in this trial. these studies demonstrate that it is possible to detect immune response to mucosal vaccination targeted at the nasopharyngeal lymphoid tissue by examining antibodies in nasal secretions. we have also collected saliva and feces from many of these animals and will analyze those to determine their utility as alternative indicators of mucosal response. we could demonstrate enhanced response, compared to controls, in sera from some calves vaccinated mucosally using an edible vaccine, but only post-challenge. this would be important as a protective response to natural exposure, but is not useful for demonstration of immunogenicity in response to vaccination per se. additionally, though it may be adequate to stave off pneumonia during the course of natural infections, the recall response was not adequate to provide protection against an experimental challenge sufficient to induce pneumonia using a single bolus exposure. therefore, it may be necessary to further refine challenge protocol to enable differentiation, for example by adjusting challenge dose to animal weight, prechallenge serum titer or other criteria. additionally it is important to continue to examine immune response to mucosal antigen exposure, to improve our understanding of factors that lead to its stimulation and those parameters that reflect stimulation. this will assist in finding new and innovative means to enhance responsiveness, including adjuvants and delivery systems, and improved methods for detection of immunogenicity. author p. shewen is co-author on patents that protect the commercial vaccine presponse and receives loyalty revenue from wyet/fort dodge related to this vaccine. she currently holds a contract with dow agrosciences that funds an unrelated project. with these exceptions, she and her co-authors have no financial or personal relationship with other people or organizations that could inappropriately influence or bias the paper entitled ''challenges in mucosal vaccination of cattle''. isolation unit for excellent care of calves. the natural sciences and engineering research council of canada; the ontario ministry of agriculture, food and rural affairs; the ontario cattlemen's association and the agricultural adaptation council, and dow agrosciences funded various portions of this research. plant-derived vaccines and antibodies: potential and limitations oral vaccination of animals with antigens encapsulated in alginate microspheres mucosal vaccines: an overview mucosal b cells: phenotypic characteristics, transcriptional regulation, and homing properties immunity in the female bovine reproductive tract based on response to campylobacter fetus m cells at locations outside the gut posttranslational modification of therapeutic proteins in plants bovine respiratory syncytial virus iscoms-protection in the presence of maternal antibodies mucosal veterinary vaccines: comparative vaccinology serologic responses of young colostrum fed dairy calves to antigens of pasteurella haemolytica a mucosal immunization and adjuvants: a brief overview of recent advances and challenges role of mannheimia haemolytica leukotoxin in the pathogenesis of bovine pneumonic pasteurellosis towards development of an edible vaccine against bovine pneumonic pasteurellosis using transgenic white clover expressing a mannheimia haemolytica a leukotoxin fusion protein gene gun-mediated dna immunization primes development of mucosal immunity against bovine herpesvirus- in cattle suppository-mediated dna immunization induces mucosal immunity against bovine herpesvirus- in cattle advances in mucosal vaccination immune response versus mucosal tolerance to mucosally administered antigens a novel structure for antigenic presentation of membrane protein from enveloped viruses equine herpesvirus type (ehv- ) as a predisposing factor for rhodococcus equi pneumonia in foals: prevention of the bifactorial disease with ehv- immunostimulating complexes maternally and naturally acquired antibodies to mannheimia haemolytica and pasteurella multocida in beef calves plant-made vaccines: biotechnology and immunology in animal health frequencies of injection-site lesions in muscles from rounds of dairy and beef cow carcasses vaccination of calves with leukotoxic culture supernatant from pasteurella haemolytica characterization of ovine nasal associated lymphoid tissue and identification of m cells in the overlying follicle-associated epithelium epidemiological study of enzootic pneumonia in dairy calves in saskatchewan internalization of iscom-borne antigens and presentation under mhc class i or class ii restriction bronchoalveolar washing cells and immunoglobulins of clinically normal calves lymphocyte homing: chemokines and adhesion molecules in t cell and iga plasma cell localization in the mucosal immune system key: cord- - wfsr iw authors: yotsapon, thewjitcharoen; siriwan, butadej; areeya, malidaeng; nalin, yenseung; soontaree, nakasatien; nampetch, lekpittaya; worawit, kittipoom; sirinate, krittiyawong; thep, himathongkam title: trends in influenza and pneumococcal vaccine coverage in thai patients with type diabetes mellitus - : experience from a tertiary diabetes center in bangkok date: - - journal: j clin transl endocrinol doi: . /j.jcte. . sha: doc_id: cord_uid: wfsr iw trends in influenza and pneumococcal vaccine coverage in thai patients with type diabetes mellitus - : experience from a tertiary diabetes center in bangkok background: routine vaccination is an important part of preventive services in treating patients with type diabetes (t dm). there are no available data in temporal trends of vaccination coverage rates in both influenza and pneumococcal vaccines among thai patients with t dm. aim: this study aimed to elucidate influenza and pneumococcal vaccination trends and to identify factors that affect vaccination rates in those patients. method: a retrospective study of randomly medical records stratified by diabetologists was conducted in patients with t dm from - at theptarin hospital, a private multi-disciplinary diabetes center in bangkok. adherence to influenza and pneumococcal vaccinations according to current guidance on adult immunization in thailand had been studied. the rate of both vaccinations from each diabetologist had also been recorded. results: a total of , medical records (female . %, mean age . ± . years, bmi . ± . kg/m( ), a c . ± . %, median duration of diabetes years) were retrospectively reviewed covering a -year period. we audited , selected outpatient visits for influenza and pneumococcal vaccinations rates as key performance index in each year. the overall vaccination rate was . % for influenza, . % for the pneumococcal vaccine, and only . %, for both vaccines. the trends of influenza vaccination rates increased from . % in to . % in but the trends of pneumococcal vaccination rates were relatively stable at less than %. the rate of both vaccinations varied considerably from - % among our diabetologists. age ≥ years, duration of dm ≥ years, the presence of chronic respiratory disease, and moderate to severe charlson comorbidity index (cci) score were positively associated with both received vaccinations. conclusions: the completeness and timeliness of influenza and pneumococcal vaccinations were unsatisfactory in thai patients with t dm. more efforts are needed to increase both influenza and pneumococcal vaccination rates. a retrospective study of randomly medical records stratified by diabetologists was conducted in patients with t dm from - at theptarin hospital, a private multi-disciplinary diabetes center in bangkok. adherence to influenza and pneumococcal vaccinations according to current guidance on adult immunization in thailand had been studied. the rate of both vaccinations from each diabetologist had also been recorded. results: a total of , medical records (female . %, mean age . ± . years, bmi . ± . kg/m , a c . ± . %, median duration of diabetes years) were retrospectively reviewed covering a -year period. we audited , selected outpatient visits for influenza and pneumococcal vaccinations rates as key performance index in each year. the overall vaccination rate was . % for influenza, . % for the pneumococcal vaccine, and only . %, for both vaccines. the trends of influenza vaccination rates increased from . % in to . % in but the trends of pneumococcal vaccination rates were relatively stable at less than %. the rate of both vaccinations varied considerably from - % among our diabetologists. age ≥ years, duration of dm ≥ years, the presence of chronic respiratory disease, and moderate to severe charlson comorbidity index (cci) score were positively associated with both received vaccinations. vaccination is one of the most effective interventions to control transmission, decrease morbidity and mortality of seasonal influenza [ ] . patients with type diabetes mellitus (t dm) are a key target of routine annual influenza vaccination and periodically pneumococcal vaccination as epidemiologic studies suggested that these patients are at high risk for complications, hospitalization, and death from influenza and pneumococcal disease [ ] . an increased incidence of pneumococcal infection followed by influenza infection had been observed [ ] . as a result, both annual influenza vaccination and adherence to pneumococcal vaccination are an important part of preventive services in treating patients with t dm from various organizations [ ] [ ] [ ] . although it has been recommended that persons with chronic diseases and those at increased risk of influenza complications should be vaccinated yearly, only a small proportion of high-risk individuals all over the world actually receive influenza vaccination especially in asian countries [ ] . the world health organization (who) proposed in that the influenza vaccination rate should attain coverage rate of % among the high-risk groups [ ] . however, the current median influenza coverage rate is merely . % among european countries [ ] . when compared with western countries, influenza vaccination coverage rate remains considerably low in most asian countries [ , ] . while influenza vaccination has been focused as key to prevent influenza pandemic in the future, the importance of pneumococcal vaccination should also receive attention in the immunocompromized patients including people with diabetes. invasive pneumococcal diseases (such as meningitis and bacteremia) and pneumonia from streptococcus pneumoniae are associated with increased mortality among individuals with diabetes [ ] . therefore, the advisory committee on immunization practices (acip) recommends pneumococcal vaccination in individuals with diabetes [ ] . there are currently two types of pneumococcal vaccines -pneumococcal conjugate vaccine (pcv ) and pneumococcal polysaccharide vaccine (ppv ). guidelines for pneumococcal immunization across the world are complex and vary greatly between countries in terms of age groups and risk groups recommended for vaccination, as well as which vaccine should be administered. in thailand, our current national guidance on adult immunization still reflects the previous version of acip recommendation which suggested routine pcv for adults ages years and older and followed with ppv one year later [ ] . for people with diabetes younger than years, only ppv is suggested to be administered and repeated every years. despite various campaigns and free influenza vaccination for high-risk groups from the thai government, annual influenza vaccination uptake in the general thai population remained suboptimal at the rate of lower than % [ ] . there are no available data in temporal trends of vaccination coverage rates in both influenza and pneumococcal vaccines among thai patients with t dm. based on the available data among patients with t dm in east asian countries [ ] [ ] [ ] , the annual influenza vaccination rate was only - % and pneumococcal vaccination rate was less than %. in an effort to further improve both vaccines coverage rates, it is necessary to understand the current trends and associated factors of vaccination coverage rates. the primary objective of this study is to determine the trends of influenza and pneumococcal vaccine uptakes in individuals with t dm who attended a routine outpatient diabetes clinic at our hospital. the secondary objective is to identify factors that affect vaccination rates in those patients. the current study is a retrospective analysis of randomly sampled paper-based medical records, stratified by diabetologists, each with annual medical records of - samples. it was conducted in patients with t dm from - at theptarin hospital, a private multi-disciplinary diabetes center in bangkok, thailand. this study was a part of our annual quality improvement program which has been carried out since in order to improve various aspects of diabetes care and benchmark results in each diabetologists. over , registered t dm patients follow-up regularly at our diabetes center. patients with age < years, patients with type diabetes mellitus (t dm) and patients with other types of diabetes were excluded. the data on patient characteristics, smoking status, glycemic control, pattern of diabetes treatments, adherence to influenza and pneumococcal vaccinations according to current guidance on adult immunization in thailand were collected [ ] . we used medical records as a source to assess the receipt of influenza and pneumococcal vaccinations. the vaccination venue could be either inside our hospital or other healthcare services. because influenza vaccination is provided for free in people with diabetes in the government healthcare programs since , some patients might receive free influenza vaccination elsewhere. the presence of comorbidities was determined by the charlson comorbidity index (cci) [ ] which composed of medical conditions. each comorbidity category has an associated weight (from to ) and the sum of all the weights results in a single comorbidity score for each patient. a score of zero indicates that no comorbidities was found. the higher the score, the more likely the predicted outcome will result in higher mortality. patients were divided into three groups: mild, with cci scores of - ; moderate, with cci scores of - ; and severe, with cci scores ≥ [ ] . the rate of both influenza and pneumococcal vaccinations from each diabetologist over the study period was also collected. this study was approved by the institutional review board (irb) committee of theptarin hospital (ec no. - continuous variables were presented as mean ± standard deviation (sd) a total of , medical records (female . %, mean age . ± . years, bmi . ± . kg/m , a c . ± . %, median duration of diabetes years) with , selected outpatient visits were selected based on results from random sampling method as shown in figure . this number of medical records represented % of all visits during the study period. in this retrospective study, % of all selected medical records had been audited for more than once (ranging from - times) during the -year period. insulin usage rate was . % and moderate to severe cci (cci≥ ) were presented in . % of all patients. the details of audited patients were presented in table . the overall vaccination rate was . % for influenza, . % for the pneumococcal vaccine, and only . % for both vaccines. when stratified by each diabetologist, the rate of both influenza and pneumococcal vaccinations varied considerably from - % during the study period. as shown in figure , influenza vaccination rates show an increasing trend going from . % in to . % in but pneumococcal vaccination rates remain relatively stable at less than %. when the vaccination coverage rates were stratified by age groups, younger patients consistently received influenza and pneumococcal vaccinations less than elderly patients as revealed in figure . however, the rate of both influenza and pneumococcal vaccinations remained suboptimal in t dm patients aged ≥ years with only one-third of these patients having received both vaccines. in t dm patients with severe comorbidities (cci≥ ), only . % of these patients received influenza vaccination and only . % of these patients received pneumococcal vaccination as shown in figure . when stratifying the rate of vaccinations by bmi category, the influenza vaccine coverage rate was lowest in patients with bmi < . kg/m when compared with other bmi categories but the pneumococcal vaccine coverage rate was lowest in patients with bmi ≥ kg/m as shown in figure . in the univariate analysis, factors associated with influenza vaccination were older age, female, duration of dm ≥ years, current smoking, the presence of chronic pulmonary disease, insulin usage, and moderate to severe cci. however, only older age, long-duration of dm ≥ years, the presence of chronic pulmonary disease, and moderate to severe cci remained significant in the multivariate analysis as shown in table . these four factors also remained significant in the multivariate analysis of associated factors in pneumococcal vaccinations as shown in table . based on multivariate analysis, t dm patients with cci≥ were more likely to receive influenza vaccine (or = . ; ci % . - . ) and pneumococcal vaccine (or = . ; ci % . - . ). our main findings from this study were that the trends of influenza vaccination rates increased over the -year study period but remained suboptimal as half of t dm patients did not receive influenza vaccination. for pneumococcal vaccination, the rate of vaccination was relatively stable at less than % througout the study period. the rate of both influenza and pneumococcal vaccinations varied considerably from - % among our diabetologists. the strongest predictive factors to receive both influenza and pneumococcal vaccinations were the presence of moderate to severe comorbiditis. our results implied that t dm had largely been ignored as an indicator for influenza and pneumococcal vaccines unless the patients have complex comorbidities. these results highlight the need for pro-active vaccination service to younger patients with t dm. in thailand, the ministry of public health has been providing seasonal influenza vaccine to people with chronic illness free of charge since . however, eligible patients must receive influenza vaccine from the public sector or private providers who participate in the national health insurance plan [ ] . despite having this program in place for over a decade, the uptake of influenza vaccination among thai people remained suboptimal. for pneumococcal vaccine, the patients must cover the cost of this vaccine themselves. therefore, the pneumococcal vaccine coverage rate is much lower than in other countries [ , ] . beside socio-economic status, attitudes and beliefs of eligible patients toward vaccination play a major role in the decisionmaking process [ , ] . adult vaccination is often undervalued and there is a lack of assertiveness from healthcare professionals when compared with childhood vaccination. despite more opportunities to get vaccinated in patients with t dm when visiting routine outpatient clinics, vaccination rates for these populations have been suboptimal all over the world. vaccination coverage has been set as one of the key measures for successful diabetes program and also a key public health action to prevent the spread of infectious diseases [ ] . physicians and related healthcare professionals should take a role to review immunization histories and to provide vaccinations for their patients. our present results suggest that active hospital-based vaccination in adult patients with t dm needs improvement and more effective reminder systems for attending diabetologists should be implemented. based on our study, the different vaccine coverage rates by different age groups imply that different targeted interventions should be employed. younger t dm patients should receive more information and be more aware of the importance of vaccines as one of the core components in diabetes care. however, healthcare professionals rarely offer information or discuss routine vaccinations with people with diabetes in busy clinic settings. insufficient information to patients from healthcare professionals, and/or lack of assertiveness by treating physicians had been cited as one of the main barriers to increase vaccination rates [ ] . attitudes towards vaccination have changed over time especially in vaccine-hesitant individuals [ ] . some patients who refused vaccines in the past might change their minds to actively receive vaccines during pandemic period or if their physician insists on the importance of vaccine as a part of their diabetes care. vaccine hesitancy exists across all socioeconomic strata of the population. patient-oriented and trust-worthy information should be offered to these people. our findings are also in keeping with a recent study from france that falling vaccine coverage rate could be observed after a flu pandemic [ ] . as the trend of influenza vaccination rate in our cohort continuously increased until the peak rate at almost % in and then the trend dropped the year after. there was a peak period of seasonal flu activity in thailand during - . this phenomenon is explained by the possibility of vaccine hesitancy effect regarding its effectiveness against the pandemic [ ] . another possible explanation is our hospital policy to start collecting influenza vaccination as a key quality improvement program since . therefore, it could affect the surge of vaccination rate in the first year after implementation. however, these observations underscore the need for sustainable interventions to increase vaccination uptake. even among european union countries, none could achieve the target for influenza vaccination of % in people living with chronic disease (the median uptake rate was only %) [ ] . global efforts to increase seasonal influenza vaccine coverage rate must involve more proactive strategies from healthcare providers around the world to prevent the future influenza pandemic. during influenza outbreaks, pneumococcal vaccines may help prevent secondary pneumococcal infections [ ] . the rate of pneumococcal vaccination uptakes in patients with t dm are variable and difficult to benchmark when compared with influenza vaccine coverage rate. in contrast to some higher income countries such as south korea which the coverage rate of ppv dramatically increased after the national policy to give free vaccine in all elderly koreans aged ≥ years [ ] , pneumococcal vaccine has to be paid out-of-pocket in thailand. although pediatricians generally recommend pcv in infants, it has not been included in the national immunization program and the vaccine coverage is still low in children [ ] . pcv vaccine has been approved for adults in thailand in immunocompromized conditions and people with diabetes age ≥ years old since but lack data to establish costeffectiveness in general people. as a result, less than - % of thai people with t dm received pneumococcal vaccination from a previous study in thailand [ ] . as shown in this study, the coverage rate of our patients with severe comorbidities was almost times greater than patients with mild comorbidities. this data implies that the importance of pneumococcal it is important to note that our study has several limitations. first, this study was conducted only in a private hospital in bangkok. the findings could not be generalized to other patients with t dm in thailand. the socioeconomic factor influences the decision to receive both vaccines in many patients. in private settings, the patients have to pay the cost of influenza and pneumococcal vaccine for themselves. therefore, this study may have underestimated the rate of influenza vaccination if patients did not inform the treating physicians that they were already received influenza vaccination from other places. for the pneumococcal vaccination, our vaccine coverage rate may be overestimated from the patients with higher socio-economic status in private settings. similarly, the health beliefs and knowledge of influenza among various diabetologists in our hospital could affect the overall rate of vaccination in our study. but our study could serve as a reference for future studies on vaccinations among thai people with diabetes. second, data on vaccination in some patients were documented by treating physicians as self-report data from their patients. the recall bias from these patients could affect the results. however, an earlier study reported that self-reporting may be the only effective and feasible way to gather data from diverse population [ ] . additionally, this study was conducted based on medical audits over the -year period with a uniform format. it would not affect greatly the trend of vaccination coverage rates. third, some factors such as education level, economic status, previous history of vaccine-preventable hospitalizations could not be retrieved from our medical records which might affect the associated factors in receiving both vaccines [ ] . finally, the sample size of audited medical records was not planed as this study was a part of quality improvement program since . the stratification by characteristics that may impact the results improves the sample quality but a convenience sample may not reliably infer to a population. in conclusion, the completeness and timeliness of influenza and pneumococcal vaccinations were unsatisfactory in thai patients with t dm as reported from previous studies around the world. to the best of our knowledge, this study provides an insight into preventive care services for thai patients with t dm. even though the positive trend had been observed for influenza vaccination, the pneumococcal vaccination rates especially in younger patients remained severely suboptimal. our findings suggest that younger t dm patients are overlooked when compared with elderly patients. an increase in vaccination coverage rates should be encouraged as a key quality improvement initiative [ ] . use of health information technology for identification of unvaccinated patients, promoting a positive attitude toward vaccination to patients, and periodic assessment with giving feedback to treating physicians should be employed to help achieve higher vaccination rates. the data used to support the findings of this study are available from the corresponding author upon request. the authors declare that there is no conflict of interests regarding the publication of this paper. before submission. ks and ht made substantial contributions to the discussion of results. all authors read and approved the final manuscript. not applicable. this retrospective study is approved by the ethics board committee of note: factors achieving a p-value < . from the univariate analysis were included in the multivariate models to determine associated positively factors with pneumococcal vaccinations. vaccines for the prevention of seasonal influenza in patients with diabetes: systematic review and metaanalysis use of influenza and pneumococcal vaccines in people with diabetes impact of preceding flu-like illness on the serotype distribution of pneumococcal pneumonia american diabetes association. . comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes- diabetes canada clinical practice guidelines expert committee. influenza, pneumococcal, hepatitis b and herpes zoster vaccinations japanese clinical practice guideline for diabetes acceptance and uptake of influenza vaccines in asia: a systematic review influenza vaccines: who position paper how close are countries of the who european region to achieving the goal of vaccinating % of key risk groups against influenza? results from national surveys on seasonal influenza vaccination programmes influenza vaccine supply task force (ifpma ivs). seasonal influenza vaccine dose distribution in countries seasonal and pandemic influenza: global fatigue versus global preparedness the influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults use of pcv and ppsv vaccine for adults with immunocompromising conditions infectious disease society of thailand: recommended adult and elderly immunization schedule seasonal influenza vaccine coverage among high-risk populations in thailand influenza vaccination coverage and factors affecting adherence to influenza vaccination among patients with diabetes in taiwan influenza and pneumococcal vaccine coverage rates among patients admitted to a teaching hospital in south korea influenza vaccination coverage of population and the factors influencing influenza vaccination in mainland china: a meta-analysis a new method of classifying prognostic comorbidity in longitudinal studies: development and validation charlson comorbidity index helps predict the risk of mortality for patients with type diabetic nephropathy immunization policy development in thailand: the role of the advisory committee on immunization practice successful introduction of an underutilized elderly pneumococcal vaccine in a national immunization program by integrating the pre-existing public health infrastructure impact of the national routine vaccination program on -valent pneumococcal polysaccharide vaccine vaccination rates in elderly persons in japan patient's behaviors and missed opportunities for vaccination against seasonal epidemic influenza and evaluation of their impact on patient's influenza vaccine uptake characteristics associated with the uptake of influenza vaccination among adults in the united states vaccine hestiancy around the globe: analysis of three years of who/unicef joint reporting form data trends in seasonal influenza vaccine coverage of target groups in france trajectories of seasonal influenza vaccine uptake among french people with diabetes: a nationwide retrospective cohort study comparison of dual influenza and pneumococcal polysaccharide vaccination with influenza vaccination alone for preventing pneumonia and reducing mortality amongthe elderly: a meta-analysis cost-utility analysis of -and -valent pneumococcal conjugate vaccines: protection at what price in the thai context? the effectiveness of holistic diabetic management between siriraj continuity of care clinic and medical outpatient department practical recommendations for the management of diabetes in patients with covid- validation of self-report of influenza and pneumococcal vaccination status in elderly outpatients influenza vaccination rate and its association with chronic diseases in china: results of a national cross-sectional study a review of the key factors to improve adult immunization coverage rates: what can the clinician do? the authors wish to thank dr.tinapa himathongkam for excellent language editing and dr. krittadhee karndumri for assisting in statistical analysis. parts of this manuscript had previously been presented as a poster in international diabetes federation (idf) meeting , busan, south korea. no source of funding was applied in this retrospective study. key: cord- -yvgvyif authors: french, jeff; deshpande, sameer; evans, william; obregon, rafael title: key guidelines in developing a pre-emptive covid- vaccination uptake promotion strategy date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: yvgvyif this paper makes the case for immediate planning for a covid- vaccination uptake strategy in advance of vaccine availability for two reasons: first, the need to build a consensus about the order in which groups of the population will get access to the vaccine; second, to reduce any fear and concerns that exist in relation to vaccination and to create demand for vaccines. a key part of this strategy is to counter the anti-vaccination movement that is already promoting hesitancy and resistance. since the beginning of the covid- pandemic there has been a tsunami of misinformation and conspiracy theories that have the potential to reduce vaccine uptake. to make matters worse, sections of populations in many countries display low trust in governments and official information about the pandemic and how the officials are tackling it. this paper aims to set out in short form critical guidelines that governments and regional bodies should take to enhance the impact of a covid- vaccination strategy. we base our recommendations on a review of existing best practice guidance. this paper aims to assist those responsible for promoting covid- vaccine uptake to digest the mass of guidance that exists and formulate an effective locally relevant strategy. a summary of key guidelines is presented based on best practice guidance. as we work to develop a range of safe and effective covid- vaccinations, the anti-vaccination movement has already fired the first shots in what will be a global public health battle. research shows that general vaccine hesitancy (i.e., 'the delay in acceptance or refusal of vaccines despite the availability of vaccination services') is rising for several diseases, resulting in serious disease outbreaks. for example, european countries experienced more than cases of measles in [ ] . vaccine hesitancy has also steadily increased in more than % of countries since [ ] . given the potential to undermine vaccination coverage, all states must take steps to understand the extent and nature of hesitancy and to start promoting covid- vaccine uptake. as the who recommends, 'each country should develop a strategy to increase acceptance and demand for vaccination' [ ] . each country must consider the appropriate time to start promoting the uptake of covid- vaccines based on its specific trajectory of covid- infection and its ability to provide access to vaccination. as covid- vaccination uptake develops, governments should continue to promote other protective behaviors such as handwashing and physical distancing. this paper aims to set guidelines that governments and regional bodies across the world should take to enhance the impact of their pro-vaccination strategy. we base our summary on recommended best practice with the aim of assisting professionals to digest the mass of guidance that exists in the hope that the summary contained will inform the guidelines needed to maximize uptake of covid- vaccines. it is imperative that planning for a covid- vaccination uptake strategy begins in advance of vaccine availability for two reasons. first, countries will need to determine population sub-groups and build a consensus about the order in which these will get access to the vaccine. second, we should reduce fear and concern and create demand for vaccines. a key part of this strategy is to counter the anti-vaccination movement that is already promoting hesitancy and resistance. since the beginning of the covid- pandemic, we have witnessed a tsunami of misinformation and conspiracy theories that have the potential to reduce vaccine uptake. to make matters worse, sections of populations in many countries display low trust in governments, official information about the pandemic, and the official approach in tackling the epidemic. the who advocates a pre-emptive pro-vaccination strategy that psychologically inoculates the population and maximizes uptake of vaccines as they become available [ ] . this paper sets out the core elements of such a strategy. the paper explores key issues that relevant organizations must address and summarizes best practices that should be addressed when developing behavioral influence strategies to promote the uptake of covid- vaccines effectively, efficiently, and ethically as they become available. this paper does not set out a full review or commentary on the thousands of scientific papers and national and international guidance documents that already exist with respect to promoting vaccine uptake and reducing vaccine hesitancy. the volume and dispersed nature of this literature is, in some ways, an impediment to action as few people will have a full grasp of the multiple fields of research that inform it. the paper also does not attempt to set out a full planning model or a 'how-to' guide, as numerous well-tested examples already exist [ ] [ ] [ ] [ ] . the paper does not provide a comprehensive set of references; instead, it cites select evidence summaries and guidance documents to aid further reading. finally, we have not included a separate evaluation strategy, as each of the key guidelines will need an integrated monitoring and evaluation strategy to enable continuous improvement. context matters. each government and public health service face its own set of unique challenges. different countries also have differing resources, capacities, capabilities, assets, and constraints. regardless of such settings and challenges, governments and relevant bodies can action a number of key processes identified in the literature that will enhance vaccine uptake. we set out these key action areas in the guidelines below. see table . it is highly likely that in the coming months the who and other public health institutions will issue guidance about how to optimize the uptake of covid- vaccines. we present the guidelines set out in this paper as an ideal model based on the lessons learned from successful intervention programs to inform such guidance. organizations, however, should approach each action area in a locally relevant way. it is also clearly a big ask to address all the recommended guidelines identified, but the more of these actions that can be applied, the more likely it is that a successful uptake strategy will be delivered. it is important that a systematic approach to planning is adopted. there are numerous planning models from the fields of health promotion and social marketing that authorities can use to define objectives, design processes, and conduct monitoring and evaluation of efforts to promote vaccine uptake [ ] . the most crucial action is to set out a transparent (open access) and a logical plan that covers all the essential components contained in the guidelines included in this paper. however, a coordinated and a systematic approach will require strong leadership. behaviour change plans should also be informed by lessons from the fields of management, logistics, and emergency and disaster planning such as the highlight, audience, behaviour, intervention, test (habit) behaviour disaster change planning framework [ , ] . authorities should also consider lessons and tips set out in several detailed planning models and guides developed specifically for vaccine promotion efforts such as: who. guide to tailoring immunization programs (tip) for infant and child vaccination [ ] . the tip principles apply to communicable, non-communicable, and emergency planning where behavioral decisions influence outcomes [ ] https://www.who.int/immunization/programmes_ systems/global_tip_overview_july .pdf?ua= european centre for disease control (ecdc). technical guide to social marketing https://www.ecdc.europa.eu/en/publications-data/social-marketing-guide-public-healthprogramme-managers-and-practitioners who. improving vaccination demand and addressing hesitancy. https://www.who.int/ immunization/programmes_systems/vaccine_hesitancy/en/ ecom: effective communication in outbreak management (ecom) [ ] . the e.u. funded ecom project brings together multiple disciplines to develop an evidence-based behavioral and communication package for health professionals and agencies throughout europe in case of significant outbreaks of infectious diseases. http://ecomeu.info/ tell me. review of population behavior and communication during pandemics: https://www. tellmeproject.eu/ human center design for health. a comprehensive set of tools developed by unicef to apply the human-centered design approach to challenges facing health services, with a particular emphasis on demand for immunization and health services. https://www.hcd health.org/resources social science research for vaccine deployment in epidemic outbreaks. a practical guide to using social science research and insights to better understand social, behavioral, cultural, community and political dynamics as part of efforts to introduce vaccines in epidemic outbreak settings. https://opendocs.ids.ac.uk/opendocs/bitstream/handle/ . . / / pracapproach% .pdf?sequence= &isallowed=y further generic planning guidance can be found at: building better health: a handbook for behavioral change. "the handbook blends proven disease prevention practices and behavioral science principles into a one-of-a-kind, hands-on manual." [ ] (p. xiii). cdcynergy planning tool for social marketing. centers for disease control and prevention planning tool for social marketing, atlanta, ga. also available is cdcynergy "lite", intended for those who have previous social marketing experience and those who are familiar with the full cdcynergy edition. https://www.thecommunityguide.org/resources/cdcynergy applying behavioral insights-simple ways to improve health outcomes. a tool for the application of behavioral insights to improving health outcomes from the world innovation summit for health. https://www.imperial.ac.uk/media/imperial-college/institute-of-global-health-innovation/ behavioral_insights_report-( ).pdf if governments develop vaccine uptake programs based only on expert opinion, they are likely to be suboptimal [ , ] . what is required is an approach that seeks to gather as much understanding as possible about what people say will prevent, encourage, and assist them in taking up vaccines. authorities must understand what people value and what they fear when developing an effective promotional program. a targeted approach that uses a different intervention mix for different subsets of the population will be more effective. people do not respond uniformly to preventive interventions. for example, being older, female, and more educated is associated with a higher likelihood of adopting protective behaviors [ , ] . 'insight' data about citizens' attitudes, beliefs, wants, and behaviors should inform interventions. insights are 'deep truths' and understanding about why people act as they do. such insights can be developed from formative qualitative and quantitative survey research, observational data, demographic data, service use data, problem or issue tracking data, and epidemiological data. the development of deep insights into people's lives, with a focus on what will or will not motivate or enable people to take up vaccination, is a crucial investment that must be made to inform all aspects of vaccination promotion uptake strategy. a key component of behavioral planning is the setting of measurable behavioral objectives that are relevant and timely in relation to maximizing vaccine uptake. setting measurable goals related to uptake, attitudes, intention, understanding and beliefs will help focus behavioral planning and enable meaningful ongoing tracking and evaluation of impact [ ] . segmentation is key to success. segmentation is the identification of groups who share similar beliefs, attitudes and behavioral patterns. segmentation goes beyond demographic, epidemiological, and service uptake-based targeting. segmentation includes data about people's attitudes, values, understanding and observed behaviors. population segmentation models enable public heath planners to tailor interventions to specific audiences [ ] . fournet et al. have identified four unprotected and under-protected population groups that could form the basis for the development of a locally developed strategy [ ] : • 'the hesitant'-those who have concerns about perceived safety issues and are unsure about needs, procedures and timings for immunizing. • 'the unconcerned'-those who consider immunization a low priority and see no real perceived risk of vaccine-preventable diseases. • 'the poorly reached'-those who have limited or difficult access to services, related to social exclusion, poverty and, in the case of more integrated and affluent populations, factors related to convenience. • 'the active resisters'-those for whom personal, cultural, or religious beliefs discourage them from vaccinating. other segments that need dedicated foci are health and social care workers. studies have revealed that certain healthcare workers hesitate to vaccinate themselves or their family members [ , ] . the ecdc provides guides and toolkits for healthcare workers, immunization program managers, and public health experts, to support their efforts in addressing vaccine hesitancy [ ] . frontline workers can be a significant source of trusted advice and information but are often not optimally used in such roles. these workers lack training and support in advocacy roles and may also lack a full awareness of risks and safety issues associated with the disease and vaccination. governments and responsible agencies should facilitate support structures that increase worker awareness and willingness to act as public health advocates. to effectively promote and maintain demand for a covid- vaccine, governments and regional bodies must develop an insight-informed pro-vaccination strategy that includes action to reduce the impact of four kinds of competition: • active competition from the ani-vaccination movement • passive competition in the form of inaccurate media coverage • competition from negative social norms • competition in the form of structural and economic factors effective campaigning against vaccine misinformation should focus on the dangers of the disease as well as on the benefits of the vaccines, which can include highlighting protection. such approaches draw on the powerful motivator of fear of loss along with the possibility of gain of positive health [ ] . intervention designers should involve the target populations in building campaigns, and use data-supported insights about what will and what will not motivate them to take up vaccine programs and about how to frame the promotion of vaccination. a competition strategy that seeks to reduce the impact of those promoting hesitancy that emphasizes fact-checking and myth-busting may do more harm than good. such approaches often repeat misinformation as part of rebuttal strategies. engaging directly with conspiracies often spreads rather than closes down such views. people often exhibit what lord calls confirmation bias; they look and accept information that fits with their existing views and reject information that runs counter to their existing views [ ] . so, when repeating misinformation in order to debunk it, people may just hear the misinformation. a more effective approach is a combination of positive messaging that emphasizes the protective (individual, family, and community) benefits of the vaccine and the loss associated with not being vaccinated (death, poor health, loss of freedom and social solidarity, inability to travel, etc.) [ , ] . anti-vaccination advocates should not be left free to spread misinformation. public health authorities and their coalition partners, including both the traditional and digital media sectors, should proactively work together to reduce and remove at speed false content and misleading information. traditional media providers should be supported and briefed so that they are aware of anti-vaccination propaganda identified by public health authorities and do not repeat it. traditional media and social media sectors should also provide authorities with the information they have detected that anti-vaccination advocates are propagating so that information can be rebutted. public health agencies should seek protocols with media providers about the issue of how journalistic balance will be addressed. agreements should be put in place about how the media will identify and flag false and misleading anti-vaccination information and advocates. in this regard authorities and media channel providers should be alert to 'astroturfing' (anti-vaccination advocates disguising their views as coming from grass roots movements) and act swiftly to expose such tactics. finally, agreements should be developed about how and when misleading information and advocates of such information should be removed and flagged as being problematic on social media. distrust in elites and experts and political populism can also fuel antivaccination sentiment [ ] . social norms and cultural influences can have a significant effect on people's willingness at the population level to take up vaccine programs [ ] . as an initial step, authorities need to understand what informs social norms and beliefs. persuasive efforts should appeal to the values and beliefs that people already hold, such as a desire to protect family members, rather than a focus on factual or probabilistic messaging. validating people's existing motivations and using them to encourage behaviour is more effective than trying to shift people's world view. if, however, people hold incorrect opinions about the social norms prevailing in their community, for example, the erroneous belief that most people oppose vaccination, it can be helpful to inform them that a high percentage of people do in fact, support vaccination. subjective social norms, i.e., those that are informed by what we think key others in our social circles believe, are also crucial in promoting vaccine uptake [ , , ] . opinion leaders in the anti-vaccination community may hold negative attitudes and beliefs, so intervention organizers should also develop interventions with such key informants to address these concerns and seek to turn such informants into advocates for vaccination. previous reviews of vaccine demand campaigns using a systematic process, such as in the area of human papilloma virus (hpv) vaccine, have found that myths and misinformation, often prevalent in communities, can also pose significant barriers to vaccine adoption. evans et al. studied several hpv and cervical cancer awareness studies in low-and middle-income countries (lmics) [ ] . these studies confirm many widely reported barriers to hpv vaccination; these include myths (e.g., the vaccine causes infertility), beliefs that it will increase promiscuity, negative social norms within social groups, and concerns about safety and efficacy. solutions to these barriers include: • increasing knowledge about the risks prevented by the vaccine. promoting understanding that the community of interest is at risk; improving beliefs in vaccine safety, effectiveness, and community benefit. • dispelling unfounded myths. building a social norm that vaccination uptake is widespread and accepted in society (descriptive and injunctive normative beliefs). vaccine uptake strategy must address difficulties in accessing vaccines due to cost, lack of transportation to vaccination sites or clinics, and/ or a lack of a cold-chain network. authorities need to work with partners across government, ngos, communities, and the for-profit sector to reduce these barriers. poor access can reduce confidence in and demand for the vaccine. vaccine uptake promotion should thus facilitate availability and convenience. it is vital that countries review their public health finances early on to allocate funds to vaccinate their populations, as many countries already carry large debts. to inoculate the entire global community will require significant resources. countries with lower incomes will need to develop plans to access support from the international aid programs provided by governments, u.n. bodies and foundations, and other sources to secure adequate supplies of vaccines. promoters of the covid- vaccine should also consider that their efforts do not negatively impact on the availability and the uptake of other vaccine programs, predominantly for children. public health organizations rarely have sufficient resource capacity to develop, deliver, and maintain population-level change-focused programs. building and sustaining coalitions of organizations and individuals who can assist through the provision of resources, expertise, credibility and access is a crucial early action that needs to be addressed. critical asset identification and management falls into three main categories: government capacity coordination, private sector and ngo sector mobilization, and the mobilization of civil society. building alliances within government and across departments is a crucial aspect of asset identification and mobilization [ ] . there is a need to develop plans and structures to coordinate action between government agencies and departments and organizations such as hospitals, clinics and schools [ ] . an alliance or coalition team should also coordinate mechanisms and resources and set out chains of command and responsibilities. the ngo and private sectors can play a pivotal role in promoting the uptake of vaccines. partnerships with the pharmaceutical industry to develop, manufacture, promote, and distribute vaccines are underway across the world. many other for-profit organizations can also be harnessed to provide logistical and promotional support. the ngo sector is also well placed in terms of its reach, high level of understanding about local communities, and high levels of trust to act as a critical advocate and network for vaccine uptake. the third leg of the asset and capability resource base is civil society, represented by community groups and associations such as religious groups, community associations, recreational groups and community charities and volunteers. these groups and communities can play a crucial role in encouraging vaccine uptake and assisting with distribution and access. however, the part that civic society can play in promoting and helping with vaccine uptake is highly country-specific; therefore, local plans will need to reflect the role that such groups can play [ ] [ ] [ ] . developing and maintaining a vaccine promotion coalition of government, the private sector, the ngo sector, and civic society requires resources and staff with expertise in creating and managing stakeholder relationships. authorities need to identify the resources needed to undertake these essential tasks, set objectives, monitor progress, and provide feedback. well planned, evidence-based, and theory-informed health communication and health marketing can significantly impact behavior and vaccine uptake [ , , ] . well-designed campaigns, together with the application of behavioral science techniques, need to be supported by ease of access to vaccines, distribution networks and logistics, and taking notice of broader socio-economic and cultural factors [ , ] . those responsible for creating demand for the vaccine need to work with vaccine suppliers, administrators, and those delivering vaccination to bring together a full mix of demand-side and supply-side interventions. the intervention mix needs to include coordinated action in the fields of prioritization and access policy, supply systems, and promotions strategy. prioritization is especially critical, given insufficient availability, especially after the initial months of vaccine launch. more important than building general demand are building awareness and support for covid- vaccination prioritization plans and fostering high acceptance among people in priority groups. the key to promoting demand is a deep understanding of what will enable and encourage uptake. campaign managers should conduct formative research including secondary research based on published literature and case studies and primary research with interviews and surveys in each population to gain audience-specific insights. governments will need to deliver and communicate what mix of incentives and penalty interventions will be used to promote demand [ ] . demand strategy will also need to be supported by the development of a compelling, insight informed and segmented promotion that speaks to people's needs, values, and wants. health communicators must develop narratives that emphasize the positive personal, family, and community benefits associated with vaccine uptake. the demand strategy will need to include guidelines that reduce the influence of anti-vaccination advocates (see sections below for critical steps to consider when developing a competitor strategy). the demand strategy must also utilize positive narratives in both traditional and social media and apply behavioral influence tactics informed by behavioral sciences [ , ] . the who recommends that every country should include ongoing community engagement and trust-building programs. programs should be focused on confidence-building and active hesitancy prevention, together with regular national assessments of population concern and trust [ , [ ] [ ] [ ] . trust is built and maintained through transparency, constancy, active listening programs, and encouraging dialogue. agencies and governments need to share knowledge about certainty and uncertainty. governments and public health agencies also need to pre-empt and address any safety issues that are expressed or felt by the public or media [ ] . governments should also be transparent about vaccine licensing, manufacture, and prioritization planning. consistency of both messaging and policy directives is also crucial. the absence of these conditions will trigger confusion and reduce trust [ ] . anti-vaccination attitudes do not always relate to factors like level of education [ ] . instead, they are often related to anger and suspicion towards elites and experts and increasing support for anti-establishment political concerns. governments should listen actively and build dialogue, encouraging continuous feedback from citizens, key commentators, and influencers. regular proactive public media and influencer briefings should also form a central plank of trust-building strategy. the application of citizen-focused and human-centered design principles can also enhance program development and implementation [ ] . relevant agencies should realize the need for a coordinated mix of interventions to promote vaccine access, led by a strong leadership team [ ] . promoting uptake through the media and community advocates is a critical element of any pro-vaccination strategy, but it is not a panacea for convincing everyone reluctant to vaccinate. research shows that behavioral change is a complex process that entails more than having adequate knowledge about an issue. uptake and hesitancy are also related to cultural factors, attitudes, motivations and experiences, social norms, and structural barriers. understanding the multiple factors involved in people's decisions is, therefore, key to success. governments and public health authorities can enhance the effectiveness of their efforts by combining multiple strategies [ ] . for example, they could integrate financial and non-financial incentives, call and reminder interventions, along with penalties for non-compliance by imposing restrictions on travel, education, or employment [ ] . vaccine access information, requirements and support will need to reflect each country's vaccination implementation strategy. will it be mandatory? will there be penalties for non-compliance? communicators should deliver implementation and access strategies through a segmented approach that provides specific and relatable information to identified subgroups of the population about how and when they can have access to vaccination. call mechanisms will need to be established and monitored as part of this element of the strategy. with regard to vaccine selection, assuming that the medical fraternity has developed several safe and effective vaccines by , governments and public health authorities will need to explain to the population why they selected a particular vaccine in terms of its efficacy, safety, cost, etc. authorities will also need to explain their reasoning for the prioritization model for the vaccination that they adopt. for example, if a risk-based approach is adopted in which older people and care workers are prioritized over younger people and non-essential workers, this needs to be explained. governments and regional bodies need to explain and justify these decisions in terms of health protection, social and economic imperatives, safety and cost imperatives. schedules and timetables for total population vaccination should also be developed and shared before vaccination roll out begins so that everyone understands when they will get access. ideally authorities should share their plans for vaccine roll out prior to availability so that there is time for ethical and procedural issues to be publicly debated and a consensus reached. a coordinated national approach to communication will be successful among many groups, but not all [ ] . success depends on the nature and degree of immunization hesitancy and the degree of segmentation. tailored messages focusing on known motivators for specific groups are more likely to produce a desired behavioral response than a 'one size fits all' approach [ ] [ ] [ ] . to produce tailored messages, we recommend quantitative and qualitative formative research and ascertaining the efficacy of strategies with pre-test research before launch. as stated previously, there is a need to set out a compelling narrative that avoids 'backfire effects' [ ] , validates people's concerns, and addresses both fear of loss and the positive gain that will accrue from vaccine uptake. as tversky and kahneman have demonstrated, when confronted with choices we are averse to any that might result in perceived loss [ ] . we also do not like being confronted with complex choices. it follows that, if governments want to influence people to take up vaccination, they are more likely to be successful if the strategy emphasizes the positive gains accrued from vaccination, the loss that will occur if vaccination is refused, and that access to vaccines is easy. we know that the perceived attractiveness of options varies when communicators frame the same choice differently. therefore, the language used, the imagery, the messengers, and audio-visual effects are all important considerations that communicators should pilot test. as stated previously, authorities should tailor their promotional strategies by subgroups of the population, as each segment will respond differently to varied messaging and narratives. familiarity and trust in the messenger, as well as the message, is also a crucial success feature in tackling vaccine hesitancy [ , ] . authorities should determine which campaign face and voice should be used based on formative research with the target audience. messages that come from a variety of trusted sources are likely to make a vaccine promotion programs more successful. spokespeople recruited from trusted groups, including healthcare professionals and relatable members of the public, can enhance the effectiveness of campaigns. high-profile personalities can also be effective in communicating messages, as they lend their prestige and trust to the health communication activity. the use of religious leaders (like the cooperation offered by muslim religious leaders in india to communicate the importance of polio vaccination), community influencers and third-party advocates, such as teachers, can also improve support for vaccination uptake [ ] . as part of long-term public health strategy, governments and public health agencies should enhance media and digital literacy in schools and community settings, specifically related to health and vaccine topics [ ] . newly acquired literacy will equip the public to identify reliable sources of information and encourage reporting of misinformation to social media providers and regulating authorities. the news and general media can contribute significantly to address fears and risk perceptions, which can hurt vaccine uptake [ ] . it is, therefore, necessary to develop a proactive strategy for working with traditional media. any media management and engagement strategy that is developed will need to include proactive, rolling media briefings, story generation, editorial feeds, facilitating access to medical and other clinical and public health experts, advisers, and data. the media management and engagement strategy will also need to include / media monitoring and rebuttal/correction systems. communicators should mediate ongoing relationships between media contacts and experts who can provide accurate opinions on all aspects of vaccine promotion and safety. authorities should additionally monitor the strength of this relationship and address rapidly any conflicts that may arise. the responsibility of government agencies and others advocating for covid- vaccination is to communicate better, more visible, and more highly credible messages than the sceptics. successful media engagement is more likely when the public health system has developed a strong collaborative and open relationship with key editors, sub-editors and journalists. public health authorities and governments should continuously nurture trust and positive working relationships with media organizations so that the audience views the former as accessible and trustworthy. this will, however, require government authorities to be transparent, honest, and open regarding vaccine safety and effectiveness data that could be, or is, worrisome. anti-vaccination advocates abound on facebook, twitter, whatsapp, and youtube. social media platforms are already buzzing with misinformation about covid- vaccine safety, development, and planned rollout, months before vaccines are ready to be used at population level. it is encouraging to see such media platform owners starting to act against the anti-vaccination movement. for example, instagram avoids health misinformation in its explore page; youtube has demonetized anti-vaccination videos and gofundme has recently taken down anti-vaccination fundraising appeals. governments and their public health agencies need to develop a dialogue and joint strategy with social media platform providers to review and action against anti-vaccination misinformation and vaccine hesitancy promotion. governments and regional bodies should convince or regulate platform providers to remove misinformation. public health authorities need to build a proactive covid- vaccine trust capacity for active engagement in the social media space as part of their overall promotional strategy [ ] . social media platforms are now the primary information source and communication channel for a large and growing number of citizens. public health agencies need to invest in building teams of specialist staff trained and capable of understanding how to build and maintain social media presence. the key responsibilities of public health staff focused on social media are the development of and support for continuous positive story streams, nurturing multiple supportive voices, and amplification of pro-vaccination grassroots advocates. these dedicated staff need to support pro-vaccine influencers, advocates and social networks. public health staff can also assist in the identification of and responses to false social media posts. the team should address such negative posts instantly to prevent the decline of trust in public health authorities. we know, for example, that parents who are resistant to getting their children vaccinated are more likely to have based their decision on information obtained on the internet [ ] . the strategic and tactical guidance set out above provides a framework for promoting the uptake of covid- vaccines as they become available. this paper also acknowledges the importance of evidence and theory-driven behaviour change tools in addressing vaccine hesitancy. this is consistent with who's recent establishment of the technical advisory group on behavioral insights and sciences for health [ ] . key to the success of promoting vaccine uptake will be a significant and sustained strategic program, including strengthening of local capacities, to build and maintain confidence and trust [ ] . a crucial factor in the delivery of such a trust-building and demand building approach is the need for investment in communication, behavioral influence, and community engagement capacity and capability. communication and behavioral influence are often underfunded or under-resourced in public health organizations and within government ministries. building communication and behavioral influence capacity and expertise should be a priority. it is now often said that everything will be different in the post covid world; hopefully one difference will be a commitment to investment in developing and delivering the key action elements set out in this paper. this investment will need to be sustained over time in line with best practice requirements regarding risk communication and community engagement so that we are better prepared for inevitable future events [ ] . the authors acknowledge that countries, high-, low-and middle-income, have been using many of the guidelines described in this manuscript to foster high vaccination coverage. the challenges are not that they are unaware of the actions described here but rather: ( ) they have very limited resources (e.g., money, people) to implement all the actions at the scale the authors are recommending; and ( ) they are responsible for promoting and achieving compliance with vaccination schedules, not just a single vaccine. governments and relevant bodies should bear these limitations in mind as they consider our guidelines. world health organization. the guide to tailoring immunization programs; world health organisation vaccine hesitancy around the globe: analysis of three years of who/unicef joint reporting form data- - executive agency for health and consumers. project malmanagement in public health in europe a literature review on effective risk communication for the prevention and control of communicable diseases in europe behavioural change guide for the victoria emergency services. habit framework; ipsos diagnosing the determinants of vaccine hesitancy in specific subgroups: the guide to tailoring immunization programmes (tip). vaccine effective communication in outbreak management (ecom) building better health: a handbook for behavioral change the uk response to coronavirus is the greatest science policy failure for a generation influenza pandemic: perception of risk and individual precautions in a general population. cross sectional study demographic and attitudinal determinants of protective behaviours during a pandemic: a review factors associated with uptake of vaccination against pandemic influenza: a systematic review european center for disease control. technical guidance. social marketing guide for public health programme managers and practitioners measles still spreads in europe: who is responsible for the failure to vaccinate? eurosurveillance under-vaccinated groups in europe and their beliefs, attitudes and reasons for non-vaccination; two systematic reviews vaccine hesitancy and self-vaccination behaviors among nurses in southeastern france european centre for disease prevention and control. catalogue of interventions addressing vaccine hesitancy technical report; european centre for disease prevention and control guides/toolkits a psychological perspective on economic biased assimilation and attitude polarization: the effects of prior theories on subsequently considered evidence changes in suicide rates following media reports on celebrity suicide: a meta-analysis mass killings in the united states from to : social contagion or random clusters? suicide life-threat populist politics and vaccine hesitancy in western europe: an analysis of national-level data vaccine hesitancy: understanding better to address better social norms guidebook: a guide to implementing the social norms approach in the european centre for disease prevention and control. conducting health communication activities on mmr vaccination design and evaluation of a branded narrative-story based intervention to promote hpv vaccination in rwanda policy and system change and community coalitions: outcomes from allies against asthma social marketing and social movements: creating inclusive social change coalitions community coalitions for prevention and health promotion towards a million change agents. review of the social movement's literature, implications for large scale change in the nhs compilation of social marketing evidence of effectiveness. key references briefing paper.international social marketing association (isma) and affiliated national and regional associations effectiveness of social marketing interventions to promote physical activity among adults: a systematic review house of lords, science and technology select committee department of health and human services office of planning, research and evaluation strategies for addressing vaccine hesitancy-a systematic review leveraging behavioural insights to respond to covd- evidence-based community engagement in the development and humanitarian contexts european centre for disease prevention and control. a literature review of trust and reputation management in communicable disease public health risk communication and social mobilization in support of vaccination against pandemic influenza in the americas revealed: populists far more likely to believe in conspiracy theories. the guardian applying tools from human-centered design to social marketing planning insightful social marketing leadership combating vaccine hesitancy: teaching the next generation to navigate through the post truth era. front use of mass media campaigns to change health behaviour centres for disease control and prevention. gateway to health communication and social marketing practice government communication network and the central office of information. communications and behaviour change when corrections fail: the persistence of political misperceptions rational choice and the framing of decisions methods to overcome vaccine hesitancy social marketing in india health literacy and vaccination: a systematic review making a drama out of a crisis. a multidisciplinary study of news media coverage of a public health crisis and the role of emotion using social media to create engagement: a social marketing review a postmodern pandora's box: anti-vaccination misinformation on the internet technical advisory group on behavioural insights and sciences for health by failing to prepare, you are preparing to fail: lessons from the h n 'swine flu' pandemic this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license acknowledgments: not applicable. the authors declare no conflict of interest. key: cord- -wyy rvqb authors: ashwell, douglas; murray, niki title: when being positive might be negative: an analysis of australian and new zealand newspaper framing of vaccination post australia's no jab no pay legislation date: - - journal: vaccine doi: . /j.vaccine. . . sha: doc_id: cord_uid: wyy rvqb vaccination rates are an ongoing global concern. many developing and developed countries have rates of vaccination below rates required for herd immunity, for differing reasons. one way in which to communicate information about vaccination to the wider public is via the use of the news media. communication agenda-setting and framing theory generally hold that the news media sets the issues of importance to society and also tells us how we should think about those issues. emphasis framing theory however, would suggest that positively-framed statements in the media may actually be viewed as persuasive in a coercing way, leading to resistance to the messages. further, this theory claims that negative news media is viewed as more credible and therefore, more easily accepted. we were interested to explore the framing of news reports about vaccination and the potential effects this framing may have had on the wider public over the years – in both australia and new zealand (when changes in vaccination policy and publicity respectively were on the agenda). we undertook a content analysis of articles and emphasis frame, type of message, and other variables recorded. in both australia and new zealand, the news media messages were predominately positively framed and yet the vaccination rates of new zealand particularly (where no policy changes mandating vaccination took place) have been decreasing. we suggest the media emphasis on positive vaccination reporting may be having the opposite effect of engendering resistance to vaccination within those who are vaccine-hesitant. vaccination is a contentious issue worldwide (see [ ] for a review). the world health organisation (who) sets immunisation rates of at least % vaccination coverage by [ ] to enhance herd immunity and protect populations from potentially serious diseases. however, rates of immunisation for different antigens vary significantly. global coverage rates in ranged from approximately % for rotaviruses, % for pneumococcal diseases, % for hepatitis b, % for measles (first dose) % for measles (second dose), and % for diphtheria-tetanus-pertussis [ ] . more people now question the necessity of vaccinations in a largely disease-free first-world population [ , ] , and with recent developments in terms of covid- it would be reasonable to assume that this questioning would be minimised. unfortunately, however, recent research has modelled that in fact the opposite might occur with anti-vaccination views being held by the majority in ten years' time if interventions are not put in place [ ] . concerns exist in many countries about falling vaccination rates. for example, the who has expressed concerns about the rise of the anti-vaccination movement in italy, with the incoming government during their electoral campaign ''promising to oppose the pre-existing law that made vaccinations mandatory" [ ] . in both australia and new zealand controversy emerged around the screening of the anti-vaccination film 'vaxxed'. the film attempts to link the measles, mumps, and rubella (mmr) vaccine to autism and is directed by ''discredited gastroenterologist andrew wakefield" [ ] . at the time of writing this article a billboard produced by the new zealand anti-vaccination group warnings about vaccination expectations (waves) was placed on auckland's southern motorway posing the question ''if you knew the ingredients in a vaccine would you risk it?" the billboard was removed the day it was erected after complaints were received by the advertising standards authority [ ] . these examples illustrate how prevalent and current the issue of vaccination is in many countries. the news media play a vital role in communicating vaccination messages to the public [ , ] . while increasing numbers of individuals find their news through social media, over % of stories they are exposed to come from news websites [ ] . therefore, information supplied by the media about vaccines can influence the public's attitudes and beliefs towards them (see [ , , ] ). although the news media can promote pro-vaccination messages, they have also been held responsible for exacerbating the efforts of anti-vaccination groups because of an ''inadequate scientific knowledge base within the media, and an irresponsible tendency towards the emotional" [ ] . speir [ ] goes further arguing the media are tempted to turn single, alleged incidents of adverse vaccine effects into ''major disasters" whereas ''by contrast the successful prevention of diseases in terms of millions of individuals is virtually ignored" (p. s ). given the influence of the media on public attitudes and behaviours toward vaccination, it is important to understand how the media frame vaccination and how these frames impact the wider public. a small number of studies have examined the news media's reporting of vaccination in new zealand and australia separately. in a study of newspaper articles occurring between and , leask and chapman [ ] found the australian newsprint media reported vaccination with an emphasis frame on vaccine-preventable diseases and the issue of low immunisation rates. the coverage also emphasised that the responsibility for vaccination resides with the individual. the threat of vaccine-preventable diseases was conveyed in a number of ways including personification, panic language, stories of personal tragedy, and tales from the pre-vaccination past. these messages were often delivered by representatives of professional medical bodies [ ] . using a larger sample of stories ( ) leask and chapman [ ] found . % of the stories had anti-vaccination statements. these statements contained one or more of the following subtexts: ( ) cover-up -arguments that the real facts about the safety of vaccines was being suppressed. ( ) excavation of the 'facts' -real 'truth' seekers had to find the true facts of vaccination. ( ) unholy alliance for profit -accusations of collusion between government and big pharmaceutical companies, so the latter could increase profits. ( ) towards totalitarianism -vaccination was 'forced' on the community by the government. ( ) us and them -those opposed to vaccination were portrayed as caring parents against the impersonal medical profession. ( ) vaccines as poisonous chemical cocktails -argues vaccines contain dangerous chemicals. ( ) vaccines as cause of idiopathic ills -vaccination blamed for a range of conditions including autism. ( ) back to nature -the body was perfect and able to defend itself without the need to turn to antibiotics and vaccines. a number of stories also portrayed the vaccine debate as a religious crusade between those for and opposed to vaccines [ ] . a more recent study examined the reporting of the hpv vaccine by the australian press finding a number of themes including these: australian pride in vaccine development; details and progress of the national vaccination program; vaccine safety; hpv vaccination's future; whether or not males could and/or should get the vaccine; issues related to sexual activity and the vaccine; and issues about decision-making for acceptance of the hpv vaccine [ ] . a study of new zealand print media between and found the coverage was predominantly neutral towards vaccination ( %) with % of stories framed as positive for vaccination and % opposed [ ] . another study examining headlines used in new zealand newspaper stories reporting the meningococcal b immunisation campaign found that % of the headlines were scientifically inaccurate and another % were misleading [ ] . since the previous australian and new zealand studies cited, a number of events have exacerbated the vaccine debate, including the lancet retraction of the now infamous wakefield study linking the mmr vaccine to autism and the vaxxed film mentioned prior. more importantly for this study is the introduction by australia of the no jab -no pay law in january , a policy not adopted by new zealand. the law meant parents who had children under the age of who were fully immunised or under a government recognised catch-up scheme could receive ''the child care benefit, the child care rebate and the family tax benefit part a end-of-year supplement" [ ] . families who did not vaccinate their children would lose the equivalent of $ . per fortnight, $ per annum, in family tax credits. parents could no longer use conscientious objection or objections on non-medical grounds as reasons to be exempted from losing their tax credits. some states in australia go further with unvaccinated children not being allowed to enrol in pre-schools or childcare centres unless they are vaccinated or have a medical exemption to vaccination. given these more recent events and the policy difference between the two countries regarding vaccination the current study compares newspapers from both countries (a first cross-cultural comparison) to understand any differences in how the reporting is framed, who are the main news sources, the arguments both for and against vaccination that are contained in the stories, and how those who are unwilling to vaccinate their children are labelled. we specifically focus in on emphasis framing theory in making sense of our results. emphasis framing theory argues that when stories or statements are framed in a negative way, they are deemed more credible to readers [ ] . further, positive frames of stories or statements are viewed by readers in a negative light also as attempting to persuade them in some way; for example, advertisements that positively review a product are rightly viewed as attempting to persuade people to purchase that product. these understandings will, it is hoped, lead to implications for the media on best practice reporting of vaccination information. four australian and four new zealand newspapers were selected for the study. newspapers were chosen to replicate previous studies and also for ease of access to archives in contrast to broadcast news. according to roy morgan [ , ] over million new zealanders and . million australians read print newspapers in . most of new zealand's relatively small population (approximately million), is served by four large metropolitan dailies; two in the north island, the dominion post and the new zealand herald, and two in the south island, the press and the otago daily times. there is no national daily newspaper as new zealand's unique and rugged geography has historically hindered the development of one or two national daily newspapers. in contrast australia has two national dailies with the australian, chosen for this sample, having the largest circulation. in order to have an equal number of newspapers from both countries a further three, large, well established metropolitan dailies, two from new south wales, the daily telegraph and sydney morning herald and one from victoria, the the age were selected on advice from an australian colleague (see table ). limiting the sample to these four australian newspapers did mean newspapers from queensland, western australia, south australia, and tasmania were not included. however, newspapers in these states have smaller circulations in comparison to the newspapers chosen. all items, including opinion pieces and letters to the editor (ltes) relating to vaccination or immunisation, were considered for inclusion for the period / / through / / . items were found via a search on the australian/new zealand reference centre database via ebsco host using the following key words: vaccine, vaccinate, vaccination, immunise, and immunization. the first date coincided with the introduction of australia's no jab-no pay law and the cut-off date was decided to be the end of the month in which the study commenced. sourcing articles from the database meant the researchers did not have access to the original newspaper articles and therefore accurate measurements of column inches could not be conducted. in addition, database stories did not always contain photographs and so these were unable to be examined as part of the analysis. a total of articles were found and all were carefully read to ascertain what type of article they were. for example, columns and opinion pieces were identified as different to news articles as the author's name and occupation were often quoted at the beginning of an article and there were often no sources quoted. for example, a story entitled ''attacks on science a call to arms for academics" by the new zealand herald [ ] began with ''dr jarrod gilbert is a sociologist at the university of canterbury. . ." illustrating it was an opinion piece rather than a news story. likewise, ltes were also easily identified as they were short, contained within a group of likeminded items, and the authors were identified by name and the town they came from. once all the items were read, were discarded as they were not about vaccination. for example, one dealt with immunity in terms of legal prosecution. the remaining articles were subjected to a content analysis coding for the following: type of article sources used emphasis of the frame of the story e.g., anti (negative) or pro (positive) towards vaccination labels to describe people unwilling to vaccinate and those who do vaccinate emotive or loaded terms appearing type of anti-vaccination argument leask and chapman's [ ] subtexts were used to identify the anti-vaccination arguments included in articles. we used emphasis framing to determine if the argument of the media story was largely positive in nature (pro-vaccination) or negative in nature (anti-vaccination). a sample of % of the coding of one australian and one new zealand newspaper was subjected to a test of intercoder reliability. agreement was % on framing of the article, % on the type of article, % on number of sources seen, and % on the type of sources. although we found some discrepancies in the type of sources seen, these were minor e.g., a school official versus a state education spokesperson or a medical professional versus a health spokesperson. from the / / through / / the selected newspapers published stories concerning vaccination. a slightly higher number of stories appeared in new zealand newspapers ( versus in the australian newspapers). the majority of the stories were news stories % ( ), % were opinion pieces, and the remaining % were letters to the editor. the number of sources appearing in all the stories were . these included: medical sources -gps, nurses, and representatives from government health bodies politicians -australian prime minister, and mps from both government and opposition parties in both countries, education officials -school principals, school board members university researchers parents of children affected by vaccine preventable diseases anti vax spokespeople government officials -officials from government departments other than health bodies adult sufferer -adults who are suffering from vaccine preventable diseases non-vax parent -parents who do not vaccinate their children parent -sources identified as simply parents and the vaccination status of their children is unknown other -sources who were not lte authors and whose affiliation could not be ascertained fig. shows the differences between sources in the australian and new zealand stories. more medical or health sources were used in the new zealand stories ( vs. ) whereas more political sources appeared in australian newspapers ( vs. ). in all the stories only anti-vaccination activists or spokespersons were used as sources. overall, stories of the entire sample were found to contain a 'negative' emphasis using some of the anti-vaccination arguments identified by leask and chapman [ ] . the most common of these was 'vaccination causes idiopathic ills" appearing times in the stories. the next largest argument mentioned was 'towards totalitarianism' appearing times in the stories. 'unholy alliance' appeared four times, 'cover-up' three, 'poisons' two, and 'back to nature' and 'us and them' once each. 'excavation of facts' did not appear at all. in a number of instances these arguments were not raised by anti-vaccination campaigners, instead those in favour of vaccination raised them to refute these arguments. in addition to analysing the stories for anti-vaccination arguments, the research also identified stories with a positive emphasis, and noted the types of pro-vaccination arguments. these types of arguments appeared in of the stories with stories containing more than one pro-vaccination argument. table illustrates these arguments and their distribution between the australian and new zealand newspapers. as shown in table , the australian newspapers appeared to talk of vaccination more in terms of protecting the community or society than new zealand newspapers which strongly argued that vaccines prevented and protected against disease. another aspect of the stories analysed was the type of emotive terms used by the newspapers analysed. these are shown in table . the new zealand newspapers were more likely to describe increased cases of particular diseases as 'outbreaks' or 'epidemics' unlike their australian counterparts. australian newspapers were more likely to speak about 'vaccine-preventable diseases' and also refer to 'deadly diseases'. twelve stories contained more than one emotive term. both australian and new zealand newspapers were inclined to suggest those opposed to vaccinations were putting their own and other children at risk. the final analysis examined the labels used to describe those persons opposed to vaccination and those persons who supported vaccination. these terms are listed below: two or three terms were used to describe persons who were pro-vaccination. doctors were ''pushing vaccines" and one was called a ''pharma whore". finally, vaccines were labelled ''a victim of their own success". in cross-country comparisons, australia and new zealand do not differ largely from each other in the number of stories published in the / / through / / period. differences were found in the sources most prevalent in vaccination stories between the two countries. the medical/health profession dominated new zealand stories, but political sources dominated the australian media, largely due, it is suggested, to the january arrival of the no jab -no pay campaign, making vaccinations mandatory for families that receive certain government benefits. given the change in the political environment surrounding vaccination in australia, it may be that medical arguments for vaccination become of less import to readers than the potential financial impacts of non-vaccination choices. rates of explicit opting-out of the vaccination schedule for children (known as vaccinerefusal or conscientious objection) are often reported as quite low ( . %) in australia [ ] , ranging from . % to . % in new zealand [ ] . considering that a vaccine refuser's medical concerns regarding vaccination may not be superseded by financial concerns, this suggests that the change in the australian political landscape may have instead impacted on the decisions of those who are vaccine-hesitant (or face other barriers to vaccination such as costs and transport [ ] or antipathy [ ] , but do not identify as against vaccination. emphasis framing theory has been applied in several situations, including psychology, political communication, and public opinion [ ] , and the implications are vast for a number of fields including health. koch and peter [ ] posit that people learn socially to expect credible news from traditional mass news media and to expect this news media to be negative; therefore, the association between negative news media and credibility is built. when news media messages are positive, the credibility relationship is weakened. as positive news media messages about vaccination could also be viewed as advertising, a sense of coercion results from positively framed messages, suggesting that readers may find them less credible in terms of factual information. it could be that readers do not wish to see persuasive information (perceived as akin to advertising) in a perceived 'factual' or 'neutral/balanced' space, particularly with contentious topics such as vaccination. wallack and dorfman [ ] note that the traditional view of mass media with regard to public health is to view it as an ''educational strategy primarily to provide individuals with more information to make better health choices" (p. , italics in original). this view of the media with regard to vaccination positions the media as a 'teacher' or 'authority' on the topic, which may in turn lead to resistance to the message particularly when a reader's own or known other's experiences of vaccination differ [ ] . happer and philo [ ] also argue that journalism is not only about balanced reporting but also sensationalising topics to sell papers claiming that ''news reporting is increasingly shaped by this construction of polarisation and conflict. . ." (p. ). this polarisation in reporting on climate change in happer and philo's [ ] study led to opposing opinions to those emphasised in the media. when looking at sources in the news stories, happer and philo [ ] also found that although readers/viewers trusted the scientist or expert on their topic of climate change, they did not trust the science itself. public trust in politician statements about climate change was also very low. this led happer and philo [ ] to conclude that ''[i]n spite of general sympathy towards the issue and a recognition of its importance, the overall picture of current audience reception was therefore one of confusion, cynicism and distrust about public communications." (p. ). further, even when met with compelling evidence about climate change, the majority of participants who emphasised its importance and changed their attitude toward it, did not show any behavioural changes six months on [ ] . this framing effect has implications for vaccination messages in the media. indeed, studies have found a link between negative information about vaccines in news reports and negative messages about vaccination spreading via social media [ ] , and negative hpv vaccine news reports and subsequent low vaccination rates [ ] . in a systematic review, catalan-matamoros and penafiel-saiz [ ] , noted that of the studies from a variety of countries, % (n = ) were framed around negative information about vaccines. only two studies showed positive framing and messaging about vaccines in news articles [ ] . these findings illustrate the difficulty faced by those trying to communicate to vaccine-hesitant parents. as shown above, negative information is linked to negative messages being spread in social media and lowered vaccination rates. whilst positive information can be seen as a form of persuasion and advertising and thus can cause those who read such information to distrust or resist the messages. in the current study we found that the majority of stories in new zealand and australian media were presented in a positive frame. if the framing effect implied above is correct, positive framing would suggest that readers are less likely to view these messages as credible and view the stories as an attempt to persuade them. when people consciously feel an attempt at persuasion, they tend to resist those messages (known as reactance) [ , , ] , and react negatively to its points (reactance lowers the perceived truth of a message) [ , , ] . therefore, news media that provide a positive frame on vaccination as an activity that people should undertake, may actually be contributing to reactance in the form of lower vaccination uptake and/or lower belief in the efficacy/ need for vaccines. as our study showed, emotively loaded terms and pejorative labels were used in the popular media to argue against anti-vaccination. use of these terms could cause readers to react negatively to the pro-vaccination message. as found by comrie et al., [ ] , immunisation decision-makers reported being disconcerted by vaccination promotional material that denigrated non-vaccinators. in particular, the nz slogan 'be wise, immunise' was touted as suggesting that anyone who did not vaccinate was stupid, which led to defensiveness and reactance. indeed, in new zealand since december , immunisation coverage rates have been decreasing [ ] . this is due to a variety of factors (see [ ] , but the possibility exists that media portrayal of vaccination may be contributing to this decline. it must be noted here however, that vaccine hesitancy and/or uptake is a complex decision-making area, and we do not wish to imply that news articles alone are responsible for declining vaccination rates. social media and how these sites influence vaccination attitudes and actions or inactions is another space of study which needs further research. indeed, it would be useful to determine the relationships (if any) between social media messages and traditional print/online messages, and how those messages are portrayed and taken up by readers/viewers in similar or different ways. decades of framing theory research suggest that the traditional media such as newspapers influence people's views on topics (although it was/is often thought that the framing implies the view e.g., a positive frame should imply a positive view). in this sense however, the positive framing in the media does not appear to be having a positive effect. as a comparison, australian vaccination rates are increasing (for one-and five-year olds since ) [ ] and the majority of the australian stories were also found to be positively framed. however, the political environment of australia is different from that of new zealand, where vaccinations are mandatory to receive specific financial benefits. this would suggest that any media effect is perhaps moderated by the impact of pressing financial concerns for persons receiving such benefits. the emphasis framing interpretation does seem to be a conundrum given that negative reports about vaccination, particularly if viewed as more credible, may have similar negative flow-on effects on vaccination uptake and belief in efficacy or the need for vaccines. the answer may lie in the presentation of neutral, balanced information only in media reports with the goal of informing the general news media public. however, this is easier said than done. balancing positive and negative vaccination information is a contentious field with scientific studies supporting vaccination often 'balanced' in media stories at the same level of credibility as vaccine deniers whom are without a basis in scientific studies. balance as defined by end-users in a previous study [ ] , noted that caregivers making decisions about vaccination for pre-school children wanted clear factual information only, e.g., the number of deaths attributed to the vaccine versus the number of deaths attributed to the disease, and then be left to make their own decisions. this information also needed to come from a credible source. sources that are obviously positive towards vaccination (e.g., government health departments) could be viewed as attempting to persuade, so where this information is to come from and who is to deliver it is a question. comrie et al. [ ] found end-users were particularly convinced by health information from health professionals they trusted. trusting relationships between health professionals and vaccination decision-makers are key but must be combined with the presentation of factual information and perhaps the viewing of that information as neutral and factual, rather than positive/persuading or negatively framed. if information presented in a negative frame leads to perceived heightened credibility and trustworthiness of the source and the message, the implication is that information could be presented in terms of general negative 'worst case scenario's' or the use of 'negative' pictures of children inflicted with the disease. critics of this approach note that picturing the diseases themselves can be perceived as 'fearmongering' by the public and even by health professionals [ , ] . therefore, use of such pictures could be viewed as 'persuasive' but in a negative light, which may have the same negative affect on behaviour as positively framed persuasion. comrie and colleagues [ ] also found that immunisation decisionmakers in general welcomed the pictures of diseases (partial pictures rather than whole child pictures though) as 'factual' information so they could make an informed choice about vaccination. subtilities in presenting such information should be explored in future research. it is interesting to note that some of the negatively framed statements made in media stories were attributed to vaccination supporters who raised these statements only to refute them. therefore, these negative frames were present in a positivelyemphasised article. future research would benefit from focusing on the impact of negatively-framed or positively-framed statements in the context of opposite-emphasised media stories. overall, . % of the stories in the entire sample contained a 'negative' emphasis, whereas leask and chapman [ ] found in their sample of articles in australia that only . % contained a negative emphasis of some type. a partial possibility for this difference could be that a new zealand sample was included in the current study, where a focus seemed to be more on medical information presented (regarding the vaccines), in contrast with the australian media's focus more on political information and community/social benefits. the type of information reported in forms of medical vs political (and individual vs. social), could mean that more negative emphases on vaccination could be found in articles with a more individualistic medical focus. anti-vaccination arguments are often made in terms of the impact on the individual [ ] . this argument also suggests future research to investigate the impact of individualistic vs. community-focused communications on subsequent intention to vaccinate. interestingly, the type of anti-vaccination arguments found by leask and chapman [ ] , were found also in the current study (bar one), albeit at differing frequencies. the findings suggest that the same types of anti-vaccination messages are continuing to be revisited over time, further suggesting that communications in the media and elsewhere have had little effect on addressing concerns behind these messages in the last two decades. leask and chapman [ ] note that the majority of their articles showed a positive or promotional message regarding vaccination, which was also replicated in this study. indeed, this study adds nine types of pro-vaccination messages as developed from the content analysis to leask and chapman's [ ] eight types of antivaccination messages. these types of anti-and pro-vaccination messages provide a framework from which to determine changes or continual patterns in communications over time. in terms of patterns of types of anti-vaccination messages, the top two arguments mentioned in our data were 'vaccination causes idiopathic ills' and 'towards totalitarianism'. leask and chapman's [ ] top two anti-vaccination messages were 'excavation of the facts' (which did not appear in our sample at all) and 'us and them' (which appeared only once). it may be that although similar antivaccination arguments occur over time, the prevalence of these arguments is changing. further, using the new nine types of provaccination messages, as noted above, we can see distinct types of arguments being used in australia and new zealand, who have different political approaches to vaccination. the one similarity is the 'vaccines prevent disease' message which topped both countries' pro-vaccination arguments, but from there, the countries diverge with new zealand focused on 'vaccines protect against disease' and australia focused on 'vaccines protect community/society'. this again could be due to the different individualistic vs. community ideologies of the two nations proposed by this study with regard to vaccination. leask has extended this work in , identifying five parental vaccination group types including the 'unquestioning acceptors', the 'cautious acceptors', the 'hesitant', the 'late or selective vaccinator', and the 'refuser' [ ] . these authors found that different communication strategies were needed in health professional and parent interactions for each of these groups to advocate for quality decisions on vaccination. therefore, it is not only the content of the anti-vaccination argument that must be addressed, but such content must be approached in line with the communication strategies of the parents. this study is a content analysis of articles from two countries. the focus of analysis is on the media reports, and links to wider society's views and actions are suggested. however, this study did not investigate the direct and/or indirect links between media consumption and vaccine uptake and/or views. therefore, this link is an assumption of the research, which may or may not be accurate. some information does suggest that a link exists between media reports on vaccination and subsequent uptake rates or adverse vaccine event reporting (for example, see [ ] and [ ] . although the majority of news media articles studied were positively framed, suggesting that vaccination is portrayed in the media as a useful health activity to engage in, the subsequent expected influence on positive uptake of vaccination and views towards vaccination were not evidenced in wider society. many factors impact a caregiver's vaccination decision, only one of which is the influence of the media. however, it is also possible that the positive emphasis of media stories has an unexpected reverse effect when looked at via emphasis framing theory and its view that negative media stories are viewed as credible, while positive news media stories on topics such as vaccination may lead to unwanted feelings of coercion and therefore reactance/resistance. further research is needed to confirm the relationship indicated by these findings. journalists and media commentators must reflect on the impact of their positioning of health articles. neutral, factual reporting to help construct an informed public is needed, rather than positively or negatively slanted articles. credit authorship contribution statement douglas ashwell: conceptualization, methodology, investigation, writing -original draft, writing -review & editing. improving new zealand's childhood immunisation rates vaccinology: past achievements, present roadblocks and future promises australian department of health. no jab, no pay new requirements fact sheet. immunisation. immunise australia programme australian department of health. immunisation coverage rates for all children australian immunisation register. national vaccine objection (conscientious objection) data making sense of perceptions of risk of diseases and vaccinations: a qualitative study combing models of health beliefs, decisionmaking and risk perception anti-vaccination movements and their interpretations a content analysis of news coverage of the hpv vaccine by how is communication of vaccines in traditional media: a systematic review mass media coverage and influenza vaccine uptake australian newspaper coverage of human papillomavirus vaccination communicating infant immunisation information: resource development and evaluation how the anti-vaxxers are winning in italy. the independent improving childhood vaccination rates bad news: the influence of news coverage and google searches on gardasil adverse event reporting attacks on science a call to arms for academics immunization in the print media -perspectives presented by the press the role of the media in the construction of public belief and social change the online competition between pro-and anti-vaccination views the hpv vaccine and the media: how has the topic been covered and what are the effects on knowledge about the virus and cervical cancer? effects of equivalence framing on the perceived truth of political messages and the trustworthiness of politicians helpful or harmful? how frequent repetition affects perceived statement credibility an attempt to swindle nature': press anti-immunisation reportage - the cold hard facts' immunisation and vaccinepreventable diseases in australia's newsprint media - communicating with parents about vaccination: a framework for health professionals from social media to mainstream news: the information flow of the vaccine-autism controversy in the us, canada, and the uk vaccination communication strategies: what have we learned, and lost, in years i approve this message: effects of sponsorship, ad tone and reactance in presidential advertising national and dhb immunisation data reinforcement or reactance? examining the effect of an explicit persuasive appeal following an entertainment-education narrative emphasis framing and political decision making commenting and tagging: effects of sharing news stories on facebook giving boys a shot: the hpv's vaccine portrayal in canadian newspapers misinformation lingers in memory: failure of three pro-vaccination strategies the use of gain-or loss-frame messages and efficacy appeals to dissuade excessive alcohol consumption among college students: a test of psychological reactance theory australian newspaper readership, months to over million new zealanders read newspapers in perception of risk of vaccine adverse events: a historical perspective vaxxed: from cover-up to catastrophe ( ) information for parents anti-vaccine billboard highlights lack of trust in authorities petousis-harris h. the use and misuse of media headlines: lessons from the menzb tm immunisation campaign media advocacy: a strategy for advancing policy and promoting health world health organisation global and regional immunization profile niki murray: conceptualization, investigation, writing -original draft, validation, writing -review & editing. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. supplementary data to this article can be found online at https://doi.org/ . /j.vaccine. . . . key: cord- -c fry authors: dong, fen; tacchi, luca; xu, zhen; lapatra, scott e.; salinas, irene title: vaccination route determines the kinetics and magnitude of nasal innate immune responses in rainbow trout (oncorhynchus mykiss) date: - - journal: biology (basel) doi: . /biology sha: doc_id: cord_uid: c fry simple summary: many pathogens exploit the olfactory route to reach critical organs in the body such as the brain or lungs. thus, effective onset of an early innate immune response in the nasal epithelium is key to stopping pathogen progression. the stimulation of nasal immunity by vaccines may depend on the type of vaccine and vaccination route. the goal of this study was to evaluate the ability of a live attenuated viral vaccine to stimulate innate immunity in the olfactory organ of rainbow trout, a teleost fish of commercial aquaculture value. the kinetics and magnitude of the innate immune response depended on the route of vaccination, with the strongest and fastest responses recorded in intranasally vaccinated fish. injection vaccination had an intermediate effect, whereas immersion vaccination resulted in delayed and weak nasal innate immunity. injection vaccination, even with the vehicle control, induced mortality in fingerlings, whereas nasal and immersion vaccines were safe. challenge experiments with the live virus revealed that nasal and injected vaccines conferred very high and comparable levels of protection, but immersion vaccination only induced transient protection. in conclusion, the route of vaccination determines the type, magnitude and velocity of the innate immune response in the nasal epithelium of animals. abstract: many pathogens infect animal hosts via the nasal route. thus, understanding how vaccination stimulates early nasal immune responses is critical for animal and human health. vaccination is the most effective method to prevent disease outbreaks in farmed fish. nasal vaccination induces strong innate and adaptive immune responses in rainbow trout and was shown to be highly effective against infectious hematopoietic necrosis (ihn). however, direct comparisons between intranasal, injection and immersion vaccination routes have not been conducted in any fish species. moreover, whether injection or immersion routes induce nasal innate immune responses is unknown. the goal of this study is to compare the effects of three different vaccine delivery routes, including intranasal (in), intramuscular (i.m.) injection and immersion (imm) routes on the trout nasal innate immune response. expression analyses of immune-related genes in trout nasopharynx-associated lymphoid tissue (nalt), detected significant changes in immune expression in all genes analyzed in response to the three vaccination routes. however, nasal vaccination induced the strongest and fastest changes in innate immune gene expression compared to the other two routes. challenge experiments days post-vaccination (dpv) show the highest survival rates in the in- and imm-vaccinated groups. however, survival rates in the imm group were significantly lower than the in- and i.m.-vaccinated groups dpv. our results confirm that nasal vaccination of rainbow trout with live attenuated ihnv is highly effective and that the protection conferred by immersion vaccination is transient. these results also demonstrate for the first time that immersion vaccines stimulate nalt immune responses in salmonids. vaccination has become the most effective method of preventing infectious diseases in farmed fish [ ] . the ideal vaccine must provide long-term protection at both mucosal barriers and systemic tissues. the most common vaccination strategies in farmed fish are injection (intramuscular or intraperitoneal), immersion and oral vaccination [ ] [ ] [ ] . the majority of fish vaccines are delivered by injection, as it is considered the most effective vaccination route [ ] . however, the stimulation of mucosal immune responses by injection vaccines may be delayed compared to mucosal vaccines [ ] . nasal immunity is key to stopping the progression of neurotropic and respiratory pathogens to other body tissues such as the lower respiratory tract or the central nervous system. recent studies have identified nasal vaccination as an effective method to control infectious diseases in fish [ ] [ ] [ ] . nasal vaccines offer many advantages over other types of vaccines such as: (i) a needle-free delivery system; (ii) the induction of strong local and systemic immune responses; (iii) the need for low amounts of antigen. in support, nasal vaccination elicits both local and systemic innate and adaptive immune responses in rainbow trout without the need for an adjuvant [ , ] . combined, all these aspects make nasal vaccination a very attractive mucosal vaccination route for the control of aquatic infectious diseases in farmed fish. immersion vaccination is one of the most desirable ways to deliver vaccines in fish farms due to the ability to mass vaccinate large numbers of fingerlings without handling them one by one. during immersion vaccination, every mucosal surface of the fish, including the olfactory organ, is exposed to the diluted vaccine for a short period of time. however, several studies have evaluated how immersion vaccination induces immune responses in the skin, gut and gills of different fish species [ ] [ ] [ ] , the contribution of the fish nasopharynx-associated lymphoid tissue (nalt) during the immune response of immersion vaccines is yet to be determined. teleost nalt is formed by myeloid and lymphoid cells located at the tips and neuroepithelial regions of the olfactory lamellae that response to nasal antigens [ , ] . previous studies using a bath infection model with the parasite ichthyophthirius multifiliis (ich) have revealed that this parasite infects the trout olfactory organ and that trout nalt mounts innate and adaptive immune responses against this protozoan parasite [ ] . interestingly, the same study detected the highest parasite loads in the olfactory organ compared to common target tissues such as the skin and gills days after infection. these findings suggest that the olfactory organ may be a key site for antigen uptake during immersion vaccination and that nalt likely mounts immune responses to immersion vaccines. infectious hematopoietic necrosis virus (ihnv) is classified in the family rhabdoviridae and causes economically important disease known as infectious hematopoietic necrosis (ihn). ihn is a problem in salmonid farms worldwide, especially for atlantic salmon (salmo salar) and rainbow trout (oncorhynchus mykiss) which suffer significant morbidities and mortalities [ ] [ ] [ ] . we have previously reported that nasal vaccination using a live attenuated ihnv vaccine is highly protective both and days post-vaccination (dpv) [ ] . interestingly, ihnv immersion vaccination only elicits moderate levels of protection in rainbow trout [ , ] , but a comparison of all three routes of vaccination with the same vaccine formulation has not been conducted to date in any salmonid species. in this study, we compared three vaccination routes (intranasal (in), intramuscular injection (i.m.) and immersion (imm) on trout nasal innate immune responses using a live attenuated ihnv vaccine and found strong and quick immune responses in the olfactory organ in-vaccinated group. injection and immersion vaccines also triggered innate immune responses in rainbow trout nalt, albeit of a different magnitude and kinetics than those elicited by the in route. challenge experiments confirmed that immersion vaccination is not as effective against ihn compared to the nasal and injection routes. our findings open up new questions regarding how different teleost mucosa-associated lymphoid tissues (malt) and systemic lymphoid tissues communicate in response to pathogens and vaccines. the specific-pathogen-free (spf) rainbow trout ( . g mean weight, clear springs broodstock operations) were obtained from clear springs foods inc. (buhl, id, usa). fish were maintained in -l tanks that received single-pass ultraviolet-light-treated spf spring water at a constant temperature of . • c and a dissolved oxygen content of . ppm. spf status of brood stock was confirmed routinely in the entire facility. fish were fed twice daily with a commercial rainbow trout diet (clear springs foods inc.). a vaccine trial was conducted with a live attenuated ihnv as described in our previous study [ ] . the ihnv vaccine was experimentally generated at clear springs foods by serial passage in vitro as previously described [ ] . three vaccine routes were tested: intranasal vaccine method (in), intramuscular (i.m.) injection and immersion (imm) delivery. groups of spf rainbow trout were immunized by either pipetting µl of a live attenuated ihnv suspension that contained × plaque-forming units (pfu)/ml into the right nare (in), or by injecting µl of live attenuated ihnv suspension ( × pfu/ml) into the dorsal musculature just anterior to the dorsal fin (i.m.) or by immersion (imm) in pfu/ml for h in tank water. for in and i.m. groups, vaccine was diluted in pbs. a mock immunized group received µl of pbs both in and i.m. and were also immersed in pbs for h. duplicate -fish groups from each treatment were challenged with ihnv at and dpv. briefly, fish were anaesthetized in ms- ( mg/l, syndel, usa) and injected intraperitoneally (i.p.) with ( dpv) and ( dpv) pfu of live ihnv (isolate - [ ] ) ( figure ). an additional -fish group from each treatment was mock-challenged by injecting pbs at each challenge interval. after virulent ihnv challenge, each -fish group was held in separate l aquaria that received flow through • c ultraviolet light-treated spring water. all groups were monitored for mortalities for days post-challenge. dead fish were monitored every day at a.m. by two laboratory technicians and any dead animals removed with a clean net. ten percent of the deceased animals were checked for presence of ihnv by plaque assay on epithelioma papulosum cyprini cells (epc) from common carp (cyprinus carpio) [ ] . at each time point, fish (n = ) were anesthetized in ms- and bled from the caudal vein to avoid blood contamination in the olfactory tissue. trout olfactory organs were dissected at , and dpv (in, i.m. or imm) and placed in sterile . ml eppendorf tubes containing ml of trizol (invitrogen) and stored at − • c until use. total rna was extracted from both olfactory rosettes of each fish by homogenization using sterile tungsten carbide beads ( mm, qiagen) and shaking ( times for min) in a tissuelyser ii (qiagen). rna was extracted following a standard phenol-chloroform extraction protocol. the rna pellet was washed in % ethanol, air dried and resuspended in rnase-free water. rna concentrations were determined by spectrophotometry (nanodrop nd ) and the integrity of the rna was determined by electrophoresis (agilent bioanalyser, ). rna samples were stored at − °c until use. cdna was synthesized using µg of total rna per sample as previously described [ ] . the qpcrs reactions ( -µl reaction volume) consisted of µl of a diluted cdna template ( ng of total rna equivalents), . µl of power sybr green pcr master mix ( ×, applied biosystems) and nm forward and reverse primers. reactions were run in triplicate. the amplification profile consisted of an initial denaturation step at °c for min, and then cycles of • c for s and • c for min followed by melting (dissociation stage) from to • c in an abi prism (applied biosystems) sequence detection system. a negative control (no template) reaction was also performed for each primer pair. a sample from the serial dilution was run on a % agarose gel and stained with red gel stain and viewed under ultraviolet light to confirm a band of the correct size was amplified. in order to determine the efficiency of the amplification for each primer pair, reactions were carried out using serial tenfold dilutions of pooled cdna on the same plate as the experimental samples. the efficiency was calculated as e = (− /s) , where s is the slope generated from the serial dilutions, when log dilution is plotted against ∆ct (threshold cycle number). expression levels were normalized to those of the trout elongation factor a (ef- a) which was used as a single house-keeping gene. the relative expression level of the genes was determined using the pfaffl method [ ] . the primers used for qpcr are shown in table . all primer sets were designed to span an exon-exon boundary. absence of amplification of genomic dna contamination for each primer set was checked by standard pcr using total rainbow trout dna samples from a pool of lymphoid tissues of vaccinated fish as template. kaplan-meier survival curves were plotted to state the mortality of vaccination trials and challenge experiments. data were analyzed in prism version . (graphpad). data are expressed as mean ± standard error (s.e). unpaired student's t-tests were used for analysis of differences between groups. fisher's exact test of conditional independence for a × contingency table was used for follow-up tests using prism version . . p-values less than . were considered statistically significant. in this study, we vaccinated rainbow trout with live attenuated ihnv or pbs by different delivery routes (figure a -d) and then investigated changes in expression of immune-related genes at , and dpv in trout nalt by qpcr. these genes were selected based on a previous transcriptomics study performed in trout nalt dpv [ ] . at one dpv, il b and tgfb expression were greatly up-regulated (~ -and~ . -fold, respectively) in the in group, but not in the i.m. or imm groups. moreover, the pro-inflammatory cytokines tnfa, il and il were also significantly up-regulated dpv in the in group (~ . -,~ . -and~ . -fold) but not in the other two vaccinated groups (figure a ). in fact, il expression was down-regulated . -fold in nalt of i.m. vaccinated fish dpv. the il a expression was up-regulated~ . -and~ . -fold in both in and i.m. vaccinated groups dpv respectively, but not for the imm group. the expression of ck a, a chief nasal chemokine in trout, was only significantly up-regulated in in vaccinated fish dpv. the expression levels of il r, a marker for memory t cells following acute infections [ , ] , were significantly higher (~ . -fold) in in vaccinated fish, with no change in expression detected in the i.m. and imm groups. interestingly, except for the db and db expression in the imm-vaccinated group, all four beta defensin genes (omdb - ) examined were up-regulated in trout nalt dpv in all vaccinated groups compared to mock-vaccinated controls. four dpv, ck a as the most up-regulated gene (~ -fold) in the in group, followed by il , il r and tgfb (~ -,~ . -and~ -fold, respectively) ( figure b) . interestingly, whereas il b and il expression was still significantly higher compared to controls, il and tnfa expression levels were already similar to those of controls in the in group. at this timepoint, expression levels of omdb- , omdb- and omdb- had also returned to basal levels in all vaccinated groups. however, omdb- expression was significantly elevated in all vaccinated groups compared to controls (~ . - . -fold), indicating a unique behavior of this beta defensin in trout nalt. with regards to the i.m. and imm groups at dpv, transcription levels of tnfa, il b and il were significantly higher in the imm group but not the i.m. group, indicating that pro-inflammatory responses occur in trout nalt following imm vaccination albeit with a delay ( days vs. day) compared to the in route. (unpaired student's t-test) * p < . , ** p < . , *** p < . . one of the most remarkable findings of this study was the difference in the transcription kinetics of the innate immune responses that occur in nalt depending on the route of vaccination. as shown in figure c , i.m. injection resulted in significant up-regulation of tnfa (~ . -fold), il (~ -fold), il b (~ . -fold), and il (~ . -fold) expression dpv, while the expression of these genes was already down-regulated in the in group at this timepoint compared to dpv and showed very modest or no change in expression in the imm group (figure c ). ck a expression remained significantly up-regulated in both the in and i.m. groups (~ . -and~ . -fold, respectively) but no changes in expression was recorded in the imm group ( figure ). regarding beta defensins, no changes in expression were observed in any of the vaccinated groups compared to controls dpv except for a significant down-regulation in omdb- expression (~ . -fold) in the in vaccinated group (figure c,d) . taken together, these data show that in vaccination triggers quick (day ) and potent pro-inflammatory and anti-inflammatory immune responses in trout nalt and that these responses are rapidly dampened by day . imm vaccination also results in innate immune responses in trout nalt but these have lower magnitude and a delayed onset (day ) compared to those elicited by in vaccination. finally, i.m. injection vaccination also induces innate immune responses in trout nalt, but those occurred even later (day ) compared to the other two vaccination routes and with a magnitude more similar to the imm group than to the in group. percent cumulative mortalities for all vaccination trials are shown in table . fisher's exact tests show the survival in different vaccinated groups and challenged to pathogen (table ) . at dpv, survival rates in the in and imm groups ranged between % and % (p-value = in vs. i.m., table ), whereas the unvaccinated group had a mean survival rate of % (figure a) . i.m. vaccinated and challenged fish had a mean survival rate of . % (figure a) . i.m. vaccination without challenge resulted in a survival rate of % (percent cumulative mortality = %) (figure b and table , fisher's exact test p-value = . ), indicating losses due to the injection procedure and not the pathogen challenge in some fingerlings. table . statistical analyses of the survival between the different vaccinated groups and challenged to pathogen. significance symbols indicate the p-value: * p < . , ** p < . , *** p < . . at dpv, the mean survival rate of the unvaccinated and challenged group was %. the mean survival rate of the challenged imm group was % compared to the in and i.m. groups, which showed % protection (figure a,b) . fisher's exact tests show sufficient evidence for differences between the imm vaccinated group and the in-or i.m.-vaccinated group (p-value = . and . , respectively, table ) and no differences between the in and i.m. groups (p-value = , table ). vaccination has become the most effective method of preventing infectious diseases in farmed fish. the majority of the fish vaccines are delivered by injection, as it is still considered the most effective vaccination route [ ] . injection vaccination, however, is labor-intensive and can result in side-effects that impact fish welfare [ ] . injected vaccines do not directly stimulate mucosal surfaces, the first tissues to be infected by pathogens. mucosal vaccines for fish, such as immersion or oral vaccination may be the simplest and most cost-effective vaccination methods, especially is small fish, but they usually result in sub-optimal and short-term protection [ , ] . to date, very few viral vaccines have been developed for immersion because of their low efficacy [ ] . nasal vaccination, although labor-intensive, has been shown to be effective against viral and bacterial diseases, to be safe, and to stimulate both mucosal and systemic immunity in fish [ , ] . importantly, nasal vaccination provides additional welfare benefits for the fish as well as the handling staff, since needle use is avoided. vaccines based on live attenuated viruses have been amongst the most successful, cost-effective immune interventions in medical history [ , ] . live attenuated viral vaccines for fish typically elicit a strong and sustained immune response to the target disease [ ] . attenuated live vaccines are safe under most circumstances, although there are some risks such as the presence of residual virulence in vaccinates or virulence in immunocompromised hosts [ ] . in our results, we found no mortality in the in-vaccinated group after challenge with virulent ihnv, demonstrating once again that nasal delivery in rainbow trout is safe. furthermore, challenge experiments showed that the nasal route is very effective both at and dpv. some of these benefits are illustrated in the data from the present study, where we recorded % mortality in the unchallenged i.m.-vaccinated group but no mortalities in the unchallenged in or imm groups. although immersion vaccination is less labor-intensive and mimics natural exposure to infection [ ] , our data confirm that immersion vaccination with a live viral vaccine only affords short-lived immunity in rainbow trout, even in a prolonged exposure set-up like the one used in this study. teleost nalt shares the main features of other teleost mucosa-associated lymphoid tissues (malt) and mounts strong immune responses following infection or vaccination [ , ] . importantly, previous studies in trout demonstrated that intranasal antigen delivery results in very rapid and potent innate immune responses [ , ] and modest circulating specific antibody titers [ ] . here, we evaluated the expression of immune-related genes including cytokines, il r, the chemokine ck a and four β-defensins and found unique kinetics in the local nalt immune responses depending on the route of immunization. neuronal tissues such as the olfactory epithelium are particularly susceptible to pathological inflammation and, therefore, tight regulation of pro-inflammatory immune responses is critical [ ] . our gene expression studies clearly show a rapid pro-inflammatory state in trout nalt following nasal ihnv vaccination. the pro-inflammatory response was characterized by the elevated expression of classical cytokines including il b, il , il and tnfa. interestingly, our time series study revealed that the pro-inflammatory signature was no longer detected by dpv. moreover, elevated expression of anti-inflammatory cytokines il and tgfb was also recorded early on in response to intranasal ihnv vaccination, suggesting a tissue repair response. combined, these results highlight the ability of nalt to mount inflammatory responses against novirhabdoviruses while limiting the magnitude and duration of this response in order to protect tissue integrity. il- and its receptor il- r play critical roles in b and t cell growth, maturation and activation [ , ] . additionally, il- is involved in cd + and cd + memory t cell responses [ ] . at mucosal barriers, il- promotes il- a responses against respiratory bacterial infection [ ] and aids in the elimination of activated lymphocytes in the inflamed mucosa [ ] . our data show that in and i.m. vaccination induce il r expression in nalt, however, immersion vaccination results in transient down-regulation or no changes in nalt il r expression. this important finding may reflect the need to regulate inflammatory lymphocytes in the olfactory tissue in response to high antigenic doses such as those applied in nasal vaccination with this vaccine. moreover, the differential regulation of il r expression noted in each experimental group may shape the local and systemic b and t cell responses elicited by each of the vaccination routes. further studies are needed to support or reject this hypothesis. the β-defensin family of genes plays a significant role in antibacterial and antiviral immunity in fish [ , [ ] [ ] [ ] . previous studies showed up-regulation of β-defensins and other antimicrobial peptide (amp) genes in the kidney of brown trout infected with the novirhabodvirus viral hemorrhagic septicemia virus (vhsv) [ ] . however, the expression of antimicrobial peptides in the trout olfactory organ had not been investigated to date. our results highlight the key role of β-defensins as early antimicrobial effectors, in this case, in response to a viral antigen. importantly, induction of β-defensin gene expression in nalt was highest when the vaccine was delivered intranasally, compared to the other two routes. we observed that one of the four β-defensin genes studied, omdb- , showed a unique expression pattern characterized by a more sustained up-regulation compared to the other three β-defensin genes. similarly, in vhsv-infected brown trout, omdb- expression changes in the kidney differed from those of other amp genes [ ] . future studies should determine the unique function of each amp in the context of nasal immunity. chemokines play pivotal roles in coordinating leukocyte migration in immunity and inflammation [ , ] . in rainbow trout, the ccl -like chemokine ck is strongly expressed both at the mrna and protein level in mucosal tissues such as gill, gut and skin, suggesting its role as a mucosal chemokine [ ] . local nasal production of ck a plays a central role in antiviral immune protection both locally and systemically in trout [ ] . specifically, ck a is chemotactic in vitro and in vivo and recruits cd α + lymphocytes to the nasal mucosa [ ] . in line with these findings, our results show that the ck a mrna levels increase significantly in nalt after immunization with live attenuated ihnv vaccine both by nasal delivery and injection. previous studies revealed increased ck expression in the liver of trout infected by i.p. injection with vhsv [ ] and in the fin bases of trout following bath infection with vhsv [ ] . remarkably, we found that the immersion vaccinated group showed no change in ck a expression in nalt, suggesting that this route does not effectively stimulate this chemokine in the olfactory organ. therefore, it is unlikely that recruitment of immune cells such as cd α + lymphocytes into the olfactory organ occurs in response to this vaccination mode, perhaps explaining the lower effectiveness of this route compared to the other two. although we did not evaluate ck a responses at other malt in our immersion experiment, such studies will reveal if our observation in trout nalt is unique to nalt or universal across all malt following immersion vaccination. one of the caveats of the present study is that we did not measure transcriptional type i ifn responses or ifn-stimulated genes (isgs), known to play an important role in teleost antiviral immunity [ ] [ ] [ ] . we previously reported strong modulation of antiviral immunity genes in rainbow trout nalt days post nasal vaccination with live attenuated ihnv [ ] . given the rapid onset of type i ifn responses against novirhabdoviruses previously found in other studies in teleosts [ , ] , we predict that, similar to the genes investigated here, the vaccination route and antigen dose will be major determining factors of the type i ifn response in trout nalt. the teleost olfactory organ, although not a respiratory surface, shares many anatomical, cellular and molecular features with the mammalian olfactory system [ ] . thus, teleost fish models have been proposed as comparative models for human nasal infections and immunity [ ] . several viral pathogens infect the human host via the nasal epithelium including influenza virus [ ] and sars-cov- [ ] . understanding innate immunity in the nasal mucosa is therefore critical for the effective design of immunoprophylactic strategies against respiratory and neurotropic viruses. interestingly, currently, none of the covid- vaccines currently being tested in clinical trials are being delivered intranasally. our results indicate the immediate and potent immune responses in the trout nasal mucosa are best achieved when vaccines are delivered intranasally, and it is likely that this is the case in humans too. in conclusion, the present study shows that trout nalt mounts innate immune responses after vaccination with live attenuated ihnv vaccine regardless of the route of vaccination. importantly, the route of vaccination and antigen dose determine the magnitude, type and kinetics of the nalt innate immune responses. specifically, the responses induced by direct delivery of the vaccine into the nasal cavity of trout are not mimicked by neither injection nor immersion vaccination. finally, future studies should further investigate whether the limited stimulation of mucosal immune responses in nalt by immersion vaccination may explain the suboptimal protection conferred by this route in this or other vaccine models. this study shows that nasal vaccination with a live attenuated ihnv vaccine induces fast and potent innate immune responses in trout nalt. intramuscular vaccination with live attenuated ihnv vaccine induces a slightly delayed and less potent innate immune responses in trout nalt. immersion vaccination with live attenuated ihnv vaccine causes delayed and mild innate immune responses in trout nalt. finally, whilst nasal and injection vaccination are highly protective against ihn, immersion vaccination provides only transient protection. advances in fish vaccine delivery status and future perspectives of vaccines for industrialised fin-fish farming a review of fish vaccine development strategies: conventional methods and modern biotechnological approaches th -like immune response in fish mucosal tissues after administration of live attenuated vibrio anguillarum via different vaccination routes nasal immunity is an ancient arm of the mucosal immune system of vertebrates evaluation of dual nasal delivery of infectious hematopoietic necrosis virus and enteric red mouth vaccines in rainbow trout (oncorhynchus mykiss nasal vaccination of young rainbow trout (oncorhynchus mykiss) against infectious hematopoietic necrosis and enteric red mouth disease efficacy of a bivalent vaccine against eel diseases caused by vibrio vulnificus after its administration by four different routes polymeric immunoglobulin receptor and mucosal igm responses elicited by immersion and injection vaccination with inactivated vibrio anguillarum in flounder (paralichthys olivaceus) efficacy of a polyvalent immersion vaccine against flavobacterium psychrophilum and evaluation of immune response to vaccination in rainbow trout fry (onchorynchus mykiss l.) tissue microenvironments in the nasal epithelium of rainbow trout (oncorhynchus mykiss) define two distinct cd α + cell populations and establish regional immunity mucosal immunoglobulins protect the olfactory organ of teleost fish against parasitic infection epidemiological characteristics of infectious hematopoietic necrosis virus (ihnv): a review molecular characterization of the virulent infectious hematopoietic necrosis virus (ihnv) strain - infectious hematopoietic necrosis virus recombinant infectious hematopoietic necrosis virus and viral hemorrhagic septicemia virus glycoprotein epitopes expressed in aeromonas salmonicida induce protective immunity in rainbow trout (oncorhynchus mykiss) infectious hematopoietic necrosis virus: advances in diagnosis and vaccine development current trends in immunotherapy and vaccine development for viral diseases of fish. in current trends in the study of bacterial and viral fish and shrimp diseases development of passive immunotherapy for control of infectious hematopoietic necrosis fluorescent antibody test for the rapid diagnosis of infectious hematopoietic necrosis discovery of j chain in african lungfish (protopterus dolloi, sarcopterygii) using high throughput transcriptome sequencing: implications in mucosal immunity a new mathematical model for relative quantification in real-time rt-pcr ck a, a ccl -like chemokine that orchestrates both nasal and systemic antiviral immune responses in rainbow trout bioactivity studies of rainbow trout (oncorhynchus mykiss) interleukin- : effects on macrophage growth and antimicrobial peptide gene expression transforming growth factor-β b: a second tgf-β paralogue in the rainbow trout (oncorhynchus mykiss) that has a lower constitutive expression but is more responsive to immune stimulation response of rainbow trout (oncorhynchus mykiss) in skin and fin tissue during infection with a variant of gyrodactylus salaris (monogenea: gyrodactylidae) characterization of three novel β-defensin antimicrobial peptides in rainbow trout (oncorhynchus mykiss) bath vaccination of rainbow trout (oncorhynchus mykiss walbaum) against yersinia ruckeri: effects of temperature on protection and gene expression molecular cloning of interleukin beta from rainbow trout oncorhynchus mykiss reveals no evidence of an ice cut site gene expression profiling in naïve and vaccinated rainbow trout after yersinia ruckeri infection: insights into the mechanisms of protection seen in vaccinated fish rainbow trout interleukin- : cloning, expression and bioactivity analysis selective expression of il- receptor on memory t cells identifies early cd l-dependent generation of distinct cd + memory t cell subsets selective expression of the interleukin receptor identifies effector cd t cells that give rise to long-lived memory cells an overview of challenges limiting the design of protective mucosal vaccines for finfish review on immersion vaccines for fish: an update live attenuated vaccines: historical successes and current challenges rationalizing the development of live attenuated virus vaccines viral vaccines for farmed finfish nasal vaccination drives modifications of nasal and systemic antibody repertoires in rainbow trout olfactory sensory neurons mediate ultrarapid antiviral immune responses in a trka-dependent manner the many roles of il- in b cell development; mediator of survival, proliferation and differentiation new insights into il- signaling pathways during early and late t cell development overexpression of interleukin (il)- leads to il- -independent generation of memory phenotype cd + t cells interleukin- protects against bacterial respiratory infection by promoting il- a-producing innate t-cell response mucosal il- -mediated immune responses in chronic colitis-il- transgenic mouse model a β-defensin gene of trachinotus ovatus might be involved in the antimicrobial and antiviral immune response b-defensin in nile tilapia (oreochromis niloticus): sequence, tissue expression, and anti-bacterial activity of synthetic peptides identification and characterization of a β-defensin gene involved in the immune defense response of channel catfish, ictalurus punctatus immune response modulation upon sequential heterogeneous co-infection with tetracapsuloides bryosalmonae and vhsv in brown trout (salmo trutta) chemokines: chemistry, biochemistry and biological function chemokines and their receptors: drug targets in immunity and inflammation ck , a rainbow trout chemokine with lymphocyte chemo-attractant capacity associated to mucosal tissues early immune responses in rainbow trout liver upon viral hemorrhagic septicemia virus (vhsv) infection specific regulation of the chemokine response to viral hemorrhagic septicemia virus at the entry site the peculiar characteristics of fish type i interferons the antiviral innate immune response in fish: evolution and conservation of the ifn system insights into the antiviral immunity against grass carp (ctenopharyngodon idella) reovirus (gcrv) in grass carp an oral dna vaccine against infectious haematopoietic necrosis virus (ihnv) encapsulated in alginate microspheres induces dose-dependent immune responses and significant protection in rainbow trout (oncorrhynchus mykiss) infectious pancreatic necrosis virus triggers antiviral immune response in rainbow trout red blood cells, despite not being infective molecular and neuronal homology between the olfactory systems of zebrafish and mouse comparative models for human nasal infections and immunity influenza a viruses are transmitted via the air from the nasal respiratory epithelium of ferrets more than a respiratory virus: its potential role in neuropathogenesis we thank the technical staff at clear springs foods research. division for their help with fish maintenance. the authors declare no conflict of interest. l.t. is employed by leica biosystems amsterdam, a manufacturer of products for cancer diagnostic. this work was not financed by leica biosystems amsterdam. the authors declare no additional conflicts of interest. key: cord- -ruf rzxm authors: kee, sae yoon; lee, jin soo; cheong, hee jin; chun, byung chul; song, joon young; choi, won suk; jo, yu mi; seo, yoo bin; kim, woo joo title: influenza vaccine coverage rates and perceptions on vaccination in south korea date: - - journal: j infect doi: . /j.jinf. . . sha: doc_id: cord_uid: ruf rzxm objective: this survey was performed to assess the level of influenza vaccine coverage, to understand the driving forces and barriers to vaccination and determine vaccination interventions for the following year in korean population. methods: a national sample of community dwelling adults of age and older were surveyed by individual visits during april . demographics, state of influenza vaccination, reasons for vaccination or non-vaccination and perceptions on vaccinations were asked by questionnaire. results: influenza vaccination coverage in general population and high risk group was . % and . %, respectively. predictors for vaccination were ≥ of age, performance of regular exercise, vaccination in the previous season, experience of influenza-like illness, belief that vaccine can prevent common cold and opinion that vaccine must be taken annually. the most common reason for vaccination for both whole population and high risk groups was to prevent both influenza and common cold, while the most common reason for non-vaccination was the thought that he/she was healthy enough not to be in need for vaccination. having more information on influenza and vaccination as well as doctor's recommendation for vaccination appeared to be the most important modus operandi to encourage influenza vaccination among non-vaccinees. conclusions: doctor's recommendation was the most important factor in encouraging people to be vaccinated against influenza. doctors should be geared up with precise information and actively encourage high risk population in order to increase vaccination coverage. summary objective: this survey was performed to assess the level of influenza vaccine coverage, to understand the driving forces and barriers to vaccination and determine vaccination interventions for the following year in korean population. methods: a national sample of community dwelling adults of age and older were surveyed by individual visits during april . demographics, state of influenza vaccination, reasons for vaccination or non-vaccination and perceptions on vaccinations were asked by questionnaire. results: influenza vaccination coverage in general population and high risk group was . % and . %, respectively. predictors for vaccination were ! of age, performance of regular exercise, vaccination in the previous season, experience of influenza-like illness, belief that vaccine can prevent common cold and opinion that vaccine must be taken annually. the most common reason for vaccination for both whole population and high risk groups was to prevent both influenza and common cold, while the most common reason for non-vaccination was the thought that he/she was healthy enough not to be in need for vaccination. having more information on influenza and vaccination as well as doctor's recommendation for vaccination appeared to be the most important modus operandi to encourage influenza vaccination among non-vaccinees. influenza causes significant morbidity in both healthy population and patients with high risk conditions. healthy adults may suffer from high fever, headache and myalgia, whereas clinical manifestations are more serious in high risk patients such as elderly or patients with comorbid conditions and may even cause death due to respiratory complications. e the clinical course of influenza differs by age, immune status, characteristics of circulating influenza strains, comorbidities and pregnancy status. changes at antigenic sites of influenza virus render a new strain that can avoid the immunity induced by previous strains, thus causing influenza epidemics. the most effective way of preventing influenza is to immunize with vaccines made after prediction of antigenic variation. in one study, inactivated vaccine showed efficacy of % reduction in influenza-like illness in healthy adults when vaccine strain was well matched with predominant circulating strain. although antibody production rate is lower in people over the age of , various studies proved influenza vaccine to be effective in reducing influenza related diseases and complications, hospitalizations and mortality in this group. e the priority group who are recommended for annual vaccination includes persons aged ! years, persons with chronic illness such as chronic cardiopulmonary disease, diabetes, chronic liver disease and malignancy, residents of long term care facilities, health-care personnel and pregnant women. the center for disease control and prevention is expanding the priority group for vaccination in recognition of the significance of influenza and importance of vaccination. the priority group for influenza vaccination have been also expanded in korea; pregnant women and persons aged e years were newly added in and children of age e months were added in . people working in organizations dealing with sars (severe acute respiratory syndrome) have been newly added in response to the movement of cdc. influenza vaccine production and import are increasing in korea; while vaccines for e million people, which can cover about % of total population, were supplied in the season e , vaccine for million people were distributed in the season e . in the season e , vaccines for million people were supplied, and according to the sales statistics, it is estimated that % of total population have been vaccinated. these percentages are comparable to other countries: fedson reported in that influenza vaccine distribution per population was doses in korea, and this number is relatively high compared to northern america ( doses), western europe ( doses), southeast asia ( . dose) and worldwide ( doses). vaccine distribution rate grew even higher to doses per population in . korea shows relatively high influenza vaccine distribution rate, however, exact vaccination coverage among total population or priority group have not yet been studied. the korea centers for disease control and prevention set a goal to increase vaccination rate in the priority group to reach at least %. nevertheless, vaccination coverage rate has been calculated according to the sales record, and nationwide vaccination rate by self-report of the whole population or priority group has never been studied. precise identification of vaccination rate in the whole population as well as high risk groups is urgently needed in order to accomplish objectives of influenza vaccination policy. therefore, the aim of this study was to investigate the level of influenza vaccination coverage in adults and high risk groups, identify factors related to vaccination and opinions about influenza and influenza vaccine, and discover the way to increase vaccination coverage. this is a population based cross-sectional descriptive study. the target study population included non-institutionalized persons aged ! years living in south korea. the survey was conducted by gallup korea â , a professional research company, and face-to-face interviews were performed by trained professional interviewers from to april . in order to represent the total population, multistratified random sampling according to the principle of proportionate probability sampling was adopted to select the subjects. south korea is divided into eight provinces and seven cities and each province or city is further subdivided and stratified into e units. the number of households to be interviewed in each administrative district was calculated and decided proportionately according to the location and sizes of the district, age and gender. the statistics of from the national statistical office was used for the calculation. if the selected household could not be surveyed, an alternative household was chosen in the same manner. before the interview, the interviewer explained the purpose of the study to all the subjects and verbal informed consent was obtained by respondents who agreed to participate. the questionnaire contained questions. data on demographics such as age, gender, level of education, and level of income were obtained. questions about drinking, smoking and exercise habits and comorbid conditions were asked. the interview continued with asking whether or not the respondent was vaccinated in the season e and e . if the respondent was vaccinated in the season e , further questions on the reason of vaccination was asked. thirteen reasons were presented, and respondents were to choose as many as they wish. for non-vaccinated respondent, the reasons of non-vaccination were asked in a form of multiple choice questions with reasons. six yes-or-no questions on opinions about influenza vaccine were presented to all respondents. further yes-or-no questions about opinions on influenza and influenza vaccination were presented to high risk group. all respondents were asked whether they intended to have vaccinated in the following season. regular exercise was defined as performing exercise more than once a week, smoker as currently smoking, and regular alcohol consumer as drinking alcohol more than twice a week. high risk group was defined as either age ! years or having comorbid conditions. comorbid conditions included cardiovascular diseases such as congestive heart failure and myocardial infarction, diabetes, lung diseases including asthma and chronic obstructive pulmonary disease, chronic liver diseases including chronic hepatitis and liver cirrhosis, and malignancy. univariate analysis of factors associated with vaccination/non-vaccination was performed using c test and fischer's exact test. to describe statistical significance, the % confidence interval (ci) was computed. in logistic regression, gender, presence of comorbid conditions, age (! ), level of education, size of dwelling town, monthly income, smoking habit, drinking habit, exercise habit, vaccination in previous season, history of influenza-like illness and six opinions about influenza were included. all statistical analyses were performed using the spss . ko for windows (spss inc.) of the total responses from subjects, insincere responses were excluded and, therefore, data of ( . %) subjects were analyzed. mean age was . ae . years and subjects ( . %) were male. one hundred and seventy-four subjects ( . %) were ! years and subjects ( . %) had one or more comorbid conditions; subjects ( . %) were classified as high risk group. the coverage rates for influenza vaccination were . %, . %, . %, and . % among total adult population, high risk group, persons aged ! years and persons with comorbid conditions, respectively (table ) . influenza vaccination coverage was higher in females, increasing with age ( . % in age e years versus . % in age ! years), and in persons with any comorbid condition. as for the socio-demographic variables, the likelihood of receiving the vaccine increased when the education level was lower, the size of town was smaller, and the income level was lower. persons on regular exercise, non-smokers and not so regular alcohol consumers showed higher vaccination rates compared to subjects not doing regular exercise, current smokers and regular alcohol consumers, respectively. persons who had been vaccinated in the preceding season ( e ) and those with a history of influenza-like illness also showed higher rates (table ) . reasons for vaccination among vaccinees are described in table . the most common reason for vaccination in total population was 'to prevent not only flu but also common cold' ( . %), followed by 'influenza being a serious disease' ( . %), 'recommendations from friends or family members' ( . %) and 'received information from mass media' ( . %). reasons such as 'having seen people get sick/ die from flu' ( . %), 'not in good health' ( . %), 'doctor's advice' ( . %), 'have chronic disease' ( . %) were among less common reasons. the most common reasons for vaccination were not different in high risk group, however, 'have interest in vaccination because of bad health status' showed higher rank ( . %) than the total population. reasons for refusal among non-vaccinee are described in table . in total population, 'perception of good health' was the most common cause of non-vaccination ( . %) followed by 'not enough time' ( . %), 'troublesomeness of vaccination' ( . %), 'distrust in the effectiveness of vaccine' ( . %), and 'missed vaccination time' ( . %). the rank of reasons for non-vaccination was not different in high risk group but less people ( . %) chose 'in good health' as the reason. factors influencing future vaccination are summarized in table . 'more information on importance of vaccination' ( . %) was the most common factor to increase the drive for vaccination, followed by 'recommendation from doctors or nurses' ( . %). in the high risk group, this rank was reversed, and doctors or nurses' recommendation was the most influential factor for future vaccination ( . %). other options included 'if vaccine is cheaper' ( . % in total population and . % in high risk group), 'if more information is provided about influenza' ( . % and . %, respectively), 'if i have enough time' ( . % and . %, respectively), 'if i can get vaccinated at workplace' ( . % and . %, respectively) and 'if there is a way other than shots' ( . % and . %, respectively). of the total population . % and of the high risk group . % were negative about getting vaccinated and answered 'i would not take it in any situation'. opinion about influenza vaccine is described in table . more than % of both vaccinees and non-vaccinees agreed that 'vaccine can prevent influenza' and 'vaccine is safe'. more vaccinees compared to non-vaccinees agreed that 'vaccine can prevent common cold' and 'vaccine should be taken annually'. however, more non-vaccinees thought vaccine was expensive. less than % of vaccinees and non-vaccinees thought that 'you never get influenza once you are vaccinated'. in all opinions, the difference in the percentages of vaccinees and non-vaccinees were statistically significant. further questions were presented to persons of the high risk group. most of both vaccinees and nonvaccinees agreed that complications of influenza might be serious ( . % and . %, respectively) and that they had chance to hear about influenza and influenza vaccination from mass media ( . % and . %, respectively). however, more vaccinees of the high risk group compared to non-vaccinees agreed on the following opinion; influenza might be dangerous to high risk group, influenza might aggravate underlying diseases, vaccination might reduce chances of hospitalizations, and vaccination might reduce expenses for extra medication. furthermore, more than % of vaccinees agreed that they were at high risk of catching influenza, and at bad health, and that acquaintances advised them to get vaccinated, however, less than % of non-vaccinees agreed on the same opinion. in comparison, nearly % of non-vaccinees thought themselves to be in good health whereas only . % of vaccinees thought the same way. also, although more vaccinees than nonvaccinees were advised to get vaccinated, it was less than % in both groups (table ) . results of multivariate analysis to determine factors associated with vaccination are summarized in intention for vaccination in the next season was as follows: . % of total subjects and . % of the high risk group were willing to get vaccination. self-reported influenza vaccination coverage of . % in this study corresponded well to the percentage estimated from the number of vaccine doses sold ( %). moreover, the coverage in high risk group met the target set by korean cdc (> %). these coverage rates in korea in the season e is relatively high, compared to the coverage in the united states ( . % in whole population and % in high risk groups) and europe ( e % in priority group ). nevertheless, the rates are not satisfactory enough, because who set the goal of attaining vaccination coverage of the elderly population to at least % by and % by and more efforts are needed to increase the coverage rates. in univariate analysis, people of older age or persons having comorbid condition were more likely to get vaccinated, which is in concordance with studies from other countries. e since these two groups are the main target for vaccination, it implies that vaccination program in south korea is quite successful. people with healthy lifestyle habits such as regular exercise, non-smoking and no regular alcohol consumption also had higher vaccination rate. people with healthy lifestyle may have more interest in general health, seek for preventive health care and therefore are more willing to get vaccinated. vaccination coverage in females was significantly higher in univariate analysis, and similar result was shown in another study. the fact that more females ( % versus % males) were ! years who had higher vaccination rate might be the explanation in south korea. interestingly, vaccination coverage was higher among people of lower education level, and lower income and living in smaller towns. this may be partially explained by the fact that both persons ! years and persons with chronic illnesses are more likely to be undereducated and have lower income, as is shown by south korean statistics, and similar results were also presented by jimenez et al. the government policy to administer influenza vaccine free of charge to low income group at public health centers may be another explanation: survey showed that people vaccinated at public heath centers were older, and had lower level of education and were living in a smaller town (data not shown). to prevent common cold as well as flu was the most common reason for vaccination. this is concordant with the high percentage of agreement ( . %) that vaccine can prevent common cold. also, the perception that 'influenza vaccine can prevent common cold' was a predictor for vaccination. this idea might have been responsible for the increase of vaccination rate, however, wrong attitude due to wrong knowledge must be corrected. self-perception of bad health, interest in vaccination and chronic illness were common reasons for vaccination in high risk group, showing their interest in health. 'confidence in health' was the most common reason for non-vaccination ( %) in both all adults groups and high risk groups, followed by 'being too busy', 'because it is troublesome' and 'miss vaccination time'. among nonvaccinees with non-vaccination reason of 'miss vaccination time', % were willing to get vaccination in the following season. 'not believing in the effectiveness of vaccination' accounted for about % of the responses. these results led us to suggest some intervention to increase vaccination uptake: more efforts should be paid to convince people in the priority group who are at high risk, and to provide information on influenza and effectiveness of vaccination to increase vaccination motive. also, improvement of accessibility to vaccines such as providing vaccination at workplace may contribute to an increase of vaccination uptake. less than % of non-vaccinees reported 'side effects of vaccination' or 'fear of getting influenza by vaccination' as the reason for non-vaccination. the above result is different from other studies , and implies that people have correct knowledge on side effects of vaccines. health-care workers' recommendation for vaccination was the most important factor to influence future vaccination habit in high risk group, in agreement with other studies. , , , e booth et al. reported that e % of general physicians recommend vaccination to priority group, and song et al. showed that reminding persons of age ! to get flu shots by telephone calls or postcards significantly increased vaccination rate. in this present study, recommendations to the high risk groups by doctors and public health centers were % and %, respectively, inferring that recommendation rate from doctors in clinical practice is very low. perenboom and davidse reported that active recommendation to persons with chronic illness increased the rate of vaccination from % to . %. therefore, the role of health-care workers, especially doctors, appears to be very important in increasing vaccination rate, and therefore, they should give active recommendations. in the high risk group most of the persons were aware of the fact that influenza is a serious disease and it may be more dangerous or produce more complications in persons with chronic illness. furthermore, more than half of them believed that influenza vaccination might reduce hospital admission and extra medical expenses, showing that they have correct perception on influenza and influenza vaccine. however, while more than % of vaccinees in the high risk group agreed that they were not in good health and at high risk of catching influenza, and they are interested in vaccination because of bad health, only . % and . % of non-vaccinees, respectively, agreed on that. also, . % of vaccinees were advised to get vaccinations while only . % of non-vaccinees did receive the advice. this shows apparent difference in the perception of one's health between vaccinees and non-vaccinees and, therefore, efforts should be made to inform people about the priority group of vaccination in order to increase coverage rate. forty-three and three-tenth of total subjects and . % of the high risk groups were willing to get vaccination in the coming season, and the percentage in high risk groups exceeds the rate in the season e as well as the target of korea cdc ( . % and %, respectively). persons who had been vaccinated previously were more willing to have vaccination in the following season (table ) , and this correlates with other studies , , that previous vaccination is the most significant predictive factor for future vaccination. moreover, belief that 'vaccine must be taken annually' was a predictor for vaccination. efforts to increase vaccination rate in priority group for at least one season may have influence over vaccination for several years. this may be particularly useful in the situation of vaccine shortage, when it is recommended by authorities that supply of vaccines should take precedence to priority group. the strength of this study lies in the fact that survey was conducted on individual interview basis and meanings of questionnaire were explained thoroughly even to the elderly, and thus receiving precise answers. there are some limitations in the study. first, high risk group consisted of only persons ! or persons with comorbid condition, and therefore, the whole priority group were not included in the analysis. secondly, the survey was conducted in april, when it was past the influenza season and therefore recall bias might have occurred. thirdly, the presence of comorbid condition and vaccination uptake were totally relied on self-reports of the subjects and therefore actual presence of illness or vaccination uptake might have been over-or under-estimated. in summary, the significance of influenza and importance of vaccination were well perceived, especially, among the high risk groups and . % in total population and . % of the high risk group showed intention to have vaccination, which is very encouraging. since giving correct information and health-care personnel's recommendation to vaccination would greatly influence vaccination rate, doctors should be geared up with precise information and actively recommend them to get influenza vaccinations. impact of influenza on mortality in relation to age and underlying disease influenza-attributable mortality among the elderly in switzerland population-based study on incidence, risk factors, clinical complications and drug utilisation associated with influenza in the united kingdom influenza pandemic caused by highly conserved viruses with two receptor-binding variants effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens effects of a large-scale intervention with influenza and -valent pneumococcal vaccines in adults aged years or older: a prospective study influenza vaccination in community-dwelling elderly: impact on mortality and influenzaassociated morbidity influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly clinical effectiveness of influenza vaccination in persons younger than years with high-risk medical conditions: the prisma study prevention and control of influenza, recommendations of the advisory committee on immunization practices pandemic influenza and the global vaccine supply the macroepidemiology of influenza vaccination (miv) study group. the macroepidemiology of influenza vaccination in countries korea statistics information system influenza vaccination coverage rates in five european countries-a population-based cross-sectional analysis of two consecutive influenza seasons world health organization. prevention and control of influenza pandemics and annual epidemics (agenda item prevalence and predictors of influenza vaccination among frail, community-living elderly patients: an international observational study influenza vaccination coverage rates in germany factors associated with influenza vaccination among elderly spanish women influenza coverages in spain and vaccination-related factors in subgroup aged e predictors of influenza vaccine acceptance among healthy adults crosssectional study on influenza vaccination factors affecting influenza vaccination among attendees at a senior center factors associated with influenza and pneumococcal vaccination behavior among high-risk adults implementation of influenza immunisation policy in general practice: to effectiveness of telephone and postcard reminders for the influenza vaccination: a study in the elderly who have visited a family practice center in a tertiary care hospital increasing the coverage of vaccination against influenza by general practitioners patient acceptance of influenza vaccination influenza vaccination. knowledge, attitudes, and behavior among high-risk outpatients update: influenza vaccine supply and recommendations for prioritization during the e influenza season. mmwr morb mortal wkly rep: key: cord- -q o lrh authors: rachaniotis, nikolaos; dasaklis, thomas k.; pappis, costas title: controlling infectious disease outbreaks: a deterministic allocation-scheduling model with multiple discrete resources date: - - journal: j syst sci syst eng doi: . /s - - -z sha: doc_id: cord_uid: q o lrh infectious disease outbreaks occurred many times in the past and are more likely to happen in the future. in this paper the problem of allocating and scheduling limited multiple, identical or non-identical, resources employed in parallel, when there are several infected areas, is considered. a heuristic algorithm, based on shih’s ( ) and pappis and rachaniotis’ ( ) algorithms, is proposed as the solution methodology. a numerical example implementing the proposed methodology in the context of a specific disease outbreak, namely influenza, is presented. the proposed methodology could be of significant value to those drafting contingency plans and healthcare policy agendas. control actions in an epidemic model typically include vaccination of susceptibles, treatment or removal (e.g., quarantine) of infectious persons, and reduction of the contact rate between susceptible and infectious persons (average number of infective contacts per infected person per unit time) via restricting movement between districts, school closures, etc. (riley et al. ) . the key parameter for many epidemiology models is the basic reproduction number r , which is defined as the average number of secondary infections produced when one infected individual is introduced into a host population where everyone is susceptible to the disease (hethcote ) . when control actions are implemented, however, not all contacts will be susceptible to infection. in this case the effective reproduction number r e is used which takes into account the time-dependent variations in the transmission potential of the agent triggering the outbreak (nishiura & chowell ). the objective of the control actions described above is to decrease the value of the effective reproduction number below one. due to control actions infected individuals may not pass the infection to susceptible individuals during their infectious period and eventually the infection dies out. the literature regarding epidemics containment is vast (coburn et al . in most cases, several disease transmission modeling approaches are utilized for assessing the possible effects of control interventions. these interventions could be pharmaceutical (use of antiviral drugs or vaccines), non-pharmaceutical (closure of schools, voluntary quarantines over a wide area, social distancing and travel limitations) or any combination thereof. for modeling the progression of the disease several approaches have been presented in the literature. these approaches range from simple compartmental models based on differential equations (alexander et limited vaccine supplies as well as limited ancillary medical supplies are among the resources to be allocated in the case of influenza outbreak control. as vaccination remains in the forefront of any influenza control strategy, the usage of limited vaccine stockpiles and their optimal allocation among sub-populations play a crucial role (particularly vaccination of at-risk individuals). several studies consider aspects of prioritization by using age-targeted allocation strategies , lee et al. ) . a more specific problem of this category is the allocation of limited vaccine supplies targeting both at-risk groups and age-dependent groups of susceptible individuals ( the remainder of the paper is structured as follows: the statement of the problem is presented in section . in section the modelling approach is provided. a heuristic algorithm for solving the problem is proposed in section . a numerical example implementing the proposed methodology in the context of a specific disease outbreak (influenza) is presented in section , where a detailed epidemic transmission model capturing realistic disease patterns is coupled with the proposed modeling approach. in section the main findings of the study, its limitations as well as fruitful areas for further research are discussed. the paper ends with some concluding remarks. a realistic problem when health policy makers implement a mass vaccination campaign is the treatment of specific groups of the population. for example, when controlling an outbreak attributed to a deliberate bioterrorist action, public health officials should pay special attention to people unable to proceed to vaccination centres either because they are house bound (elderly, incapacitated etc.) or they are in institutions (department of health ). the same holds for disease outbreaks attributed to natural causes. for example, during the last pandemic influenza outbreak a(h n )v most countries launched mass vaccination campaigns. in the case of greece, public health authorities commissioned several mobile medical teams to vaccinate certain groups of the greek population like house bound individuals or institutionalized ones. allocating and scheduling limited number of resources for vaccination is a complex problem because: a) different subgroups may have different risk of infection and/or complications following it, b) epidemics of infectious diseases are nonlinear and dynamic, c) the time horizon impacts the scheduling decision, since short-term considerations may not yield the same results as long-term ones (brandeau ) . regarding the second point, note that preventing one person from getting infected now could result in many individuals being saved from infection in the future. Τhe problem of allocating and scheduling mobile medical teams can be assigned to targeted populations or individuals. the following regarding the resources (mobile medical teams) to be allocated are assumed: • the mobile medical teams can be considered as parallel (identical or nonidentical) unrelated resources with constant service rates. • more than one medical team may be allocated to a specific regional population. • pre-emption is not allowed. thus, the situation where a medical team is called to visit a population in a specific region while it is employed in another one is not allowed. • control actions rely on vaccination of specific groups of the population (house bound and/or institutionalized individuals etc.). • all the available medical teams at any time are employed for controlling the epidemic. • the resources' traveling times are assumed to be negligible, since any mobile medical team can reach any population in a time period of a few hours, which is not significant compared to the control actions lasting for at least several days. let: { } ( ( ), ( ), , ( )) n r t r t r t  be the vector of the number of medical teams assigned for vaccination in every regional population this is the problem's decision vector variable. the number of new infections at any time instance can be calculated using as input any existing disease transmission model (from compartmental modeling to agent-based modeling approaches). the problem presented in the previous section is a time-dependent version of the well-known static discrete resource allocation problem with a single resource constraint, which has been thoroughly studied (ibaraki & katoh , shih . in this problem (where m t =m and r i (t)=r i ), the number of different assignments is , thus its complexity increases rapidly as m and n increase. the solution methodologies for the static discrete resource allocation problem proposed in the literature are branch-and-bound algorithms (mjelde , shih , dynamic programming techniques (bretthauer & shetty , ibaraki & katoh ) and a greedy incremental algorithm (shih ) . the heuristic for tackling the problem presented in this paper, which has not been addressed until now according to the best of the authors' knowledge, is a combination of shih's ( ) algorithm and a variation of the algorithm used in (pappis & rachaniotis ). in the latter the problem of scheduling multiple resources employed as parallel identical or non-identical processors (multi-processor tasks) for wildfires' suppression was examined. a low-order polynomial time algorithm was proposed for scheduling resources according to their availability and the fires' severity. the selection of the proposed methodology can be justified by the fact that shih's algorithm is very fast to implement and yields satisfactory solutions (ibaraki and katoh ) , whereas pappis and rachaniotis ( ) algorithm has an empirically proven satisfactory performance in the quite similar dynamic problem of wildfire containment. an informal description of the algorithm used in this paper is the following: • step : allocate resources to populations according to the incremental algorithm (shih ) for solving the respective static discrete resource allocation problem. the vaccination time duration under the current assignment is calculated. finally, it has to be explicitly stated at this point that the vaccination rate is time varying, synchronized with the course of the epidemic diffusion and the medical teams availability, thus r e is accordingly adjusted over time. to system of ordinary differential equations: ( ) it should be noted that the aforementioned system ( ) mobile medical teams with a significant service rate are assigned to greece's administrative health districts (ahds). their main task is to vaccinate people unable to proceed to local vaccination centres, whereas the remainder of the population can be administered the vaccine in mass immunization centres (hospitals). the targeted subpopulations in this study consist of the following groups of individuals: a) home living people aged years or older, b) institutionalized elderly people and, finally, c) housebound individuals with kinetic problems. data regarding basic demographical characteristics (subpopulations sizes' estimations) from greece's ahds is used as input for the model (figure and table ). values of the sveir epidemiological model may be seen in table . a simplifying assumption is that subpopulation mixing between districts is not considered. there are at least three arguments to justify this assumption. first, subpopulations' mixing is negligible compared to mixing within districts. second, the time lag between the initial cases countrywide and the first cases in the remaining districts is captured by the different epidemic outbreak times. third, targeted population consists of individuals that are not highly movable (since they are either elderly people or house-bound individuals). therefore, from an epidemiological point of view, the interactions of these sub-groups of individuals between different regions may be considered as negligible. there were difficulties in the accurate estimation of model's parameters', given: • the various factors affecting their measurement and their actual values. • the fact that the real burden of the disease (number of influenza cases) is not captured. for example, many infections are undetected due to the usually mild nature of the disease. individuals with these symptoms do not usually seek medical attention. in addition, laboratory testing by the hellenic center for disease control & prevention (www.keelpno.gr) focuses mainly on selected incidents (hospitalized cases). as a consequence, the surveillance data reported do not necessarily reflect the true incidence of the disease, which is likely to be underestimated. in the event of an influenza outbreak, public health authorities should try to ensure that widespread community transmission does not occur. all of the response scenarios examined here involve the implementation of a targeted reactive vaccination campaign for different resource allocation policies (table ). in particular, the sensitivity of the number of infected individuals to two factors: amount of resources allocated and delays in implementing the vaccination campaign have been examined. the results generated by the numerical implementation of types of control scenarios for a time period of days for the targeted subpopulations are presented: • the baseline scenario where no intervention (vaccination) takes place. the r value is constant and approximately equal to . , which is inside the limits used in the influenza epidemics literature (boëlle et al. ). • the fixed-strategy approach where a single mobile medical team is assigned to each district. this is used only to prove that vaccination is mandatory for the targeted subpopulation, therefore the mobile medical teams' allocation, which is the only way of vaccinating them, is essential. • the maximum resources scenario where each district is assigned a constant number of medical teams by using the size of each districts' population as the main driver. • the heuristic approach that allows the dynamic re-allocation of teams between districts. for the second scenario five different vaccination initiation days are considered, i.e. , , , or days after the beginning of transmission (matrajt et al. ). the assumptions made are that the number of vaccines necessary for the targeted subpopulations is available at the vaccination's initiation day and that the epidemic initiates in attica region with case, then in central macedonia with case in day and in all other districts with cases in day , similar to the initial cases' pattern that appeared in the last pandemic influenza outbreak a(h n )v in . this is quite reasonable, since greece is a country with isolated mountainous areas and hundreds of habited islands. initially, for each possible vaccination initiation day, the solution (number of infective individuals) yielded by the fixed strategy scenario where the number of available mobile medical teams is and one team is allocated per district, is compared to the baseline scenario, where no vaccination takes place. all numerical solutions of the model were obtained using r programming language (r core team ) and ms excel and the results are illustrated in table . the fixed strategy scenario outperforms the baseline scenario (the percentage difference of total infective cases ranges from . % to %), even when the minimum number of a single mobile medical team is allocated per ahd, as long as the vaccination starts early (i.e. vaccination initiates until the th day after the beginning of transmission), thus rendering the vaccination necessary. in the case where the vaccination starts days after the beginning of the transmission it seems that the number of infections averted is very small (only cases) compared to a no vaccination policy. this happens due to the fact that the peak of the epidemic takes place around day in most of the districts and any vaccination effort beyond this time window is deemed unnecessary. therefore this vaccination initiation day is not considered when the third and fourth scenarios are examined. for building the third and fourth scenarios it has been considered that the number of mobile medical teams allocated to the ahds is proportional to their population size. more precisely, the smallest sub-population has been used as the main driver for proportionally assigning vaccination units to the rest of the sub-populations ( table ). the smallest sub-population has been assigned a single vaccination unit. the total number of teams in this case is equal to , assuming, of course, that such a capacity will be available for controlling a massive influenza outbreak. this is the "maximum resources" allocation scenario. the rationale behind this comparison (third and fourth scenario) is to find a better way to allocate the same amount of resources while reducing the cumulative number of infected individuals in each district. for each possible vaccination initiation day, the solution (number of infective cases) yielded by the heuristic algorithm is compared to the baseline scenario, (no vaccination) and the maximum resources scenario (constant number of allocated mobile medical teams to each district by using population drivers as seen in table ). the numbers of infected individuals under the three scenarios are presented in table and the mobile medical teams' initial allocation to ahds at a specific allocation day according to the heuristic algorithm implementation is depicted in table . finally, the cumulative infected cases for the three scenarios are depicted in figure . table number of infected persons under the baseline scenario, the maximum resources scenario and the heuristic algorithm solution table mobile medical teams' initial allocation according to the proposed heuristic algorithm the gantt chart in figure illustrates the number of allocated mobile medical teams that dynamically changes and the vaccination completion time for every ahd in the case of applying the heuristic algorithm when the vaccination initiates at day d= . the entire vaccination campaign is completed in days, which is an acceptable limit in order for it to be considered necessary and helpful, taking into account the already mentioned fact that the epidemic peak is around day . data from table suggests that the maximum resources scenario clearly outperforms the baseline (no vaccination) scenario. the percentage difference of total infective cases ranges from . % to . % respectively, increasing when the vaccination campaign initiates earlier. the heuristic algorithm's solution also outperforms the maximum resources scenario where the percentage difference of total infected cases ranges from . % to . % respectively. although this percentage reduction is small, in practice it could be translated into - less deaths per , infective cases averted. from table it is evident that the medical teams' allocation takes place the next day after the vaccination initiates. moreover, when vaccination's initiation is delayed, the number of teams allocated to ahds with larger targeted subpopulations (ahd and predominantly ahd , athens' district) is increased. this was expected, since the marginal benefit (averted infective cases) in these areas when one additional team is allocated is higher than the corresponding loss from allocating one team less in areas with smaller sub-populations, as anticipated if the law of diminishing returns is considered. finally, it has to be explicitly stated here that at least one team is allocated per district during the whole vaccination period, even if the algorithm would yield less infections in the case where no team is allocated. this is due to the fact that no ahd's targeted subpopulation can be left without treatment at any circumstance for social, political and humanitarian reasons (for instance, the vaccination campaign could be politicized or become subject of contention, fair allocation of resources, etc.). in addition, this is the only way for the elderly and/or housebound individuals to actually receive protection against influenza virus (through immunization). therefore, the allocation of just one medical team per district reflects the minimum health care standards provided to this group of people. a mathematical model and a heuristic algorithm have been presented for facilitating in-context evaluation of alternative resource allocation policies when infectious disease outbreak control decisions are to be made. the present study contributes to the body of knowledge by taking into account mobile medical teams scheduling and by allowing the possibility of dynamic re-allocation of resources during the course of the outbreak. to the best of the authors' knowledge this is among the first attempts where the general resource allocation problem is concerned with mobile medical teams scheduling (rachaniotis et al. ). several resource allocation scenarios have been simulated. in particular, a passive (do nothing) 'baseline' and three active responses have been considered. apart from straightforward resource allocation practices (one mobile medical team per district), the effects of proportionally allocating medical teams to each health district based on demographic criteria (populations' size), as proposed in several public health planning guides (hupert et al. ), have also been examined. the results show that the strategy proposed by the heuristic algorithm always outperforms a pro rata resource allocation strategy and significant differences exist with respect to the under the conditions presented, the results could be used to set general a priori guidelines for control actions on certain sub-populations for other infectious disease outbreaks. the results are very sensitive to the assumptions regarding the initiation day of the immunization campaign, i.e. the longer the delay for initiating the vaccination campaign, the worst the performance of all the resource allocation scenarios. this is largely attributable to the fact that the effects of a delayed immunization campaign do not proceed at the pace of the epidemic and, thus, more people become eventually infected. although a resource allocation policy where resources are distributed according to population criteria is presumably the fairest strategy, our results have proven that this does not yield the optimal resources utilization. in fact, the modeling approach presented gives preference to the more populated health districts. unfortunately, the results obtained in this study are not comparable to any other study as the problem of allocating discrete resources (like mobile medical teams) to perform control actions (vaccination) has not been broadly tackled so far. some limitations of the framework presented in this article should be kept in mind. most of them are closely related to the inherent uncertainties surrounding any infectious disease outbreak and especially the dynamics of disease transmission. the sveir model used in this study and its deterministic nature comes with several simplifying assumptions, especially the ones related to disease's transmission rates and vaccine's immunogenicity thresholds. for instance, social networks and contact processes that dictate disease transmission patterns or age-specific differences in the pathogenicity and transmissibility of influenza have not been considered. the usage of an individual-based model would have yielded more accurate results as it would have captured more realistic disease patterns and contact structures among all individuals in the sub-populations. it is worth noting, however, that the inclusion of a large degree of detail and heterogeneity in any epidemiological model comes at a computational cost. compartmental models are more computationally tractable and allow extensive sensitivity analysis (kaplan et al. ). in addition, epidemic models based on free mixing give larger disease outbreaks and from a public health perspective developing tools for the "worst-case" approach might be preferable. the disease progression model used in this study is not extremely complex and it might be unsuitable for guiding the selection of control interventions. however, it has been mainly used for illustrating the applicability of the proposed modeling approach which it is believed to be broadly applicable. apart from the usage of a more detailed disease transmission model, another fruitful area for further research is the utilization of the proposed methodology in combination with non-pharmaceutical intervention for controlling an outbreak. in this case social distancing and travel limitations could be coupled with pharmaceutical interventions (like an immunization campaign). aspects of cost for actually implementing the targeted vaccination campaign could also be considered and particularly how implementation costs scale up with the resource allocation policy provided by the heuristic algorithm. the approach presented could also be used in the case of infectious disease outbreaks in humanitarian emergencies. in particular, the model could be used for allocating mobile medical units to perform immunization campaigns to populations with limited access to healthcare services (due to lack of security). finally, logistical constraints for delivering the targeted vaccination campaign like limited vaccine supply or daily administration constraints and their interaction with the disease process could also be examined. efficient utilization of a set of limited resources is of paramount importance when controlling infectious disease outbreaks. in this paper the problem of allocating several discrete resources (mobile medical teams) for controlling an outbreak has been considered. vaccination of certain groups of the population (incapacitated, house bound, institutionalized etc.) has been the main control action adopted. a real-time synchronous heuristic algorithm has been proposed as the solution methodology. the modeling approach presented could serve as a decision support tool for assisting decision makers in allocating mobile medical teams for infectious disease outbreak control. the proposed methodology has been exemplified in the context of a specific disease outbreak (influenza) in greece and the results are encouraging. a nonhomogeneous agent-based simulation approach to modeling the spread of disease in a pandemic outbreak a delay differential model for pandemic influenza with antiviral treatment transmission parameters of the a/h n ( ) influenza virus pandemic: a review allocating resources to control infectious diseases the nonlinear resource allocation problem individual-based computational modeling of smallpox epidemic control strategies planning for infectious disease outbreaks: a geographic disease spread, clinic location, and resource allocation simulation a 'small-world-like' model for comparing interventions aimed at preventing and rachaniotis et al.: controlling infectious disease outbreaks: a deterministic allocation-scheduling model with multiple discrete resources j syst sci syst eng controlling influenza pandemics transmission dynamics of the great influenza pandemic of in geneva, switzerland: assessing the effects of hypothetical interventions adaptive vaccination strategies to mitigate pandemic influenza: mexico as a case study mitigation measures for pandemic influenza in italy: an individual based model considering different scenarios modeling influenza epidemics and pandemics: insights into the future of swine flu (h n ) modeling the worldwide spread of pandemic influenza: baseline case and containment interventions delaying the international spread of pandemic influenza mitigating effects of vaccination on influenza outbreaks given constraints in stockpile size and daily administration capacity a large-scale simulation model of pandemic influenza outbreaks for development of dynamic mitigation strategies smallpox mass vaccination -an operational planning framework. department of health, scottish government controlling pandemic flu: the value of international air travel restrictions modelling disease outbreaks in realistic urban social networks planning for smallpox outbreaks strategies for containing an emerging influenza pandemic in southeast asia strategies for containing a global influenza pandemic controlling infectious disease outbreaks: a deterministic allocation-scheduling model with multiple discrete resources evaluation of targeted influenza vaccination strategies via population modeling comparison of smallpox outbreak control strategies using a spatial metapopulation model optimal control of epidemics with limited resources the mathematics of infectious diseases mitigation strategies for pandemic influenza a: balancing conflicting policy objectives resource allocation problems: algorithmic approaches emergency response to a smallpox attack: the case for mass vaccination analyzing bioterror response logistics: the case of smallpox optimal resource allocation model to mitigate the impact of pandemic influenza: a case study for turkey health service resource needs for pandemic influenza in developing countries: a linked transmission dynamics, interventions and resource demand model a computer simulation of vaccine prioritization, allocation, and rationing during the h n influenza pandemic modeling optimal age-specific vaccination strategies against pandemic influenza controlling infectious disease outbreaks: a deterministic allocation-scheduling model with multiple discrete resources optimal vaccine allocation for the early mitigation of pandemic influenza optimizing vaccine allocation at different points in time during an epidemic resource allocation for epidemic control in metapopulations optimizing influenza vaccine distribution optimizing allocation for a delayed influenza vaccination campaign discrete resource allocation by a branch and bound method optimal allocation of pandemic influenza vaccine depends on age, risk and timing the effective reproduction number as a prelude to statistical estimation of time-dependent epidemic trends distribution of influenza vaccine to high-risk groups decreasing values: the case of forest fires r: a language and environment for statistical computing. r foundation for statistical computing a deterministic resource scheduling model in epidemic control: a case study transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions a numerical study on an influenza epidemic model with vaccination and diffusion controlling infectious disease outbreaks: a deterministic allocation-scheduling model with multiple discrete resources uncertainty and sensitivity analysis of the basic reproduction number of a vaccinated epidemic model of influenza economic evaluation of influenza pandemic mitigation strategies in the united states using a stochastic microsimulation transmission model a new application of incremental analysis in resource allocations branch and bound procedure for a class of discrete resource allocation problems with several constraints preparedness: the asiaflucap simulator optimal pandemic influenza vaccine allocation strategies for the canadian population a predictive decision-aid methodology for dynamic mitigation of influenza pandemics optimizing infectious disease interventions during an emerging epidemic pandemic influenza a(h n ) breakthrough infections and estimates of vaccine effectiveness in germany dynamic health policies for controlling the spread of emerging infections: influenza as an example analysis of cdc social control measures using an agent-based simulation of an influenza epidemic in a city optimal two-phase vaccine allocation to geographically different we would like to thank the two anonymous referees for their help to improve the quality of this paper.