key: cord-0046187-rtus0sx3
authors: Offit, Paul A.; Davis, Robert L.; Gust, Deborah
title: Vaccine safety
date: 2020-06-22
journal: Vaccines
DOI: 10.1016/b978-1-4160-3611-1.50078-7
sha: 08d5f26903ee5476d3012cc33b926d71af197d19
doc_id: 46187
cord_uid: rtus0sx3

nan

Because vaccines are given to healthy children and adults, a higher standard of safety is generally expected of immunizations compared with other medical interventions. Tolerance of adverse reactions to pharmaceutical products (e.g., vaccines, contraceptives) given to healthy people-especially healthy infants and toddlers-to prevent certain conditions is substantially lower than to products (e.g., antibiotics, insulin) to treat people who are sick. 25 This lower tolerance for risks from vaccines translates into a need to investigate the possible causes of much rarer adverse events after vaccinations than would be acceptable for other pharmaceutical products. For example, side effects are essentially universal for cancer chemotherapy, and 10 to 30% of people on high-dose aspirin therapy experience gastrointestinal symptoms. 26 Safety monitoring can be carried out both before and after vaccine licensure, with slightly different goals based on the methodologic strengths and weaknesses of each step. Although the general principles are similar irrespective of each country, the specifi c approaches may differ because of factors such as how immunization services are organized and the level of resources available. 27 

Vaccines, similar to other pharmaceutical products, undergo extensive safety and effi cacy evaluations in the laboratory, in animals, and in phased human clinical trials before licensure. 28, 29 Phase I trials usually include fewer than 20 participants and can detect only extremely common adverse events. Phase II trials generally enroll 50 to several hundred people. When carefully coordinated, as in the comparative infant diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine trials, 30 important insight into the relationship between concentration of antigen, number of vaccine components, formulation, effect of successive doses, and profi le of common reactions can be drawn and can affect the choice of the candidate vaccines for Phase III trials. 31, 32 Sample sizes for Phase III vaccine trials are based principally on effi cacy considerations, with safety inferences drawn to the extent possible based on the sample size (approximately 10 2 to 10 5 ) and the duration of observation (often <30 days). 31 Typically only observations of common local and systemic reactions (e.g., injection site swelling, fever, fussiness) have been feasible. The experimental design of most Phase I to III clinical trials includes 1) a control group (either a placebo or an alternative vaccine) and 2) detection of adverse events by researchers in a consistent manner 'blinded' to which vaccine Paul A. Offi t Robert L. Davis Deborah Gust

During the past 100 years, pharmaceutical companies have made vaccines against pertussis, polio, measles, rubella, and Haemophilus infl uenzae type B (Hib), among others (Table 74-1) .

As a consequence, the number of children in the United States killed by pertussis decreased from 8,000 each year in the early twentieth century to less than 20; the number paralyzed by polio from 15,000 to 0; the number killed by measles from 3,000 to 0; the number with severe birth defects caused by rubella from 20,000 to 0; and the number with meningitis and bloodstream infections caused by Hib from 25,000 to less than 300. Vaccines have been among the most powerful forces in determining how long we live. 1 But the landscape of vaccines is also littered with tragedy: In the late 1800s, starting with Louis Pasteur, scientists made rabies vaccines using cells from nervous tissue (such as animal brains and spinal cords); the vaccine prevented a uniformly fatal infection. But the rabies vaccine also caused seizures, paralysis, and coma in as many as 1 of every 230 people who used it. [2] [3] [4] [5] In 1942, the military injected hundreds of thousands of American servicemen with a yellow fever vaccine. To stabilize the vaccine virus, scientists added human serum. Unfortunately, some of the serum came from people unknowingly infected with hepatitis B virus. As a consequence, 330,000 soldiers were infected, 50,000 developed severe hepatitis and 62 died. [6] [7] [8] [9] In 1955, fi ve companies made Jonas Salk's new formaldehydeinactivated polio vaccine. However, one company, Cutter Laboratories of Berkeley, California, failed to completely inactivate poliovirus with formaldehyde. Because of this problem, 120,000 children were inadvertently injected with live, dangerous poliovirus; 40,000 developed mild polio, 200 were permanently paralyzed and 10 were killed. It was one of the worst biological disasters in American history. 10 Vaccines have also caused uncommon, but severe adverse events not associated with production errors. For example, acute encephalopathy after whole-cell pertussis vaccine, 11, 12 acute arthropathy following rubella vaccine, [13] [14] [15] [16] [17] thrombocytopenia following measles-containing vaccine, 18, 19 Guillain-Barré syndrome (GBS) after swine fl u vaccine, 20 paralytic polio following live, attenuated oral polio vaccine (OPV), 21 anaphylaxis following receipt of vaccines containing egg proteins (i.e., infl uenza and yellow fever vaccines) 22, 23 or gelatin (i.e., MMR and varicella vaccines) 24 are problems that are associated with the use of vaccines, albeit rarely. As vaccine usage increases, and the incidence of vaccine vaccine-preventable diseases is reduced, vaccinerelated adverse events become more frequent and prominent ( Fig. 74-1) . the patient received. This allows relatively straightforward inferences on the causal relationship between most adverse events and vaccination. 33 Several ways of enhancing pre-licensure safety assessment of vaccines have been developed. One of these ways includes the Brighton Collaboration (www.brightoncollaboration.org), established to develop and implement globally accepted standard case defi nitions for assessing adverse events following immunizations in both pre-and post-licensure settings. 34 Without such standards, it was diffi cult if not impossible to compare and collate safety data across trials in a valid manner. For example, in the large multi-site Phase III infant DTaP trials, defi nitions of high fever across trials varied by temperature (39.5ºC vs. 40 .5ºC), measurement (oral vs. rectal), and time (measured at 48 vs. 72 hours). 35 This was unfortunate because standardized case defi nitions had been developed in these trials for effi cacy but not for safety, even though the safety concerns provided the original impetus for the development of DTaP. 36, 37 The Brighton case defi nitions for each adverse event are further arrayed by the level of evidence provided (insuffi cient, low, intermediate, and highest); therefore, they also can be used in settings with less resources (e.g., studies in less developed settings or post-licensure surveillance).

Another of the recent advances to pre-licensure safety assessments of vaccines has stemmed from the recognition of the need for much larger safety and effi cacy trials before licensure. Because of pragmatic limits on the sample sizes of pre-licensure studies, there are inherent limitations to the extent to which they can detect very rare, yet real, adverse events related to vaccination. Even if no adverse event has been observed in a trial of 10,000 vaccinees, one can only be reasonably certain that the real incidence of the adverse event is no higher than 1 in 3,333 vaccinees. 38 Thus to be able to detect an attributable risk of 1 per 10,000 vaccinees (e.g., such as the approximate risk found for intussusception in the post-licensure evaluation of RotaShield vaccine), a pre-licensure trial of at least 30,000 vaccinees and 30,000 controls is needed. Both second generation rotavirus vaccines (RotaTeq and RotaRix) were subjected to Phase III trials that included at least 60,000 infants. 39, 40 While these trials were adequately powered to detect the problem with intussusception found following RotaShield, in general, the cost of such large trials might limit the number of vaccine candidates that go through this process in the future. 41 Nevertheless, given the need to appreciate better the safety of vaccines administered universally to healthy infants in a timely manner, there has been a call for larger studies to assess vaccine risks. This could be done either with larger pre-licensure trials, as has been done for RotaTeq and RotaRix in children, or in some organized manner post-licensure prior to scale-up to universal recommendations (e.g., rapidly and routinely performed active surveillance analysis using large-linked databases such as the Vaccine Safety DataLink). 42 Even with these measures, separate large-scale, long-term, randomized intervention trials would theoretically be the only way to study unforeseen delayed adverse effects, 42 for example, as seen with killed or high-titer measles vaccines. 43, 44 Therefore, a more likely way forward probably lies in maximizing the existing prelicensure assessment process and the post-licensure infrastructure for monitoring. Post-licensure evaluations of vaccine safety Because rare reactions, reactions with delayed onset, or reactions in subpopulations may not be detected before vaccines are licensed, post-licensure evaluation of vaccine safety is critical. Historically, this evaluation has relied on passive surveillance and ad hoc epidemiologic studies, but, more recently, Phase IV trials and pre-established large linked databases (LLDBs) have improved the methodologic capabilities to study rare risks of specifi c immunizations. 45 Such systems may detect variation in rates of adverse events by manufacturer 46, 47 or specifi c lot. 48 More recently, clinical centers for the study of immunization safety have emerged as another useful infrastructure to advance our knowledge about safety. 49 In contrast to the elegance of pre-licensure randomized trials, however, post-licensure observational studies of vaccine safety pose a formidable set of methodologic diffi culties. 50 Confounding by contraindication is especially problematic for nonexperimental designs. Specifi cally, individuals who do not receive vaccine (e.g., because of a chronic or transient medical contraindication or low socioeconomic group) may have a different risk for an adverse event than vaccinated individuals (e.g., background rates of seizures or sudden infant death syndrome may be higher in the unvaccinated). Therefore, direct comparisons of vaccinated and unvaccinated children is often inherently confounded and teasing this issue out requires understanding of the complex interactions of multiple, poorly quantifi ed factors.

Informal or formal passive surveillance or spontaneous reporting systems (SRSs) have been the cornerstone of most postlicensure safety monitoring systems because of their relative low cost of operations. [51] [52] [53] The national reporting of adverse events following immunizations can be done through the same reporting channels as those used for other adverse drug reactions, 53 as is the practice in France, 54 Japan, 55 New Zealand, 56 Sweden, 57 and the United Kingdom, 58 or with reporting forms or surveillance systems different from the drug safety monitoring systems, as done by Australia, 59 Canada, 60, 61 Cuba, 62 Denmark, 63 India, 64 Italy, 65 Germany, 66 Mexico, 67 the Netherlands, 68 Brazil 69 and the United States. 70 Vaccine manufacturers also maintain SRSs for their products, which are usually forwarded subsequently to appropriate national regulatory authorities. 28, 67 In the United States, the National Childhood Vaccine Injury Act (NCVIA) of 1986 mandated for the fi rst time that health care providers report certain adverse events after immunizations. 71 The Vaccine Adverse Events Reporting System (VAERS) was implemented jointly by the Centers for Disease Control and Prevention (CDC) and the FDA in 1990 to provide a unifi ed national focus for collection of all reports of clinically signifi cant adverse events, including, but not limited to, those mandated for reporting, 70 replacing its predecessors. 72 The VAERS form permits narrative descriptions of adverse events ( Fig. 74-2 ). Patients and their parents-not just health care professionals-are permitted to report to the VAERS, and there is no restriction on the interval between vaccination and symptoms that can be reported. Annual reminders about VAERS are mailed to physicians likely to administer vaccines. The form is pre-addressed and postage paid so that, after completion, it can be folded and mailed. Report forms, assistance in completing the form, or answers to other questions about the VAERS are available by calling a 24-hour toll-free telephone number (1-800-822-7967). Beginning in 2002, web-based reporting and simple data analyses were also available (www. vaers.org).

A contractor, under CDC and FDA supervision, distributes, collects, codes (currently using the Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) 73 ), and enters VAERS reports in a database. Reporters of selected serious events receive medical follow-up from trained nurses at 60 days after vaccination and one year after vaccination in order to provide additional information about the VAERS report, including the patient's recovery. Both CDC and FDA have online access to the VAERS database and focus their efforts on analytic tasks of interest to the respective agencies. Approximately 13,000 VAERS reports are now received annually and these data (without personal identifi ers) are also available to the public.

Several other countries also have substantial experience with passive surveillance for immunization safety. In 1987, Canada developed the Vaccine Associated Adverse Event (VAAE) reporting system, 61, 74 which is supplemented by an active, pediatric hospital-based surveillance system that searches all admissions for possible relationships to immunizations (Immunization Monitoring Program-Active [IMPACT]). 75 Serious VAAE reports are reviewed by an Advisory Committee on Causality Assessment consisting of a panel of experts. 76 The Netherlands also convenes an annual panel to categorize their reports, that are then published. 68 The United Kingdom and most members of the former Commonwealth use the yellow card system, whereby a reporting form is attached to offi cially issued prescription pads. 52 77 With so many different passive surveillance systems that collect information on various medical events following vaccination, standardized defi nitions of vaccine-related adverse events are necessary. In the past, different defi nitions were developed in Brazil, 69 Canada, 61 India 64 and the Netherlands. 68 However, real progress in implementation of similar standards across national boundaries is only beginning to be realized with the advent of the International Conference on Harmonization 78 and the Brighton Collaboration. 34 VAERS often fi rst identifi es potential new vaccine safety problems because of clusters of unusual clinical features in time or space. For example, Gullian-Barré syndrome (GBS), a rare but serious neurological disease, was the only illness reported more commonly in the second and third week than in the fi rst week after swine infl uenza vaccination in 1976. This unusual fi nding led to the initiation of special validation studies that confi rmed an increased risk for GBS following infl uenza vaccination. 20, 79 Later, in 1999, passive reports to the VAERS of intussusception among children vaccinated with RotaShield was the fi rst post-licensure signal of a problem, 80 leading to several studies that verifi ed these fi ndings. 81, 82 Further analysis of adverse events following RotaShield that were reported to the VAERS suggested that intussusception might have been the tip of an iceberg, and that other gastrointestinal problems (notably bloody stool, vomiting, diarrhea, abdominal pain and gastroenteritis) might also have been increased following vaccination. 83 Similarly, initial reports to the VAERS of a previously unrecognized serious yellow fever vaccine-associated neurotropic disease 84 and viscerotropic disease 85, 86 have since been confi rmed elsewhere. 87 Because of the success in detecting these signals, there have been various attempts to automate screening for signals using SRSs reports. New tools developed for pattern recognition in extremely large databases are beginning to be applied. 88 Several lessons are beginning to emerge from VAERS. 89-91 VAERS has successfully detected unrecognized potential reactions and obtained data to evaluate whether these events are causally linked to vaccines. 92 VAERS has also successfully served as a source of cases for further investigation of idiopathic thrombocytopenic purpura after measles-mumps-rubella (MMR) vaccine, 93 encephalopathy after MMR, 61, 94 and syncope after immunization. 95 The VAERS has been of great value for answering routine public queries (e.g., Has adverse event X ever been reported after vaccine Y?). When denominator data on doses are available from other sources, the VAERS can be used to evaluate changes in reporting rates over time or when new vaccines replace old vaccines. For example, VAERS showed that, after millions of doses had been distributed, reporting rates for serious events such as hospitalization and seizures after DTaP in toddlers were one third those after diphtheria and tetanus toxoids and whole-cell pertussis (DTP). 96 Because VAERS is the only surveillance system covering the entire U.S. population with data available on a relatively timely basis, it is the major means available currently to detect possible new, unusual, or extremely rare adverse events. 89 The reporting effi ciency or sensitivity of SRSs can be estimated if expected rates of adverse events generated from carefully executed studies are available. A higher proportion of serious events, such as seizures, that follow vaccinations are likely to be reported to the VAERS than milder events, such as rash, or delayed events requiring laboratory assessment, such as thrombocytopenic purpura after MMR vaccination. 97 The estimate of VAERS reporting completeness for intussusception using capture-recapture methods was 47%. 98 Although formal evaluation has been limited, the probability that a serious event reported to the VAERS has been diagnosed accurately is likely to be high. Of 26 patients reported to VAERS who developed GBS after infl uenza vaccination during the 1990 to 1991 season, and whose hospital charts were reviewed by an independent panel of neurologists blinded to immunization status, the diagnosis of GBS was confi rmed in 22 (85%). 99 Despite the aforementioned uses, SRSs for drug and vaccine safety have a number of major methodologic weaknesses. Under-reporting, biased reporting, and incomplete reporting are inherent to all such systems, and potential safety concerns may be missed. 97, 100, 101 Aseptic meningitis associated with the Urabe mumps vaccine strain, for example, was not detected by SRSs in most countries. 102, 103 Some increases in adverse events detected by the VAERS may not be true increases, but instead may be due to increases in reporting effi ciency or vaccine coverage. For example, an increase in GBS reports after infl uenza vaccination during the 1993 to 1994 season was found to be largely due to improvements in vaccine coverage and increases in GBS independent of vaccination. 104 An increased reporting rate of an adverse event after one hepatitis B vaccine compared with a second brand was likely due to differential distribution of brands in the public versus private sectors, which have differential VAERS reporting rates (higher in the public sector). 105 Finally, there was probably no greater threat to the ability of VAERS to generate useful information than the recent realization that a large percentage of reports claiming that vaccines caused autism were made related to pending litigation. 106 Perhaps the most important methodologic weakness of the VAERS, however, is that such signals do not contain the information necessary for formal epidemiologic analyses. Such analyses require calculation of the rate of the adverse events after vaccination (a/[a + b]) using VAERS case reports for the numerator and, if available, doses of vaccines administered (or, if unavailable, data on vaccine doses distributed or vaccine coverage survey data) for the denominator (Table 74 -2). These rates are compared with the background rate of the same adverse event in the absence of vaccination if available (c/[c + d]). Because VAERS databases provide data only for cell 'a' in Table 74 -2, and, even then, only in a biased and underreported manner, they fundamentally lack the data in the other three cells needed to calculate rates and 1) generate accurate signals of potential vaccine safety problems or 2) make a rigorous epidemiologic assessment of the role of vaccine in causation.

These studies highlight the often crude nature of signals generated by VAERS, and the diffi culty in ascertaining which vaccine safety concerns warrant further investigation. The problems with reporting effi ciency and potentially biased reporting, and the inherent lack of an adequate control group, limit the certainty with which conclusions can be drawn. Recognition of these limitations in large part has helped stimulate the creation of more population-based methods of ascertaining vaccine safety.

Vaccines may undergo clinical trials after licensure to assess the effects of changes in vaccine formulation, 107 vaccine strain, 108 age at vaccination, 109 number and timing of vaccine doses, 110 simultaneous administration 111 and interchangeability of vaccines from different manufacturers on vaccine safety and immunogenicity. 112 Unanticipated differential mortality among recipients of high-and regular-titered measles vaccine in developing countries 44 (albeit lower than among unvaccinated children) 113 led to a change in recommendations by the WHO for the use of such vaccines. 114 To improve the ability to detect adverse events that are not detected during pre-licensure trials, some recently licensed vaccines in developed countries have undergone formal Phase IV surveillance studies on populations with sample sizes that have included as many as 100,000 people. These studies usually have used cohorts in health maintenance organizations (HMOs) supplemented by diary or phone interviews. These methods were fi rst used extensively after the licensure of polysaccharide and conjugated Haemophilus infl uenzae type b vaccines. [115] [116] [117] Post-licensure studies on safety and effi cacy of infant DTaP are also continuing. 36 Extensive Phase IV evaluation of varicella vaccine includes multiyear evaluation for disease incidence and for herpes zoster, and a pregnancy registry. 118, 119 Requirements for Phase IV evaluation have even been extended to less frequently used vaccines, such as Japanese encephalitis vaccine. 120 Large linked databases, including the Vaccine Safety Datalink (VSD) project Historically, ad hoc epidemiologic studies have been employed to assess signals of potential adverse events detected by SRSs, the medical literature, or other mechanisms. Some examples of such studies include the investigations of poliomyelitis after inactivated 10, 121 and oral 122 polio vaccines, sudden infant death syndrome after DTP vaccination, 123-126 encephalopathy after DTP vaccination, 127,128 meningoencephalitis after mumps vaccination, 129 injection site abscesses post-vaccination, 130 and Gullian-Barré syndrome after infl uenza vaccination. 20, 99, 104 The IOM has compiled and reviewed many of these studies. 11, 131 Unfortunately, such ad hoc studies are often costly, time consuming, and limited to assessment of a single event or a No c d few events or outcomes. Given these drawbacks, and the methodologic limitations of passive surveillance systems (such as described for VAERS), pharmacoepidemiologists began to turn to large databases linking computerized pharmacy prescription (and later immunization) and medical outcome records. 101 These databases derive from defi ned populations such as members of HMOs, single-provider health care systems, and Medicaid programs. Such databases cover enrollee populations numbering from thousands to millions, good for examining relatively infrequent adverse events, and, because the data are generated from the routine administration of the full range of medical care, under-reporting and recall bias are reduced. With denominator data on doses administered and the ready availability of appropriate comparison (i.e., unvaccinated) groups, these large databases provide an economical and rapid means of conducting post-licensure studies of safety of drugs and vaccines. 102, [132] [133] [134] [135] The CDC participated in two pilot vaccine safety studies using large-linked databases in Medicaid and HMO populations during the late 1980s. 136, 137 These projects validated this approach for vaccine safety studies and provided scientifi cally rigorous results but were limited by relatively small sample sizes, retrospective design, and a focus on the most severe reactions after vaccination. 11 To overcome these limitations, the CDC initiated the VSD project in 1990, 132 with the goal of gathering vaccination, medical outcome (e.g., hospital discharge, outpatient visits, emergency department visits, and deaths), and covariate (e.g., birth certifi cates, census) data under joint protocol at multiple HMOs. Selection of staff-model prepaid health plans also minimized potential biases for more severe outcomes resulting from data generated from fee-for-service claims. Originally, the VSD project conducted active surveillance on approximately 500,000 children from birth through 6 years of age (with a birth cohort of 75,000, approximately 2% of the U.S. population in this age group), 132 but it expanded in 1999 to include seven HMOs (covering eight different health plans), with three HMOs also contributing information on adolescents and adults and now covers about 3% of the population. 135 Proposals for studies are initiated by scientists at the CDC or at the participating HMOs, and study protocols are reviewed and critiqued using a standardized process. There is rigorous attention to the maintenance of patient confi dentiality, and each study undergoes Institutional Review Board review.

The VSD project focused its initial efforts on examining potential associations between immunizations and a series of serious neurologic, allergic, hematologic, infectious, infl ammatory and metabolic conditions. However, the VSD project also is being used to test new ad hoc vaccine safety concerns that may arise from the medical literature, 11, 131 from VAERS, 82, 105 from changes in immunization schedules, 138 or from introduction of new vaccines. 116, 117 The size of the VSD population also permits separation of the risks associated with individual vaccines from those associated with vaccine combinations, whether given in the same syringe or simultaneously at different body sites. Such studies are especially valuable in view of combined pediatric vaccines. 139 More than 130 studies have been or are being performed within the VSD project, 135 including general screening studies of the safety of inactivated infl uenza vaccines among children, and of thimerosal-containing vaccines. Disease-or syndromespecifi c investigations either have been or are being performed, including ones investigating autism, multiple sclerosis, thyroid disease, acute ataxia, alopecia, rheumatoid arthritis, asthma, diabetes and idiopathic thrombocytopenic purpura following vaccination. In addition, the infrastructure created by the VSD project easily lends itself to a wide range of other vaccinerelated studies beyond those for safety. 132, 135 Amid these promises, a few caveats are appropriate. Although diverse, the population in the HMOs currently in the VSD project is not wholly representative of the United States in terms of geography or socioeconomic status. More importantly, because of the high coverage attained in the HMOs for most vaccines, few non-vaccinated controls are available. The VSD project must therefore rely primarily on risk-interval analyses (e.g., to study the question of whether outcome 'x' is more common in time period 'y' following vaccination compared with other time periods) (Table 74-3) . 136, 140 This approach has limited ability to assess associations between vaccination and adverse events with delayed or insidious onset (e.g., autism). The VSD project also cannot easily assess mild adverse events (such as fever) that do not always come to medical attention. 132 The current VSD project is also not large enough to examine the 2. Partition observation time for each child in the study into periods within and outside of risk intervals, and sum respectively (e.g., for a child observed for 365 days during which 3 doses of vaccine were received, total risk interval time = 3 × 30 person-days = 90 person-days; total non-risk interval time = 365 − 90 = 275 person-days). risk of extremely rare events, such as GBS, after each season's infl uenza vaccine. Finally, because vaccines are not delivered in the context of randomized, controlled trials, the VSD project may not be able to successfully control for confounding and bias in each analysis, 141 and inferences on causality may be limited. 142 Despite these potential shortcomings, the VSD project provides an essential, powerful, and cost-effective complement to ongoing evaluations of vaccine safety in the United States. 134, 135 In view of the methodologic and logistic advantages offered by large linked databases, the United Kingdom and Canada also have developed systems linking immunization registries with medical fi les. 75, 102 Because of the relatively limited number of vaccines used worldwide and the costs associated with establishing and operating these large databases, it is unlikely that all countries will be able to or need to establish their own. These countries should be able to draw on the scientifi c base established by the existing large-linked databases for vaccine safety and, if the need arises, conduct ad hoc epidemiologic studies.

More recently, there has been an increasing awareness that the utility of SRSs as potential disease registries and the immunization safety infrastructure can be usefully augmented by tertiary clinical centers. With the exception of certain regions in Italy 143 and Australia, 144,145 a similar well-organized, well-identifi ed subspecialty infrastructure has been missing for the study of rare vaccine safety outcomes in most countries.

The United States created its Clinical Immunization Safety Assessment (CISA) network with four sites in 2001, bringing together infectious disease epidemiologists, immunologists, dermatologists, and other subspecialists as needed. 49 Among their tasks will be the standardized assessment of persons who suffered a true vaccine reaction (e.g., anaphylaxis, intussusception) to improve our scientifi c understanding of the pathophysiology and risk factors of the reaction. Because most persons are vaccinated without such complications, those who suffer such reactions are clearly outliers in a biologic gaussian spectrum. New understanding of the human genome, pharmacogenomics, and immunology may now make it possible for us to truly understand the reaction and to study the safest means of revaccination when indicated. 146 For patients who had an adverse event that is not contraindicating but generates enough concern to interfere with completion of the series, the CISA centers can provide assessment and management under protocols, as was done with hypotonic-hyporesponsive episodes. 144 Some of the studies undertaken by CISA and underway include an assessment of extensive limb swelling after DTaP, a study of the usefulness of irritant skin test reactions for managing hypersensitivity to vaccines, a study of the safety of vaccinating patients with DiGeorge syndrome, an assessment of patients with Guillan-Barré syndrome after conjugate meningococcal vaccination, and the clinical evaluation of patients with serious adverse events following yellow fever vaccine administration.

Unfortunately, vaccine safety issues have increasingly taken on a life of their own outside of the scientifi c arena-arguably to society's overall detriment. Liability concerns, for example, have severely limited development of maternal immunizations against diseases such as group B streptococcus. 147 More worrisome, however, are various chronic diseases (and their advocates) in search of a simple cause, for which immunizations-as a relatively universal exposure-make all too convenient a hypothesized link. Case studies of some of these fears are discussed in the following sections.

In 1974, Kulenkampff and coworkers 148 published a series of 22 cases of children with mental retardation and epilepsy following receipt of the whole-cell pertussis vaccine. During the next several years, fear of the pertussis vaccine generated by media coverage of this report caused a decrease in pertussisimmunization rates in British children from 81 to 31% and resulted in more than 100,000 cases and 36 deaths from pertussis. 149 Media coverage of the Kulenkampff report also caused decreased immunization rates and increased pertussis deaths in Japan, Sweden and Wales. 149 However, many subsequent excellent well-controlled studies found that the incidence of mental retardation and epilepsy following whole-cell pertussis vaccine was similar in children who did not receive the vaccine. [150] [151] [152] [153] [154] [155] [156] Vaccines cause mad-cow disease By July 2000 at least 73 people in the United Kingdom developed a progressive neurological disease termed variant Creutzfeld-Jakob disease (vCJD) that likely resulted from eating meat prepared from cows with 'mad-cow' disease; a disease caused by proteinaceous infectious particles (prions). Some vaccines were made with serum or gelatin obtained from cows in England or from countries at risk for 'mad-cow' disease.

Two products obtained from cows may be present in vaccines: trace quantities of fetal bovine serum used to provide growth factors for cell culture and gelatin used to stabilize vaccines. However, the bovine-derived products used in vaccines are not likely to contain prions for several reasons. 157 First, fetal bovine serum and gelatin are obtained from blood and connective tissue respectively; neither are sources that have been found to contain prions. Second, fetal bovine serum is highly diluted and eventually removed from cells during the growth of vaccine viruses. Third, prions are propagated in mammalian brains and not in cell culture used to make vaccines. Fourth, transmission of prions occurs from either eating brains from infected animals or, in experimental studies, from directly inoculating preparations of brains from infected animals into the brains of experimental animals. Transmission of prions has not been documented after inoculation into the muscles or under the skin (routes used to vaccinate). Taken together, the chance that currently licensed vaccines contain prions is essentially zero.

The notion that the origin of AIDS could be traced to poliovirus vaccines that were administered in the Belgian Congo between 1957 and 1960 was the subject of a popular magazine article 158 and book. 159 The logic behind this assertion was as follows: 1) All poliovirus vaccines were grown in monkey kidney cells; 2) monkey kidney cells used at that time contained simian immunodefi ciency virus (SIV); 3) SIV is very closely related to HIV; 4) people were inadvertently inoculated with SIV that then mutated to HIV and caused the AIDS epidemic.

This reasoning is problematic and based on several false assumptions. [160] [161] [162] [163] First, SIV is not found in monkey kidney cells. Second, monkey, not chimpanzee, kidney cells were used to grow the polio vaccines used in Africa in the late 1950s. Third, SIV and HIV are not very close genetically; mutation to HIV from SIV would likely require decades, not years. Fourth, both SIV and HIV are enveloped viruses that are easily disrupted by extremes in pH. If given by mouth (in a manner similar to the oral polio vaccine), both of these viruses would likely be destroyed in the acid environment of the stomach. Last, and most important, original lots of the polio vaccine (including those used in Africa for the polio vaccine trials) did not contain either HIV or SIV genomes as determined by the very sensitive reverse-transcription polymerase chain reaction (RT-PCR) assay. Unfortunately, the notion that live attenuated polio vaccine could cause AIDS remains an obstacle to eliminating polio in some countries in Africa.

Simian virus 40 (SV40) was present in monkey kidney cells used to make the inactivated polio vaccine, live, attenuated polio vaccine, and inactivated adenovirus vaccines in the late 1950s and early 1960s. Recently, investigators found SV40 DNA in biopsy specimens obtained from patients with certain unusual cancers (i.e., mesothelioma, osteosarcoma and non-Hodgkins lymphoma), leading some to hypothesize a link between vaccination and the subsequent development of cancer. 164 However, genetic remnants of SV40 were present in cancers of people who either had or had not received contaminated polio vaccines; people with cancers who never received SV40-contaminated vaccines were found to have evidence for SV40 in their cancerous cells; and epidemiologic studies did not show an increased risk of cancers in those who received polio vaccine between 1955 and 1963 and those who did not receive these vaccines. 164 Taken together, these fi ndings do not support the hypothesis that SV40 virus contained in polio vaccines administered before 1963 caused cancers.

One hundred years ago, children received one vaccine-smallpox. Today children receive 14 vaccines routinely. Although some vaccines are given in combination, infants and young children could receive more than 20 shots and three oral doses by 2 years of age, including as many as fi ve shots at one time. The increase in the number of vaccines, and the consequent decline in vaccine-preventable illnesses, has focused attention by both parents and health care professionals on vaccine safety. Specifi c concerns include whether vaccines weaken, overwhelm, 165 or in some way alter the normal balance of the immune system, paving the way for chronic diseases such as diabetes, asthma, multiple sclerosis, or allergies.

Although we have witnessed a dramatic increase in the number of vaccines routinely recommended for infants and young children, the number of immunogenic proteins and polysaccharides contained in vaccines has declined (Table . The decrease in the number of immunogenic proteins and polysaccharides contained in vaccines is attributable to 1) discontinuation of the smallpox vaccine and 2) advances in the fi eld of protein purifi cation that allowed for a switch from whole-cell to acellular pertussis vaccine.

A practical way to determine the capacity of the immune system to respond to vaccines would be to consider the number of B and T cells required to generate adequate levels of binding antibodies per milliliter of blood. 166 Calculations are based on the following assumptions:

1 Approximately 10 ng/mL is likely to be an effective concentration of antibody directed against a specifi c epitope. 2 Approximately 10 3 B cells/mL are required to generate 10 ng of antibody/mL. fi rst detected about 7 days after immunization, those responses could initially be generated from a single Bcell clone per milliliter. 5 One vaccine contains about 10 immunogenic proteins or polysaccharides (see Table 74 -4). 6 Each immunogenic protein or polysaccharide contains about 10 epitopes (i.e., 10 2 epitopes per vaccine). 7 Approximately 10 7 B cells are present per milliliter of blood.

Given these assumptions, the number of vaccines to which an individual could respond would be determined by dividing the number of circulating B cells (∼10 7 ) by the average number of epitopes per vaccine (10 2 ). Therefore, an individual could theoretically respond to about 10 5 vaccines at one time.

The analysis used to determine the theoretical capacity of an individual to respond to as many as 10 5 vaccines at one time, although consistent with the biology and kinetics of vaccine- specifi c immune responses, is limited by lack of consideration of several factors. First, only vaccine-specifi c B-cell responses are considered. However, protection against disease by vaccines may also be mediated by vaccine-specifi c cytotoxic T lymphocytes (CTLs). For example, virus-specifi c CTLs are important in the regulation and control of varicella infections. 167 Second, in part because of differences in the capacity of various class I or class II glycoproteins (encoded by the major histocompatibility complex [MHC]) to present viral or bacterial peptides to the immune system, some individuals are not capable of responding to certain virus-specifi c proteins (e.g., hepatitis B surface antigen). 168 Third, some proteins are more likely to evoke an immune response than others (i.e., immunodominance). Fourth, although most circulating B cells in the neonate are naïve, the child very quickly develops memory B cells that are not available for response to new antigens and, therefore, should not be considered as part of the circulating naïve B-cell pool. Fifth, the immune system is not static. A study of T-cell population dynamics in human immunodefi ciency virus (HIV)-infected individuals found that adults have the capacity to generate about 2 × 10 9 new T lymphocytes each day. 169 Although the quantity of new B and T cells generated each day in healthy individuals is unknown, studies of HIV-infected persons demonstrate the enormous capacity of the immune system to generate lymphocytes when needed. For this reason, the assessment that individuals can respond to at least 10 5 vaccines at one time might be low.

Within hours of birth, cells of the innate and adaptive immune system are actively engaged in responding to challenges in the environment (e.g., colonizing bacterial fl ora). 170, 171 Similarly, newborn and young infants are quite capable of generating protective immune responses to single and multiple vaccines. For example, children born to mothers infected with hepatitis B virus are protected against infection after inoculation with hepatitis B vaccine (given at birth and 1 month of age). [172] [173] [174] Similarly, newborns inoculated with Bacille Calmette-Guérin (BCG) vaccine are protected against severe forms of tuberculosis presumably by activation of bacteria-specifi c T cells. [175] [176] [177] In addition, about 90 to 95% of infants inoculated in the fi rst 6 months of life with multiple vaccines, including diphtheria-tetanuspertussis, pneumococcus, Haemophilus infl uenzae type b, hepatitis B and polio, develop protective, vaccine-specifi c immune responses. 178 Conjugation of bacterial polysaccharides (such as S. pneumoniae and H. infl uenzae type b) to carrier molecules that elicit helper T cells circumvents the poor immunogenicity of unconjugated polysaccharide vaccines in infants and young children. 179, 180 Vaccines weaken the immune system Infection with wild-type viruses can cause a suppression of specifi c immunologic functions. For example, infection with wild-type measles virus causes a reduction in the number of circulating B and T cells during the viremic phase of infection, and a delay in the development of cell-mediated immunity. 181, 182 Down-regulation of cell-mediated immunity by wild-type measles virus probably results from down-regulation of the production of IL-12 by measles-infected macrophages and dendritic cells. 181 Taken together, the immunosuppressive effects of wild-type measles virus account, in part, for the increase in both morbidity and mortality from measles infection. Similarly, the immunosuppressive effects of infections with wild-type varicella virus 183 or wild-type infl uenza virus 184 cause an increase in the incidence of severe invasive bacterial infections. Live viral vaccines replicate (albeit far less effi ciently than wild-type viruses) in the host and, therefore, can weakly mimic events that occur after natural infection. For example, measles, mumps, or rubella vaccines can signifi cantly depress reactivity to the tuberculin skin test, [185] [186] [187] [188] [189] [190] [191] measles-containing vaccines can cause a decrease in protective immune responses to varicella vaccine, 192 and high-titered measles vaccine (Edmonston-Zagreb strain) can cause an excess of cases of invasive bacterial infections in developing countries. 193 All of these phenomena are explained by the likely immunosuppressive effects of measles vaccine viruses.

However, current vaccines (including the highly-attenuated Moraten strain of measles vaccine) do not appear to cause clinically relevant immunosuppression in healthy children. Studies have found that the incidence of invasive bacterial infections following immunization with diphtheria, pertussis, tetanus, BCG, measles, mumps, rubella, or live, attenuated poliovirus vaccines was not greater than that found in unimmunized children. 194-197,197a Vaccines cause autoimmunity

Mechanisms are present at birth to prevent the development of immune responses directed against self-antigens (autoimmunity). T-cell and B-cell receptors of the fetus and newborn develop with a random repertoire of specifi cities. In the thymus, T cells that bind strongly to self-peptide-MHC complexes die, while those that bind with a lesser affi nity survive to populate the body. This central selection process eliminates strongly selfreactive T cells, while selecting for T cells that recognize antigens in the context of self-MHC. In the fetal liver, and later in the bone marrow, B-cell receptors (i.e., immunoglobulins) that bind self-antigens strongly are also eliminated. Therefore, the thymus and bone marrow, by expressing antigens from many tissues of the body, enable the removal of the majority of potentially dangerous autoreactive T and B cells before they maturea process termed central tolerance. 198 However, it is not simply the presence of autoreactive T and B cells that result in autoimmune disease. Autoreactive T and B cells are present in all individuals because it is not possible for every antigen from every tissue of the body to participate in the elimination of all potentially autoreactive cells. A process termed peripheral tolerance further limits the activation of autoreactive cells. 199, 200 Mechanisms of peripheral tolerance include 1) antigen sequestration (antigens of the central nervous system, eyes, and testes are not regularly exposed to the immune system unless injury or infection occurs); 2) anergy (lymphocytes partially triggered by antigen but without co-stimulatory signals are unable to respond to subsequent antigen exposure); 3) activation-induced cell death (a self-limiting mechanism involved in terminating immune responses after antigen is cleared); and 4) inhibition of immune responses by specifi c regulatory cells. [201] [202] [203] [204] Therefore, the immune system anticipates that self-reactive T cells will be present and has mechanisms to control them. Any theory of vaccine causation of autoimmune diseases must take into account how these controls are circumvented. As discussed below, epidemiologic studies have not supported the hypothesis that vaccines cause autoimmune diseases. This is consistent with the fact that no mechanisms have been advanced to explain how vaccines could account for all of the prerequisites that would be required for the development of autoimmune disease.

At least four key conditions must be met for development of autoimmune disease. First, self-antigen-specifi c T cells or selfantigen-specifi c B cells must be present. Second, self-antigens must be presented in suffi cient amounts to trigger autoreactive cells. Third, co-stimulatory signals, cytokines, and other activation signals produced by antigen-presenting cells (such as dendritic cells) must be present during activation of self-reactive T cells. Fourth, peripheral tolerance mechanisms must fail to control destructive autoimmune responses. If all of these conditions are not met, the activation of self-reactive lymphocytes and progression to autoimmune disease is not likely to occur.

Rigorous epidemiologic studies of infant vaccines and type 1 diabetes found that measles vaccine was not associated with an increased risk for diabetes; other investigations found no association between Bacille Calmette-Guérin (BCG), smallpox, tetanus, pertussis, rubella, or mumps vaccine and diabetes. 205 A study in Canada found no increase in risk for diabetes as a result of receipt of BCG vaccine. 206 In a large 10-year follow-up study among Finnish children enrolled in a H. infl uenzae type b vaccination trial, no differences in risk for diabetes were found among children vaccinated at 3 months of age (followed later with a booster vaccine), and those vaccinated at 2 years only, or with children born prior to the vaccine trial. The weight of currently available epidemiologic evidence does not support a causal association between currently recommended vaccines and type-1 diabetes in humans. [207] [208] [209] The hypothesis that vaccines might cause multiple sclerosis was fueled by anecdotal reports of multiple sclerosis following hepatitis B immunization and two case-control studies showing a small increase in the incidence of multiple sclerosis in vaccinated individuals that was not statistically signifi cant. [210] [211] [212] However, the capacity of vaccines to either cause or exacerbate multiple sclerosis has been evaluated in several excellent epidemiologic studies. [213] [214] [215] [216] [217] Two large case-control studies showed no association between hepatitis B vaccine and multiple sclerosis 214 and found no evidence that either hepatitis B, tetanus, or infl uenza vaccines exacerbated symptoms of multiple sclerosis. 215 Other well-controlled studies also found that infl uenza vaccine did not exacerbate symptoms of multiple sclerosis. [216] [217] [218] Indeed, in a retrospective study of 180 patients with relapsing multiple sclerosis, infection with infl uenza virus was more likely than immunization with infl uenza vaccine to cause an exacerbation of symtpoms. 218 Vaccines cause allergies and asthma Allergic symptoms are caused by soluble factors (e.g., IgE) that mediate immediate-type hypersensitivity; production of IgE by B cells is dependent on release of cytokines such as IL-4 by Th2 cells. Two theories have been advanced to explain how vaccines could enhance IgE-mediated, Th2-dependent allergic responses. First, vaccines could shift immune responses to potential allergens from Th1-like to Th2-like. 219 Second, by preventing common prevalent infections (the 'hygiene hypothesis'), vaccines could prolong the length or increase the frequency of Th2-type responses. 220, 221 Although all factors that cause changes in the balance of Th1 and Th2 responses are not fully known, 222 it is clear that dendritic cells play a critical role. For example, adjuvants (e.g., aluminum hydroxide or aluminum phosphate ['alum'] contained in some vaccines) promote dendritic cells to stimulate Th2-type responses. 223, 224 Adjuvants could cause allergies or asthma by stimulating bystander, allergen-specifi c Th2 cells. However, vaccine surveillance data show no evidence for environmental allergen priming by vaccination. 225 Furthermore, local inoculation of adjuvant does not cause a global shift of immune responses to Th1-or Th2-type. 226, 227 The other hypothesis advanced to explain how vaccines could promote allergies is that, by preventing several childhood infections (the 'hygiene hypothesis'), stimuli that evolution has relied on to cause a shift from the neonatal Th2-type immune response to the balanced Th1-Th2 response patterns of adults have been eliminated. 220, 221 However, the diseases that are prevented by vaccines constitute only a small fraction of the total number of illnesses to which the child is exposed, and it is unlikely that the immune system would rely on only a few infections for the development of a normal balance between Th1 and Th2 responses. For example, a study of 25,000 illnesses performed in Cleveland, Ohio, in the 1960s found that children experienced six to eight infections per year in the fi rst 6 years of life; most of these infections were caused by viruses such as coronaviruses, rhinoviruses, paramyxoviruses and myxoviruses-diseases for which children are not routinely immunized. 228 Also at variance with the hygiene hypothesis is the fact that children in developing countries have lower rates of allergies and asthma than those in developed countries despite the fact that these children are commonly infected with helminths and worms-organisms that induce strong Th2-type responses. 229 Finally, the incidence of diseases that are mediated by Th1-type responses, such as multiple sclerosis or type 1 diabetes, have increased in the same populations as those that experienced an increase in allergies and asthma.

Although some relatively small early observational studies supported the association between whole-cell pertussis vaccine and development of asthma, 230 more recent studies have suggested otherwise. A large clinical trial performed in Sweden found no increased risk, 231 and a very large longitudinal study in the United Kingdom found no association between pertussis vaccination and early-or late-onset wheezing, or recurrent or intermittent wheezing. 232 Two studies from the VSD project have also lent data to this controversy. In one study of 1,366 infants with wheezing during infancy, vaccination with DTP and other vaccines was not related to the risk of wheezing in full-term infants, 233 and, in another study of more than 165,000 children, childhood vaccinations were not associated with an increased risk for developing asthma. 234 Finally, a study from Finland also suggested that children with history of natural measles were at increased risk for atopic illness. Such fi ndings would run contrary to the hypothesis that the increase in atopic illnesses seen in several countries is due to the reduction in wild measles resulting from immunizations. 235 Another separate concern is whether inactivated infl uenza vaccination may induce asthma exacerbations in children with pre-existing asthma. Results of studies examining the potential associations between administration of inactivated infl uenza vaccine and various surrogate measures of asthma exacerbation, including decreased peak expiratory fl ow rate, increased use of bronchodilating drugs, and increase in asthma symptoms, have yielded mixed results. Most studies, however, have not supported such an association. 236 In fact, after controlling for asthma severity, acute asthma exacerbations were less common after inactivated infl uenza vaccination than before, 237 and inactivated infl uenza vaccination appears to be associated with a decreased risk for asthma exacerbations throughout infl uenza seasons. 238 

Autism is a chronic developmental disorder characterized by problems in social interaction, communication, and responsiveness, and by repetitive interests and activities. Although the causes of autism are largely unknown, family and twin studies suggest that genetics plays a fundamental role. 239 In addition, overexpression of neuropeptides and neurotrophins has been found in the immediate perinatal period among children later diagnosed with autism, suggesting that prenatal or perinatal infl uences or both play a more important role than postnatal insults. 240 However, because autistic symptoms generally fi rst become apparent in the second year of life, some scientists and parents have focused on the role of MMR vaccine because it is 74 Chapter 74 7 fi rst administered around this time. Concern over the role of MMR vaccine was heightened in 1998 when a study based on 12 children proposed an association between the vaccine and the development of ileonodular hyperplasia, nonspecifi c colitis, and regressive developmental disorders (later termed by some as 'autistic enterocolitis'). 241 Among the proposed mechanisms was that MMR vaccine caused bowel problems, leading to the malabsorption of essential vitamins and other nutrients and eventually to autism or other developmental disorders. Concern about this issue led to a decline in measles vaccine coverage in the United Kingdom and elsewhere. 242 Signifi cant concerns about the validity of the study included the lack of an adequate control or comparison group, inconsistent timing to support causality (several of the children had autistic symptoms preceding bowel symptoms), and the lack of an accepted defi nition of the syndrome. 243 Subsequently, population-based studies of autistic children in the United Kingdom found no association between receipt of MMR vaccine and autism onset or developmental regression. 244, 245 A study in the United States within the VSD project investigated whether measles-containing vaccine was associated with infl ammatory bowel disease, and found no relationship between receiving MMR vaccine and infl ammatory bowel disease, or between the timing of the vaccine and risk for disease. 246 Soon after publication of the Lancet paper that ignited the controversy, 241 two ecologic analyses found no evidence that MMR vaccination was the cause of apparent increased trends in autism over time, 247, 248 while two other studies found no evidence of a new variant form of autism associated with bowel disorders secondary to vaccination. 249, 250 Several more recent studies have also refuted the notion that MMR vaccine caused autism. [251] [252] [253] [254] [255] [256] Because of the level of concern surrounding this issue, the CDC and the National Institutes of Health requested an independent review by the IOM. 257 The Immunization Safety Review Committee appointed by the IOM to review this issue was unable to fi nd evidence supporting a causal relationship at the population level between autistic spectrum disorders and MMR vaccination, nor did the committee fi nd any good evidence of biologic mechanisms that would support or explain such a link.

The FDA Modernization Act of 1997 called for the FDA to review and assess the risk of all mercury-containing food and drugs. This led to an examination of mercury content in vaccines. Public health offi cials found that infants up to six months of age could receive as much as 187.5 ug of ethylmercury (thimerosal) from vaccines: a level that exceeded recommended safety guidelines for methylmercury from the Environmental Protection Agency, but not those recommended by the Food and Drug Administration or the Agency for Toxic Substance Disease Registry. 258 Consequently, the routine neonatal dose of hepatitis B vaccine in infants born to hepatitis B surface antigen (HBsAg)-negative mothers was suspended in the United States until preservative-free vaccines became available, and transitioning to a vaccine schedule free of thimerosal began as a precautionary measure. 259 Currently, only the multi-dose infl uenza vaccine contains preservative quantities (i.e., 25 µg per dose) of thimerosal.

Mercury is a naturally occurring element found in the earth's crust, air, soil and water. Since the earth's formation, volcanic eruptions, weathering of rocks and burning of coal have caused mercury to be released into the environment. Once released, certain types of bacteria in the environment can change inorganic mercury to organic (methylmercury). Methylmercury makes its way through the food chain in fi sh, animals, and humans. At high levels, it can be neurotoxic. Thimerosal contains ethylmercury, not methylmercury. Studies comparing ethylmercury and methylmercury suggest that they are processed differently; ethylmercury is broken down and excreted much more rapidly than methylmercury. Therefore, ethylmercury is much less likely than methylmercury to accumulate in the body and cause harm.

Several pieces of biological and epidemiological evidence support the notion that thimerosal does not cause autism. First, in 1971 Iraq imported grain that had been fumigated with methylmercury. 260 Farmers ate bread made from this grain. The result was one of the worst, single-source, mercury poisonings in history. Methylmercury in the grain caused the hospitalization of 6,500 Iraqis and killed 450. Pregnant women also ate the bread and delivered babies with epilepsy and mental retardation. However, there was no evidence that these babies had an increased incidence of autism. Second, fi ve large studies have now compared the risk of autism in children who received vaccines containing thimerosal to those who received vaccines without thimerosal or vaccines with lesser quantities of thimerosal; the incidence of autism was similar in all groups. 261-264,264a,264b The Institute of Medicine has reviewed these studies and concluded that evidence favored rejection of a causal association between vaccines and autism and that autism research should shift away from vaccines. 264c Denmark, a country that abandoned thimerosal as a preservative in 1991, actually saw an increase in the disease beginning several years later. Third, studies of the head size, speech patterns, vision, coordination and sensation of children poisoned by mercury show that the symptoms of mercury poisoning are distinguishable from the symptoms of autism. 265 Fourth, methylmercury is found in low levels in water, infant formula and breast milk. 266 Although it is clear that large quantities of mercury can damage the nervous system, there is no evidence that the small quantities contained in water, infant formula and breast milk do. An infant who is exclusively breast-fed for six months will ingest more than twice the quantity of mercury that was ever contained in vaccines and fi fteen times the quantity of mercury contained in the infl uenza vaccine.

One known and unfortunate sequela from the uncertainty surrounding the safety of thimerosal was confusion surrounding administration of the birth dose of hepatitis B vaccine. Following the suspension of the routine use of hepatitis B vaccine for lowrisk newborns in 1999, there was a marked increase in the number of hospitals that no longer routinely vaccinated all infants at high risk of hepatitis B. 267 As a result, there have been cases of neonatal hepatitis B that could have been prevented, but were not, because of many hospitals suspending their routine neonatal hepatitis B vaccination program.

Disease prevention, especially if it requires continuous nearuniversal compliance, is a formidable task. In the pre-immunization era, vaccine-preventable diseases such as measles and pertussis were so prevalent that the risks and benefi ts of disease versus vaccination were readily evident. As immunization programs successfully reduced the incidence of vaccinepreventable diseases, however, an increasing proportion of health care providers and parents have little or no personal experience with vaccine-preventable diseases. For their riskbenefi t analysis, they are forced to rely on historical and other more distant descriptions of vaccine-preventable diseases in textbooks or educational brochures. In contrast, some degree of personal discomfort, pain and worry is generally associated with each immunization. In addition, parents searching for information about vaccines on the World Wide Web are likely to encounter web sites that encourage vaccine refusal or emphasize the dangers of vaccines. 268, 269 Similarly, the media may sensationalize vaccine safety issues or, in an effort to present 'both sides' of an argument, fail to provide perspective. 270, 271 For reasons discussed earlier, there may be uncertainty if vaccines are associated with rare or delayed adverse reactions if only because the scientifi c method does not allow for acceptance of the null hypothesis. Therefore, one cannot prove that a vaccine never causes a particular adverse event: only that an adverse event is unlikely to occur by a certain statistical probability.

The combination of these factors may have an impact on parental beliefs about immunizations. A national survey found that, although the majority of parents support immunizations, 20 to 25% have misconceptions that could erode their confi dence in vaccines. 272 Within this context, the art of addressing vaccine safety concerns through effective risk communication has emerged as an increasingly important skill for managers of mature immunization programs and health care providers who administer vaccines.

The science of risk perceptions and risk communications, developed initially for technology and environmental arenas, 273 has only recently been formally applied to immunizations. 274 For scientists and other experts, risk tends to be synonymous with the objective probability of morbidity and mortality resulting from exposure to a particular hazard. 275 In contrast, research has shown that laypersons may have subjective, multidimensional, and value-laden conceptualizations of risk. 276 Among the key principles and lessons learned about public perceptions of risk are the following:

1 Individuals differ in their perceptions of risk depending on their personality, education, life experience, and personal values; 277,278 educational materials tiered for different needs are therefore likely to be more effective than a single tier. 2 Perceptions of risk may differ dramatically among various stakeholders, such as members of government agencies, industry, or activist groups. 279 The level of trust between stakeholders has an impact on all other aspects of risk communication. 280 Trust is generally reinforced by open communication regarding what is known and unknown about risks and by providing candid accounts of the evidence and how it was used in the decision-making process. 281 3 Certain hazard characteristics, including involuntariness, uncertainty, lack of control, high level of dread, and low level of equity, lead to higher perceived risk 276 ; only risks with similar characteristics should be compared in risk communication efforts. 282 4 For quantitatively equivalent risk that is due to action (e.g., vaccination reaction) versus inaction (e.g., vaccine-preventable disease caused by non-vaccination), many people prefer the consequences of inaction to action. 283 5 When there is uncertainty about risks, patients frequently rely on the advice of their physician or other health care professionals; continuing education of health care professionals on vaccine risk issues is key. 272 6 Finally, different ways of presenting, or framing, the same risk information (e.g., using survival rates versus mortality rates) can lead to different risk perceptions, decisions, and behaviors. 284, 285 Risk communication can be used for the purposes of advocacy, public education, or decision-making partnership. 273 People care not only about the magnitude of risks, but also how risks are managed and whether they participate in the risk-management process, especially in a democratic society. 286 In medical decision making, this has resulted in a transition from more paternalistic models to increasing degrees of informed consent. 287 Some have argued that a similar transition to informed consent also should occur with immunizations. 288 However, immunization is unlike most other medical procedures (e.g., surgery) in that the consequences of the decision affect not only the individual, but also others in the society. Because of this important distinction, many countries have enacted public-health (e.g., immunization) laws that severely limit an individual's right to infect others. Without such mandates, individuals may attempt to avoid the risks of vaccination while being protected by the herd immunity resulting from others being vaccinated. 289 Unfortunately, the protection provided by herd immunity may disappear if too many people avoid vaccination, resulting in outbreaks of vaccine-preventable diseases. 290, 291 Debates in the United States have focused on whether philosophical (in addition to medical and religious) exemptions to mandatory immunizations should be allowed more universally and, if so, what standards for claim of exemption are needed. 288, 292, 293 Thus vaccine risk communications not only should describe the risks and benefi ts of vaccines for individuals, but also should include discussion of the impact of individual immunization decisions on the larger community.

Empathy, patience, scientifi c curiosity, and substantial resources are needed to address concerns about vaccine safety. Although each evaluation of a vaccine safety concern is in some ways unique, some general principles may apply to most cases. As with all investigations, the fi rst step is objective and comprehensive data gathering. 41 It is also important to gather and weigh evidence for causes other than vaccination. For individual cases or clusters of cases, a fi eld investigation to gather data fi rsthand may be necessary. 130, 294 Advice and review from a panel of independent experts also may be needed. 99, 295, 296 Causality assessment at the individual level is diffi cult at best; further evaluation via epidemiologic or laboratory studies may be required. 297 Even if the investigation is inconclusive, such studies can often help to maintain public trust in immunization programs. 298 Scientifi c investigations are only the beginning of addressing vaccine safety concerns. In many countries, people who believe they or their children have been injured by vaccines have organized and produced information highlighting the risks of and alternatives to immunizations. From the consumer activist perspective, even if vaccine risks are rare, this low risk does not reassure the person who experiences the reaction. 299 Such groups have been increasingly successful in airing their views in both electronic and print media, frequently with poignant individual stories. 268, 269 Because the media frequently raise controversies without resolution and choose 'balance' over perspective, one challenge is to establish credibility and trust with the audience. 300, 301 Factors that aid in enhancing credibility include demonstrating scientifi c expertise, establishing relationships with members of the media, expressing empathy, and distilling scientifi c facts and fi gures down to simple lay concepts. However, statistics and facts compete poorly with dramatic pictures and stories of disabled children. Emotional reactions to messages are often dominant, infl uencing subsequent cognitive processing. 302 Therefore, equally compelling fi rsthand accounts of people with vaccine-preventable diseases may be needed to communicate 74 Chapter 74 7 the risks associated with not vaccinating. Clarifying the distinction between perceived and real risk for the concerned public is critical. If further research is needed, the degree of uncertainty (e.g., whether such rare vaccine reactions exist at all) should be acknowledged, but what is certain also should be noted (e.g., millions of people have received vaccine X and have not developed syndrome Y; even if the vaccine causes Y, it is likely to be of magnitude Z, compared to the magnitude of known risks associated with vaccine-preventable diseases).

In the United States, written information about the risks and benefi ts of immunizations developed by the CDC has been required to be provided to all people vaccinated in the public sector since 1978. 303 The National Childhood Vaccine Injury Act (NCVIA) requires every health care provider, public or private, who administers a vaccine that is covered by the act to provide a copy of the most current CDC Vaccine Information Statement (VIS) to either the adult vaccinee or, in the case of a minor, to the parent or legal representative each time a dose of vaccine is administered. 304 Health care providers must note in each patient's permanent medical record the date printed on the VIS and the date the VIS was given to the vaccine recipient, or his or her legal representative. VISs are the cornerstone of providerpatient vaccine risk-benefi t communication. Each VIS contains information on the disease(s) that the vaccine prevents, who should receive the vaccine and when, contraindications, vaccine risks, what to do if a side effect occurs, and where to go for more information. Current VISs can be obtained from the CDC's National Center for Immunization and Respiratory Diseases at www.cdc.gov/vaccines and are available in over 20 languages from the Immunization Action Coalition at www.immunize. org. An increasing number of resources that address vaccine safety misconceptions and allegations also have become available, including web sites, brochures, resource kits, and videos (Table . Some studies have been conducted to assess the use and effectiveness of such materials; [305] [306] [307] [308] [309] however, more research in this area is needed.

Immunization programs and health care providers should anticipate that some members of the public may have deep concerns regarding the need for and safety of vaccines. A few may refuse certain vaccines, or even reject all vaccinations. An understanding of vaccine risk perceptions and effective vaccine risk communication are essential in responding to misinformation and concerns.

Parental vaccine acceptance in a new era: the role of health care providers and public health professionals One consequence of the success of vaccines is that an increasing number of parents as well as clinicians have little or no personal experience with or knowledge of many of the diseases that vaccines prevent. Thus, vaccine preventable diseases often are not perceived as a real threat by parents. 310, 311 Moreover, increasingly parents want to be fully informed about their children's medical care, 312 thus merely recommending vaccination may not be suffi cient. Also in this new era, stories in the media highlighting adverse events (real or perceived) may cause some parents to question the safety of vaccines.

Apart from the media attention on vaccine safety issues, a confl uence of factors has an infl uence on parents' vaccine attitudes in the present environment of a low incidence of vaccine-preventable diseases. These factors would be relatively unimportant in an environment where diseases such as polio and measles were common and people lived in fear of their children contracting disease, however they have become predominant in the current climate for some parents. Some of these factors are: 1) lack of appropriately tailored information about the benefi ts of vaccines and contrary information from alternative health practitioners, 2) mistrust of the source of the information, 3) perceived serious side effects, 4) not perceiving the risks of vaccines accurately, and 5) insuffi cient biomedical literacy. Addressing these issues is a challenge for medical and public health professionals because the typical arrangement for providing medical care does not allow full reimbursement of healthcare providers for educating patients and parents. 313 Nonetheless, it is important for us to try to meet the challenge because an understanding of the above factors and a proactive approach to vaccine education may prevent future concerns from escalating into widespread refusal of vaccines, with a consequent increased incidence of vaccine-preventable diseases.

Most people today want to be thoroughly informed about their health care. 312 The desire for more information also applies to parents with regard to medical issues for their children. Parents want to be part of the decision-making process when it comes to immunizations for their children. 314 Providing the appropriate information at the appropriate time is especially important now with the increased questioning of vaccines and with 20 states allowing philosophical exemptions in 2006.

There is an association between information and vaccine acceptance. A recent study found that while 67% of parents agreed that they had access to enough information to make a good decision about immunizing their children, 33% of parents disagreed or were neutral. 315 Parents who disagreed they had enough vaccine information had negative attitudes about immunizations, health care providers, immunization requirements and exemptions, and trust in people responsible for immunization policy. Moreover, a larger percent of parents who reported they did not have access to enough information about vaccines also had several specifi c vaccine concerns compared to parents who were neutral or agreed they had access to enough information. 315 It may be that when there is a void of accurate, trusted information, doubts about vaccines arise and misinformation is more readily accepted. Other studies have demonstrated the effect of providing information on the wellbeing of patients. For example, information is one factor that has been shown to positively infl uence a sense of control in patients with rheumatoid arthritis 316 and perceived lack of information among mothers was one reason contributing to non-immunization of children in India. 317 Using the principle of audience segmentation (partitioning a population into segments with shared characteristics), a survey study identifi ed fi ve parent groups that varied on health and immunization attitudes and beliefs. 318 The two audience segments identifi ed as most concerned about immunizations ('Worrieds' and 'Fencesitters') were chosen as the focus of a follow-up study to obtain the input of mothers in these segments in the development of evidence-based, tailored educational materials. The purpose of these materials would be to assist healthcare providers in busy offi ce settings to address questions from these two groups of parents. Presentation of these tailored brochures by children's healthcare providers to parents in an empathetic and respectful manner could aid in improving the healthcare provider-parent relationship, increasing vaccine acceptance, and ultimately preventing vaccine-preventable diseases (Table 74-6) .

VISs are typically given to parents the day the child is scheduled for their immunization. [319] [320] [321] This often places the parent in a confl ict situation of either attending to the VIS or attending to a frightened or upset child. Not surprisingly, studies have shown that parents would rather receive the information in advance of the fi rst vaccination visit. [320] [321] [322] [323] Suggested earlier times for vaccine education include prenatal clinic visits and just after delivery in a hospital. 324 A national survey indicated that 80% of providers said that a preimmunization booklet for parents would be useful for communicating risks and benefi ts to parents. 319 

The use of complementary and alternative medicine (CAM) has been increasing over the past 50 years in the US. 325 Part of this increase is due to managed-care organizations providing coverage for some CAM therapies. 326 Chiropractic care is among the top 10 most commonly used CAM therapies. 327 It is of note that some chiropractic colleges teach a negative view of immunizations. 328 In one study, one-third of chiropractors agreed that there is no scientifi c proof that immunizations prevent disease. 328 The basis for the negative views of vaccine effectiveness may lie in 1) the chiropractic doctrine that disease is the result of spinal nerve dysfunction caused by subluxation coupled with 2) the rejection of the germ theory of disease. 328, 329 It may be that some chiropractors who adhere to this belief infl uence parents against immunizing their children. In one study, parents who requested immunization exemptions for their children were more likely to report CAM use in their families than parents who did not request these exemptions. 330 This emphasizes the importance of a trusting doctor-patient relationship and providing parents with tailored information in advance of their child's immunizations; in this manner their questions are answered and they are prepared with the facts when they encounter contrary information from other sources. Reaching out to chiropractic organizations to foster a better understanding of the benefi ts of immunizations may be advantageous to medical and public health professionals.

Parental concern about immunizations has been associated with a lack of trust. For example, one of the factors infl uencing parents who choose not to vaccinate their children for pertussis is doubt about the reliability of the vaccine information. 331 In another study, parents of children with an immunization exemption were more likely to express a low level of trust in the government, in addition to other factors such as low perceived susceptibility to and severity of vaccine-preventable diseases and low perceived effi cacy and safety, compared to parents of vaccinated children. These parents were less likely to believe that medical and public health professionals are good or excellent sources of immunization information. 332 The majority of parents (84%), however, report receiving immunization information from a doctor. 165 Thus having a doctor who engenders trust providing immunization information and who is available to listen and answer questions is the optimal situation from the public health perspective. If trust in a child's doctor is low, parents may be drawn to other, less credible sources of information. 

Perceived serious side effects When a child experiences an adverse event following a vaccine, it often raises the question 'Was this vaccine necessary?' To the parent, it may appear that the risks of the vaccine are greater than the risks of not getting the vaccine. Parents who sought medical attention for any of their children due to an apparent adverse event following immunizations (6.9%) not only expressed more concern about immunizations, but were more likely to have a child who lacked one or more doses of three high profi le vaccines compared with parents who reported that none of their children had experienced an adverse event following immunization. 333 Two scenarios were seen as plausible. It may be that parents who were already concerned about vaccines before their child began their vaccination schedule were more reactive and thus sought medical attention for minor side effects (e.g., fever) or non-related problems. It is also possible that an apparent adverse event following immunization that resulted in a parent seeking medical attention for their child caused the parent's perception of vaccines to become more negative. Both possibilities may result in the parent declining future vaccines for their children.

Negative attitudes could be addressed by improving communication between clinician and parent (Table 74-7) . Benefi t-cost analysis research has shown that physician advice can produce benefi ts for health issues (e.g., problem drinking). 334 Moreover, positive communication behaviors such as humor and soliciting questions are associated with a lowered physician's risk of a malpractice suit. 335 It may be that in this era of low vaccine preventable disease incidence and increased public questioning of immunizations, improved provider communication can produce a positive net benefi t for parents (reduced anxiety), a cost benefi t to the health care system (reduced calls and medical visits for non-serious adverse events following immunization) and an improved physician-patient relationship (more trust and fewer malpractice suits).

Individuals can vary in their perception of the magnitude of vaccine risks. Studies have shown that various factors such as gender, race, political worldviews, emotional affect and trust are associated with risk perception. 336 In addition, risk perception factors such as involuntariness, uncertainty, lack of control, and high level of dread can lead to a heightened perception of risks. 337 All of which can be seen as associated with childhood immunizations. Moreover, these factors have been referred to as 'outrage' factors in the risk communication literature. Outrage can lead to a person responding emotionally and can increase further the level of perceived risk. 337 It can be diffi cult to communicate the risk of many vaccinepreventable diseases given their low prevalence in the U.S., and diffi cult to communicate the risks of serious vaccine adverse events because they affect such a small proportion of vaccine recipients. 338, 339 Several factors have been studied that might help people to better understand risk; the fi rst are comparisons. Comparisons that are similar (apples to apples) are reported to be better accepted 340 and thus, comparisons for vaccines should focus on things that generally prevent harm in children but could pose a small risk (such as bicycle helmets, car seats). The second are visual presentations that help people understand numerical risk, include risk ladders, 341 stick fi gures, line graphs, dots, pie charts, and histograms. 342 Unfortunately, there has been little research done in either of these areas. Trust in the source of the risk information is an important factor in its ability to infl uence people 343 and, as discussed above, is developed through listening and ongoing communications. 344 

In 1999, American adults had an average score of 51.2 on an Index of Biomedical Literacy designed to measure understanding of biomedical terms and constructs. Individuals with scores less than 50 would likely fi nd it diffi cult to understand medical stories about why antibiotics are not effective in combating the common cold and the relationship between certain genes and health. 345 The main factors associated with biomedical literacy are 1) level of formal education, 2) number of college level science courses and 3) age. Some characteristics of scientifi c literacy include the ability to 1) distinguish experts from the uninformed, 2) recognize gaps, risks, limits and probabilities in making decisions involving a knowledge of science or technology, 3) recognize when a cause and effect relationship cannot be drawn, 4) distinguish evidence from propaganda, fact from fi ction, sense from nonsense and knowledge from opinion. Unfortunately, parental characteristics of those least motivated to obtain timely immunizations for their children are often characterized by low educational level of either parent. 346 There is a wide gap in the level of biomedical understanding across the U.S. population and this emphasizes the need for tailored information. The need for tailored information applies Physicians should pay special attention to parents who believe their child has experienced an adverse event because of an immunization. There are several factors that increase parents' concern in this situation: their child is affected, vaccines are often not voluntary, and the process is not well understood by parents. 1 In addition, parents feel that their child was harmed by someone in whom they have placed their trust, and they sometimes must be treated by the same physician who gave the immunization. 2 This can cause a feeling of confl ict, wanting the child to be helped but not trusting the physician because he/she was involved with administering the immunization.

In discussing medical adverse events in general, Vincent suggests clinicians should follow some basic principles in order to reduce the trauma to patients harmed by treatment. 2 These suggestions apply equally to parents whose child experienced an adverse event following immunization. First, clinicians should respect the opinion of parents who say their child experienced an adverse event. Second, if the adverse event has no basis, the clinician should give the parent a complete and sympathetic explanation of why the immunization could not have caused such an effect. In many instances the presence or absence of a causal connection between an adverse event and vaccination is not readily apparent. In such cases clinicians should be honest with patients regarding this uncertainty. Finally, clinicians should be open about the apparent adverse event and discuss what measures could be taken to prevent or treat a similar event in the future. Health care providers should report all suspected adverse events following immunization to the Vaccine Adverse Events Reporting System (VAERS) (www.vaers.org), even if a causal relationship to vaccination is uncertain. to all areas of health including childhood immunizations. Immunization educational materials aimed at a middle level or a 'one size fi ts all' are not likely to satisfy all parents' needs. 345 The importance of educating parents concerned about vaccines

Why should we care about a small number of parents who are worried about vaccines for their child? We should care because it is not only ethically the right thing to do, it is practically the right thing to do. Vaccine acceptability refers to the factors that go into a parent's decision to have their child immunized. It is important not to assume that just because most parents are having their child immunized that they will continue to do so. 347 While the host of factors contributing to the parent's decision to have their child immunized (e.g., need for information, experience with adverse events) might remain stable for some time, it is possible that one or more of the factors may change so that the parent perceives the risks of vaccines to be greater than the risk of disease. This would then push the parent above a theoretical 'unacceptability threshold' where they would choose not to have their child immunized for one or more vaccines. This is especially possible as more vaccines are added to the immunization schedule. An increasing number of parents have a choice, through state philosophical immunization exemption laws or schooling their children at home. 348 Averting the future possibility of outbreaks of vaccine preventable diseases will take a concerted effort by health care and public health professionals to educate and better communicate with parents concerned about immunizations. In guidance for the clinician, the American Academy of Pediatrics suggests that pediatricians should listen carefully and respectfully to parents' immunization concerns, factually communicate the risks and benefi ts of vaccines, and work with parents who may be concerned about a specifi c vaccine or having their child receive multiple vaccines in one visit. 349 Providers can make a huge impact on vaccine acceptance by following these suggestions and those listed in Tables 74-6 and 74-7. Following some or all of these suggestions has the potential to improve the quality of the physician-parent relationship, thus resulting in a cascading effect where providing information can increase trust and increasing trust can lead to greater acceptance of and confi dence in vaccines. For healthcare providers to be able to optimally fi ll this important role however, two related issues should be addressed. The fi rst is the need for quality communication courses and training in medical schools and residencies, and training programs for both medical and public health professionals. 350, 351 The second is for managed-care organizations and medical insurance companies to adequately reimburse physicians for health education. Lack of reimbursement to physicians has been noted as a barrier to implementation of behavioral treatments for health issues such as heart disease 313 and smoking. 352 It is important to note that studies have shown education programs can be a cost savings to healthcare systems. 353, 354 We live in a world already benefi ting from vaccines that exist and there is the promise of more vaccines to come. The challenge we have now is to make sure that the promise is not lost because we did not present the benefi ts and risks of vaccines in a meaningful way acceptable to the public.

Many people look to vaccines as the 'magic bullet' solution to a number of public health problems that range from acquired immunodefi ciency syndrome to malaria. Rapid advances in bio-technology have brought the promise of these new vaccines closer to reality. 355 Novel delivery technologies, such as DNA vaccines and new adjuvants, are being explored to permit more antigens to be combined, reducing the number of injections. 139, 356 These changes in vaccines and vaccine delivery, however, will continue to provide additional challenges in proving their safety to an increasingly skeptical and risk-averse public. 357 Combined with methodologic diffi culties associated with studying rare, delayed, or insidious vaccine safety allegations, 33 well-organized consumer activist organizations, 299 Internet information of questionable accuracy, 268,269 media eagerness for controversy, 270, 300 and relatively rare individual encounters with vaccine-preventable diseases virtually ensure that vaccine safety concerns are unlikely to go away in mature immunization programs.

Concomitantly, vaccine safety concerns have also emerged as an issue in developing countries. 358 The high-titer measles vaccine mortality experience highlighted the importance of improving the quality control and evaluating the safety of vaccines used in developing countries. 44, 108 Plans to eliminate neonatal tetanus and measles via national immunization days, during which millions of people receive parenteral immunizations over a period of days, 359 pose substantial challenges to ensuring injection safety, 360 especially given concerns about inadequate sterilization of reusable syringes and needles, recycling of disposable syringes and needles, and cross-contamination resulting from the current generation of jet injectors. 361 The WHO has relatively successfully argued that safer auto-disposable syringes and disposal boxes should be 'bundled' with vaccine donations. 362 These and other new safer administration technologies are urgently needed. 363 The increasing computerization and centralization of health care services may facilitate epidemiologic studies to reassure the public about the safety of future vaccines. 101, 132 Similar to other arenas concerned with safety (e.g., aviation, 364 food 365 and blood 366 ), a comprehensive systems design approach to minimize risk and promote vaccine safety is needed. 367 New initiatives to reduce medical errors and improve patient safety are drawing lessons from non-medical systems where an evolution from traditional 'linear' thinking about errors to analyses of multiple causation at the 'systems' level has been effective in developing a culture of safety. 368 Developments in biotechnology will continue to offer better, safer vaccines. 355, 356 The availability of computerized immunization registries 369 will likely permit optimal implementation of immunization policies at the individual level, ensuring receipt of indicated vaccines, avoiding extra vaccination, and appropriate observance of valid contraindications to vaccinations. Vaccine safety research combined with genetic epidemiology may permit better characterization of risk groups for vaccine reactions. 370 Monitoring for strains that have evolved as a consequence of selective pressure from immunizations may be needed. 371 Integrated with immunization registries for both children and adults, this ultimately may offer the possibility for better prevention of both vaccine-preventable 372 and vaccine-induced diseases. 

Improving health: measuring effects of medical care

Guillain-Barré syndrome following antirabies Semple vaccine-a report of six cases

Semple rabies vaccine: presence of myelin basic protein and proteolipid protein and its activity in experimental allergic encephalomyelitis

Antibodies to human myelin proteins and gangliosides in patients with acute neuroparalytic accidents induced by brain-derived rabies vaccine

Neurological complications in adults following rabies vaccine prepared from animal brains

Observations on the occurrence of icterus in Brazil following vaccination against yellow fever

Aqueous-base yellow fever vaccine

Jaundice in army personnel in the western region of the United States and its relation to vaccination against yellow fever

A serologic follow-up of the 1942 epidemic of postvaccination hepatitis in the United States Army

The Cutter Incident: How America's fi rst polio vaccine led to the growing vaccine crisis

Adverse Effects of Pertussis and Rubella Vaccines: A Report of the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines

Pertussis vaccine and whooping cough as risk factors in acute neurological illness and death in young children

Frequency of true adverse reactions to measles-mumps-rubella vaccine: a double-blind placebo controlled trial in twins

Day-to-day reactogenicity and the healthy vaccinee effect of measles-mumps-rubella vaccination

A randomized single blind trial of a combined measles-mumps-rubella vaccine to evaluate serological response and reactions in the UK population

Gender differences in the reactogenicity of measlesmumps-rubella vaccine

Chronic arthritis

Effect of live measles vaccine on the platelet count

Measles and mumps vaccine

Guillain-Barre syndrome following vaccination in the National Infl uenza Immunization Program, United States, 1976-1977

Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Safety of infl uenza vaccination in allergic children

Safe administration of infl uenza vaccine to patients with egg allergy

Anaphylaxis to measles, mumps, and rubella vaccine mediated by IgE to gelatin

The Hazards of Immunization

Nonnarcotic analgesics: prevalence and estimated economic impact of toxicities

Evidence based vaccinology

Biologic Development: A Regulatory Overview

Non-clinical vaccine safety assessment

Comparison of 13 acellular pertussis vaccines: adverse reactions

The clinical testing of preventive vaccines

Acellular pertussis vaccine: towards an improved safety profi le

Special methodological issues in pharmacoepidemiology studies of vaccine safety

The Brighton collaboration: addressing the need for standardized case defi nitions of adverse events following immunization (AEFI)

Pertussis vaccine trials

Safety of acellular pertussis vaccine: follow-up studies

Hypotonic hyporesponsive episodes in eight pertussis vaccine studies

Adverse events and vaccination-the lack of power and predictability of infrequent events in pre-licensure study

Safety and effi cacy of an attenuated vaccine against severe rotavirus gastroenteritis

Safety and effi cacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine

Lessons learned concerning vaccine safety

Active surveillance of vaccine safety data for early signal detection

Reactions to live-measlesvirus vaccine in children previously inoculated with killed-virus vaccine

Edmonston-Zagreb measles vaccine: a good vaccine with an image problem

Special methodological issues in pharmacoepidemiology studies of vaccine safety

A randomized comparison of reactogenicity and immunogenicity of two whole-cell pertussis vaccines

DTP-associated reactions: an analysis by injection site, manufacturer, prior reactions, and dose

Analyses of adverse reactions to diphtheria and tetanus toxoids and pertussis vaccine by vaccine lot, endotoxin content, pertussis vaccine potency and percentage of mouse weight gain

Evaluation of vaccine safety post-9/11: role of cohort and case-control studies

Case series analysis of adverse reactions to vaccines: a comparative evaluation

Spontaneous reporting in the U.S

Medical errors: a common problem

Spontaneous reporting systems outside the

Thrombocytopenic purpura after measles, mumps and rubella vaccination: a retrospective survey by the French regional pharmacovigilance centres and Pasteur-Merieux Serums et Vaccins

Need for improved vaccine safety surveillance

Vaccine adverse events reported in New Zealand 1990-5

Urgent to introduce countrywide and systematic evaluation of vaccine side effects

London: Her Majesty's Stationery Offi ce

Surveillance of serious adverse events following vaccination

Surveillance of secondary effects of vaccination

Reporting vaccine-associated adverse events

Adverse reaction surveillance system for vaccination in the Republic of Cuba

Side-effects with Japanese encephalitis vaccine

Adverse events following immunization: 1990

Adverse reactions following immunization in Italy in the years 1991-93

Oral vaccines against poliomyelitis and vaccinationrelated paralytic poliomyelitis in Germany. Do we need a new immunization strategy?

International Workshop: Harmonization of Reporting of Adverse Events Following Vaccination

Adverse events following immunisation under the national vaccination programme of the Netherlands. Part VII-reports in

System of Investigation and Notifi cation of Adverse Events Following Immunization: Preliminary Report. Sao Paolo, State of Sao Paolo, Brazil, Health Department

The Vaccine Adverse Event Reporting System (VAERS)

National Childhood Vaccine Injury Act: requirements for permanent vaccination records and for reporting of selected events after vaccination

Monitoring system for adverse events following immunization

Vaccine-associated adverse events in Canada

IMPACT monitoring network: a better mousetrap

Monitoring signals for vaccine safety: the assessment of individual adverse event reports by an expert advisory committee

The WHO Programme for International Drug Monitoring, its database, and the technical support of the Uppsala Monitoring Center

International Conference on Harmonisation: Guideline on clinical safety data management: periodic safety update reports for marketed drugs

Illness after infl uenza vaccination reported through a nationwide surveillance system, 1976-1977

Intussusception among recipients of rotavirus vaccine: reports to the Vaccine Adverse Event Reporting System

Intussusception among infants given an oral rotavirus vaccine

Population-based study of rotavirus vaccination and intussusception

Intussusception, rotavirus, and oral vaccines: summary of a workshop

Centers for Disease Control and Prevention. Yellow fever vaccine: recommendation of the Advisory Committee on Immunization Practices (ACIP). MMWR 51(RR-17)

Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases

Advanced age a risk factor for illness temporally associated with yellow fever vaccination

Hepatitis and death following vaccination with 17D-204 yellow fever vaccine

Pattern recognition in health insurance claims databases

The complicated task of monitoring vaccine safety

Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)-United States

Evaluation of a surveillance system: Vaccine Adverse Event Reporting System

Hair loss after routine immunizations

Thrombocytopenia after immunization with measles vaccines: review of the Vaccine Adverse Events Reporting System (1990 to 1994)

Encephalopathy after measles vaccination: accumulative evidence from four independent surveillance systems

Syncope after immunization

The safety of acellular pertussis vaccine vs whole-cell pertussis vaccine: a postmarketing assessment

The reporting sensitivities of two passive surveillance systems for vaccine adverse events

Enhancing vaccine safety surveillance: a capturerecapture analysis of intussusception after rotavirus vaccination

Investigation of a possible association between infl uenza vaccination and Guillain-Barre syndrome in the United States

The detection of adverse reactions to therapeutic drugs

Use of automated databases for pharmacoepidemiology research

A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/ mumps/rubella vaccines

The Urabe mumps vaccine: lessons in adverse event surveillance and response

Association of the Guillain-Barre syndrome with the 1992-93 and 1993-94 infl uenza vaccines

Comparative safety of two recombinant hepatitis B vaccines in children: data from the Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink (VSD)

Vaccine adverse event reporting source: a possible source of bias in longitudinal studies

Randomised trial of alternative formulations of oral poliovaccine in Brazil

Reactogenicity of indigenously produced measles vaccine

Appropriate age for measles vaccination in the United States

Immunogenicity of combined diphtheria, tetanus, and pertussis vaccine given at 2, 3, and 4 months versus 3, 5, and 9 months of age

Simultaneous administration of measles-mumpsrubella vaccine with booster doses of diphtheriatetanus-pertussis and poliovirus vaccines

Study of booster doses of two Haemophilus infl uenzae type b conjugate vaccines including their interchangeability

A comparison of vaccine effi cacy and mortality during routine use of high-titre Edmonston-Zagreb and Schwarz standard measles vaccines in rural Senegal

Expanded Programme on Immunization (EPI)

Post-marketing surveillance of adverse events following PROHIBIT vaccine in British Columbia

Shinefi eld HR. b-CAPSA I Haemophilus infl uenzae, type b, capsular polysaccharide vaccine safety

Safety evaluation of PRP-D Haemophilus infl uenzae type b conjugate vaccine in children immunized at 18 months of age and older: follow-up study of 30,000 children

Unintentional administration of varicella virus vaccine-United States

Postmarketing safety of varicella vaccine among 44

Centers for Disease Control and Prevention. Inactivated Japanese encephalitis virus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP)

The Cutter incident

Paralytic disease associated with oral polio vaccines

Diphtheria-tetanus toxoids-pertussis vaccination and sudden infant deaths in Tennessee

Visit to Child Health Center and Sudden Infant Death Syndrome (SIDS): Evaluation of DTP Vaccination. Report to the Oslo Health Council

Sudden infant death and immunization: an extensive epidemiological approach to the problem in France-winter 1986

Immunisation and the sudden infant death syndrome. New Zealand Cot Death Study Group

The National Childhood Encephalopathy Study. Whooping Cough: Reports from the Committee on the Safety of Medicines and the Joint Committee on Vaccination and Immunisation, Department of Health and Social Security. London: HM Stationary Offi ce

Risk of serious acute neurological illness after immunization with diphtheria-tetanus-pertussis vaccine: a population-based case-control study

Adverse events associated with MMR vaccines in Japan

Outbreak of pyogenic abscesses after diphtheria and tetanus toxoids and pertussis vaccination

Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality

Vaccine Safety Datalink project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team

Surveillance of vaccine-related adverse events in the fi rst year of life: a Manitoba cohort study

Vaccine safety surveillance using large linked databases: opportunities, hazards and proposed guide

The Vaccine safety Datalink: immunization research in health maintenance organizations in the USA

Diphtheriatetanus-pertussis immunization and sudden syndrome

Risk of seizures and encephalopathy after immunization with the diphtheria-tetanus-pertussis vaccine

MMR2 immunization at 4 to 5 years and 10 to 12 years of age: a comparison of adverse clinical events after immunization in the Vaccine Safety Datalink project. The Vaccine Safety Datalink Team

Combined Vaccines and Simultaneous Administration: Current Issues and Perspective

Risk of sudden infant death syndrome after immunization with the diphtheria-tetanuspertussis vaccine

Confounding in studies of adverse reactions to vaccines

Causal Inference. Chestnut Hill, MA, Epidemiology Resources

Fourth report on the Green Channel activities and the monitoring system of reactions to vaccines in the Veneto Region: Analysis of the three year period 1997-1999, General summary

Vaccination of children following a previous hypotonichyporesponsive episode

Hypotonic-hyporesponsive episodes following pertussis vaccination: a cause for concern?

Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review

Maternal immunization: the infl uence of liability issues on vaccine development

Neurological complications of pertussis inoculation

Impact of anti-vaccine movements on pertussis control: the untold story

Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children

A 7-year survey of disorders attributed to vaccination in Northwest

Neurologic events following diphtheria-tetanus-pertussis immunization

Risk of seizures and encephalopathy after immunization with diphtheria-tetanus-pertussis vaccine

Relationship of pertussis immunization to the onset of neurologic disorders

Risk of serious acute neurological illness after immunization with diphtheria-tetanus-pertussis vaccine: a population-based case-control study

Pertussis vaccine and injury to the brain

Prions and prion diseases of the central nervous system (transmissible neurodegenerative diseases)

The Origin of AIDS: A Startling New Theory Attempts to Answer the Question 'Was It an Act of God or an Act of Man?

A Journey to the Source of HIV and AIDS

Chimpanzees and journalists

Postscript relating to new allegations made by Edward Hooper at The Royal Society Discussion Meeting on 11

Untruths and consequences: the false hypothesis linking CHAT type 1 polio vaccination to the origin of human immunodefi ciency virus

No evidence to link polio vaccine with HIV

Simian virus 40 and human disease

Do parents understand immunizations? A national telephone survey

The Protecton: the unit of humoral immunity selected by evolution

Live attenuated varicella vaccine

Risk factors for lack of response to hepatitis B vaccines: a randomized trial comparing the immunogenicity of recombinant hepatitis B vaccines in an adult population

Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection

Neonatal and early life vaccinology

Secretory IgA antibody response against Escherichia coli antigens in infants in relation to exposure

Prevention of perinatal transmission of hepatitis B virus (HBV): a comparison of two prophylactic schedules

Prevention of the HBsAg carrier state in newborns of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis-B vaccine and hepatitis-B immunoglobulin: double-blind randomized placebo-controlled study

Immune response to hepatitis B vaccine in newborns

Neonatal BCG immunization

Newborns develop a TH1-type immune response to Mycobacterium bovis bacillus Calmette-Guerin vaccination

Effi cacy of BCG vaccine in the prevention of tuberculosis: meta-analysis of the published literature

Vaccines 4th ed. Philadelphia: WB Saunders

A high degree of natural immunologic priming to the capsular polysaccharide may not prevent Haemophilus infl uenzae type b meningitis

Novel vaccine strategies to T-independent antigens

Measles, immunosuppression, interleukin-12 and complement receptors

Mechanism of suppression of cell-mediated immunity by measles virus

Invasive group A streptococcal disease in children and association with varicella-zoster virus infection

Severe pneumococcal pneumonia in previously healthy children: the role of preceding infl uenza infection

Depression of tuberculin sensitivity following measles vaccination

Suppression of cell-mediated immunity after infection with attenuated rubella virus

Effects of measles, gammaglobulin-modifi ed measles and vaccine measles on the tuberculin test

Depression of the tuberculin reaction by viral vaccines

Depression of tuberculin delayed hypersensitivity by live attenuated mumps virus

Effect of measles immunization on tuberculin hypersensitivity and in vitro lymphocyte reactivity

Measles virus vaccination of measles seropositive individuals suppresses lymphocyte proliferation and chemotactic factor production

Simultaneous administration of varicella vaccine and other recommended childhood vaccines-United States

Increased mortality after high-titer measles vaccines: too much of a good thing

Apparent decreased risk of invasive bacterial disease after heterologous childhood immunization

DTP immunization and susceptibility to infectious diseases: is there a relationship?

Mortality and morbidity from invasive bacterial infections during a clinical trial of acellular pertussis vaccines in Sweden

General nonspecifi c morbidity is reduced after vaccination within the third month of life-the Greifswald study

Childhood vaccination and nontargeted infectious disease hospitalization

Immunobiology: the Immune System in Health and Disease

Tolerance and autoimmunity

Science, medicine, and the future: tolerance and autoimmunity

Dendritic cells as a tool to induce anergic and regulatory T cells

Regulatory T cells in the control of immune pathology

Activation of natural killer cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes

Certifi ed professionals: CD4+CD25+ suppressor T cells

The Swedish childhood diabetes study: vaccinations and infections as risk determinants for diabetes in childhood

Bacille Calmette-Guerin vaccination and incidence of IDDM in Montreal

Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus

Childhood immunizations and type 1 diabetes: summary of an Institute for Vaccine Safety Workshop. The Institute for Vaccine Safety Diabetes Workshop Panel

No evidence that vaccines cause insulin dependent diabetes mellitus

Association between hepatitis B vaccine and multiple sclerosis: a case-control study

Vaccinations, demyelination, and multiple sclerosis study (VDAMS): a population-based study in the UK

Premier episode de demyelinisation du systeme nerveux central et vaccination contre l'hepatite B: etude cas-temoins pilote

Multiple sclerosis and hepatitis B vaccine

Hepatitis B vaccination and the risk of multiple sclerosis

Vaccinations and the risk of relapse in multiple sclerosis

Infl uenza vaccination in MS: absence of T-cell response against white matter proteins

A multicenter, randomized, double-blind, placebocontrolled trial of infl uenza immunization in multiple sclerosis

Effects of infl uenza vaccination and infl uenza illness on exacerbations in multiple sclerosis

Induction of autoimmunity through bystander effects: lessons from immunologic disorders induced by heavy metals

Family size, infection, and atopy: the fi rst decade of the 'hygiene hypothesis

The germless theory of allergic disease: revisiting the hygiene hypothesis

Signaling and cell death in lymphocytes

Aluminum hydroxide adjuvant initiates strong antigen-specifi c Th2 responses in the absence of IL-4-or IL-13-mediated signaling

The common vaccine adjuvant aluminum hydroxide up-regulates accessory properties of human monocytes via an interleukin 4-dependent mechanism

Do early childhood immunizations infl uence the development of atopy and do they cause allergic reactions?

In vivo priming of CD4 T cells that produce interleukin (IL)-2 but not IL-4 or interferon (IFN)-gamma and can subsequently differentiate into IL-4-or IFN-gamma secreting cells

Immunostimulatory DNA pre-priming: a novel approach for prolonged Th1-biased immunity

Illness in the Home: A Study of 25,000 Illnesses in a Group of Cleveland Families

Decreased atopy in children infected with Schistosoma haematobium: a role for parasiteinduced interleukin-10

A randomized controlled trial of the effect of pertussis vaccines on atopic disease

Pertussis vaccination and wheezing illnesses in young children: prospective cohort study. The Longitudinal Study of Pregnancy and Childhood Team

Wheezing lower respiratory disease and vaccination of fullterm infants

Childhood vaccinations and risk of asthma

Measles history and atopic diseases: a population-based cross-sectional study

Does infl uenza vaccination exacerbate asthma?

Does infl uenza vaccination exacerbate asthma? Analysis of a large cohort of children with asthma. Vaccine Safety Datalink Team

Does infl uenza vaccination prevent asthma exacerbations in children?

The genetics of autism

Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation

Ileallymphoid-nodular hyperplasia, non-specifi c colitis, and pervasive developmental disorder in children

Vaccine adverse events: causal of coincidental?

Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association

MMR and autism: further evidence against a causal association

Measlesmumps-rubella and other measles-containing vaccines do not increase the risk for infl ammatory bowel disease: a case-control study from the Vaccine Safety Datalink project

Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis

Time trends in autism and in MMR immunization coverage in California

No evidence for a new variant of measles-mumps-rubella-induced autism

Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study

No effect of MMR withdrawal on the incidence of autism: a total population study

MMR vaccination and autism: what is the evidence for a causal association

MMR vaccine and autism: an update of the scientifi c evidence

Age at fi rst measles-mumps-rubella vaccination in children with autism and school-matched control subjects: a population-based study in metropolitan Atlanta

Association of autistic spectrum disorder and the measles, mumps, and rubella vaccine: a systematic review of current epidemiological evidence

Measles-mumps-rubella vaccine and the development of autism

Measlesmumps-rubella vaccine and autism

Thimerosal in vaccines: a joint statement of the American Academy of Pediatrics and the Public Health Service

Recommendations regarding the use of vaccines that contain thimerosal as a preservative

Fetal methylmercury poisoning: relationship between concentration in single strands of maternal hair and child effects

Association between thimerosal containing vaccine and autism

Safety of thimerosal containing vaccines: a two-phased study of computerized health maintenance organization databases

Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United Kingdom does not show a causal association

Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United Kingdom does not show a causal association

Pervasive developmental disorders in Montreal

Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data

Institute of Medicine Immunization Safety Review: Thimerosal-containing Vaccines and Neurodevelopmental Disorders

Thimerosal and autism?

Lead and mercury in breast milk

Hepatitis B vaccination practices in hospital newborn nurseries before and after changes in vaccination recommendations

Antivaccination activists on the World Wide Web

Content and design attributes of antivaccination web sites

Safety of vaccinations: Miss America, the media, and public health

An attempt to swindle nature: press anti-immunisation reportage 1993-1997

Do parents understand immunizations? A national telephone survey

Improving Risk Communication

Vaccine risk communication: lessons from risk perception, decision making and environmental risk communication research

Defi ning risk

DC: Resources for the Future

The risk game

Perception of risk

The Practical Guide to Environmental Community Relations

Communicating Risk to the Public: International Perspectives

Understanding responses to risk: some basic fi ndings

Encouraging risk reduction: a decision-making approach to message design

CA: Sage

Omission bias and pertussis vaccination

Positive versus negative framing of a hypothetical infant immunization: the infl uence of involvement

Framing effects on expectations, decisions, and side effects experienced: the case of infl uenza immunization

Citizen advisory committees and environmental policy: what we know, what's left to discover

The refutation of medical paternalism

CA: Mafi eld

Massachusetts: impact on informed consent and vaccine policy

The role of altruism, free riding, and bandwagoning in vaccination decisions

Health consequences of religions and philosophical exemptions from immunization laws: individual and societal risk of measles

Individual and community risks of measles and pertussis associated with personal exemptions to immunization

Religious and philosophical exemptions from vaccination requirements and lessons learned from conscientious objectors and conscription

Processes for obtaining nonmedical exemptions to state immunization laws

World Health Organization. Surveillance of adverse events following immunization (WHO/ EPI/TRAM/93.02 Rev. 1). Geneva, World Health Organization

Reassessment of the association between Guillain-Barre syndrome and receipt of swine infl uenza vaccine in 1976-1977: results of a twostate study. Expert Neurology Group

Presented at Consultation on Studies Involving High Titer Measles Vaccines Before Nine Months of Age

Anthrax vaccine and causality assessment from individual case reports

Betraying the public over nvCJD risk

DTP: A Shot in the Dark

Communicating drug-safety information

Sources in science: who can we trust?

Using positive affect when designing health messages

CA: Sage

Public health considerations

National Childhood Vaccine Injury Act of 1986, Section 2125, Public Health Service Act, 42 USC § 300aa

Parents' responses to vaccine information pamphlets

Parent comprehension of polio vaccine information pamphlets

A polio immunization pamphlet with increased appeal and simplifi ed language does not improve comprehension to an acceptable level

Childhood vaccine risk/benefi t communication in private practice offi ce settings: a national survey

Improving vaccine risk/benefi t communication with an immunization education package: a pilot study

Survey of parents' attitudes to the recommended Haemophilus infl uenzae type b vaccine program

Psychological factors associated with the uptake of measles immunization

Patient's preferences for participation in clinical decision making: A review of published surveys

Behavioral cardiology-has its time fi nally arrived?

Risky business: challenges in vaccine risk communication

Parent attitudes toward immunizations and healthcare providers: The role of information

Control perceptions in patients with rheumatoid arthritis: the impact of the medical consultation

Maternal knowledge and perceptions about the routine immunization programme-a study in a semiurban area in Rajasthan

Immunization attitudes and beliefs among parents: Beyond a dichotomous perspective

Childhood vaccine risk/benefi t communication in private practice offi ce settings: a national survey

Risk factors for delayed immunization among children in an HMO

Parents' responses to vaccine information pamphlets

Factors Infl uencing African American Mothers' Concerns about Immunization Safety: A Summary of Focus Group Findings in Atlanta

What mothers say about why poor children fall behind on immunizations: a summary of focus groups in North Carolina

Teaching mothers about childhood immunizations

Long-term trends in the use of complementary and alternative medical therapies in the United States

Current trends in the integration and reimbursement of complementary and alternative medicine by managed care organizations (MCOs) and insurance providers: 1998 update and cohort analysis

Complementary and alternative medicine use among adults: United States

Chiropractors and vaccination: A historical perspective

Chiropractors for and against vaccines

Factors associated with refusal of childhood vaccines among parents of school-aged children: a casecontrol study

Cognitive processes and the decisions of some parents to forego pertussis vaccination for their children

Factors associated with refusal of childhood vaccines among parents of school-aged children: a casecontrol study

Association between parental concerns and medical-seeking behavior after immunization

Benefi t-cost analysis of brief physician advice with problem drinkers in primary care settings

Physician-patient communication. The relationship with malpractice claims among primary care physicians and surgeons

Trust, emotion, sex, politics, and science: Surveying the risk-assessment battlefi eld

Risk communication, the West Nile virus epidemic, and bioterrorism: responding to the communication challenges posed by the intentional or unintentional release of a pathogen in an urban setting

Safety of routine childhood vaccinations: an epidemiological review

Risk communication challenges

Risk comparisons in a democratic society: What people say they do and do not want

High risk or low: how location on a 'risk ladder' affects perceived risk

The visual communication of risk

Communicating about environmental risks: how the public uses and perceives information sources

Patient information processing and the decision to accept treatment

Biomedical communication: purposes, audience, and strategies

Barriers to vaccinating preschool children

A qualitative investigation of vaccine risk perception amongst parents who immunize their children: a matter of public health concern

Parental vaccine beliefs and child's school type

Responding to parental refusals of immunization of children

Contemporary Issues in Medicine: Communication in Medicine: Report III of the Medical School Objectives Project

Integrating communication training into a required family medicine clerkship

Hispanic physicians' tobacco intervention practices: a cross-sectional survey study

Economic impact of an infection control education program in a specialized preschool setting

Heart failure disease management: impact on hospital care, length of stay, and reimbursement

New vaccine development

What's going on in vaccine technology?

Vaccine adverse events in the new millennium: is there reason for concern?

Vaccine supply and quality: surveillance of adverse events following immunization

National immunization days: experience in Latin America

Unsafe injections in the developing world and transmission of bloodborne pathogens: a review

Modelbased estimates of risks of disease transmission and economic costs of seven injection devices in sub-Saharan Africa

WHO-UNICEF-UNFPA joint statement on the use of auto-disable syringes in immunization services. Geneva: World Health Organization, Division of Vaccine and Biologicals

Technologies for Vaccine Delivery in the 21st Century (WHO/V&B/00.35). Geneva: World Health Organization, Division of Vaccines and Biologicals

We are all safer: NTSB-inspired improvements in transportation safety

Food safety regulation: reforming the Delaney Clause

HIV and the Blood Supply: An Analysis of Crisis Decisionmaking

A multi-faceted approach to improve vaccine safety in the United States

Reporting and preventing medical mishaps: lessons from non-medical near miss reporting systems

Developing national immunization registries: experience from the All Kids Count Program

Genetic epidemiology and the future of disease prevention and public health

Mutant hepatitis B viruses: a matter of academic interest only or a problem with far-reaching implications?

Achievements in public health, 1900-1999: impact of vaccines universally recommended for children-United States

The authors are grateful to Robert Chen and Charles Hackett who contributed sections of this chapter in a previous edition of this book and for the excellent assistance on this chapter rendered by the following persons: Dan Salmon, John Iskander, Susan Scheinman, Christine Korhonen, Allison Kennedy, Michele Russell, and Tamara Murphy, Penina Haber and Gina Mootrey.