key: cord-0950186-y9z9l0ji authors: Carter-Pokras, O.; Hutchins, S.; Gaudino, J.A.; Veeranki, S.P.; Lurie, P.; Weiser, T.; DeMarco, M.; Khan, N.F.; Cordero, J.F. title: The Role of Epidemiology in Informing United States Childhood Immunization Policy and Practice date: 2020-10-14 journal: Ann Epidemiol DOI: 10.1016/j.annepidem.2020.09.017 sha: 6be1b481edbe0104b4f3205689bab77261923812 doc_id: 950186 cord_uid: y9z9l0ji One of the ten greatest public health achievements is childhood vaccination because of its impact controlling and eliminating vaccine-preventable diseases (VPDs). Evidence-based immunization policies and practices are responsible for this success and are supported by epidemiology that has generated scientific evidence for informing policy and practice. The purpose of this report is to highlight the role of epidemiology in the development of immunization policy and successful intervention in public health practice that has resulted in a measurable public health impact: the control and elimination of VPDs in the United States. Examples in which epidemiology informed immunization policy were collected from a literature review and consultation with experts who have been working in this field for the past 30 years. Epidemiologic examples (e.g., thimerosal-containing vaccines and the alleged association between the measles, mumps, and rubella (MMR) vaccine and autism) are presented to describe challenges that epidemiologists have addressed. Finally, we describe ongoing challenges to the nation’s ability to sustain high vaccination coverage, particularly with concerns about vaccine safety and effectiveness, increasing use of religious and philosophical belief exemptions to vaccination, and vaccine hesitancy. Learning from past and current experiences may help epidemiologists anticipate and address current and future challenges to respond to emerging infectious diseases, such as COVID-19, with new vaccines and enhance public health impact of immunization programs for years to come. Epidemiology is the foundation of effective immunization policy and practice in the United States . Epidemiologic methods, such as surveillance of vaccine-preventable diseases (VPDs) and vaccination coverage, risk factor identification for both disease and lack of vaccination, community intervention and effectiveness studies, and assessment of access to and quality of vaccination services have contributed to the historic reduction or elimination of many VPDs in the United States and the Americas. 1 Epidemiology has contributed to immunization policy and practice at most levels of the immunization field--from vaccine development to ensuring that vaccines reach those who need them and result in the desired public health impact, disease control, and when feasible, disease elimination. For example, surveillance and studies of childhood infectious diseases provide the basis of morbidity and mortality data used to make J o u r n a l P r e -p r o o f Immunization was selected as an example for examination of epidemiology in informing public health policy and practice because childhood immunization is one of the ten greatest public health achievements in the United States--it saves lives and is cost-effective. 1,3-6 A study of 78.6 million children 6 years of age or younger born during 1994-2013 found that routine childhood vaccination prevented 322 million cases of illnesses and 732,000 premature deaths from VPDs, resulting in a net savings of an estimated $295 billion in direct medical costs and $1.38 trillion in societal costs to the United States. 3, 6 This paper highlights the role of epidemiology in immunization policy development and public health practice that have led to major reductions in VPDs. The success of childhood immunization programs has resulted from coordinated efforts that began with a rigorous science base--including epidemiologic methods and studies--that informed decision-making, led to public health policy, and continues to guide immunization services delivery. The working definition for policy in this paper is one generally used in public health: "a law, regulation, procedure, administrative action, incentive, or voluntary practice of governments and other institutions." 7 This definition can be further summarized as described by Torjman: "those decisions that seek to achieve a desired goal that is considered to be in the best interest of all members of society." 8 J o u r n a l P r e -p r o o f Through this examination of how epidemiology contributed to the successes, we also highlight lessons learned from immunization policy and practice that may be applicable to other public health programs, particularly those priorities delineated in Healthy People 2020. 9 The United States has a robust policy-making apparatus for immunization policy development that supports all stages, from vaccine development to immunization practice. Many stakeholders in the public and private sector are engaged at each step--from the consideration of candidate vaccines to vaccination of children once the Food and Drug Administration (FDA) (Figure 2) license new vaccines. Many groups share responsibility in program implementation at the state, local, and even the health care office level in order to ensure high vaccination coverage, and reduction and control of VPDs. Vaccine development requires a large and diverse research infrastructure with funding from public and private sectors that begins by identifying diseases suitable for vaccine development ( Figures 1 and 2) . Once a candidate vaccine is developed, rigorous testing for safety, tolerability, immunogenicity, and efficacy follows with Phase I, II and III clinical vaccine trials ( Figure 1 ). The private sector funds most clinical trials to demonstrate the safety, tolerability, immunogenicity, and efficacy of a candidate vaccine while the public sector funds vaccine development for selected vaccines and establishes priorities for vaccine development. Developing new vaccines is an expensive and high-risk proposition, estimated to cost up to $500 million dollars per vaccine and is a lengthy process, often taking more than a decade to bring a vaccine from development to market. 10 The FDA in the United States plays a key role in J o u r n a l P r e -p r o o f examining a candidate vaccine for its composition and source and the methods used for, and findings from,testing the vaccine's safety, purity and potency. Only after the FDA reviews and accepts the evidence from these initial steps, will it further examine evidence from human clinical trials about safety, tolerability, immunogenicity, and efficacy for the candidate vaccine in humans After finding a candidate vaccine to be safe and efficacious in humans, FDA can then proceed to issue a license for the manufacture and commercial distribution for the vaccine ( Figure 1 ). 11, 12 Once the FDA approves a vaccine, advisory committees such as the Advisory Committee on Immunization Practices (ACIP) recommend whether a new vaccine targeted for children and adults should be included in its recommended schedules for routine immunization ( Figure 2 ). 12,13 State and local immunization programs and health care providers play major roles in ensuring that vaccine coverage of a new vaccine quickly reaches high levels, and that established vaccines maintain a high coverage level needed to reduce or control VPDs. Professional organizations, such as the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American College of Physicians (ACP), make recommendations to their members on best practices to ensure high vaccination coverage and, in collaboration with the ACIP, recommend a schedule of routine immunization. Government programs and insurance companies have a major role in the financing of vaccine purchase, and access to those vaccines. Insurance companies cover many immunizations through their health care coverage plans. Government programs, such as the Vaccines for Children Program (VFC), provide targeted funding to cover costs for all ACIP-recommended vaccines for uninsured and underinsured children ages 18 years and younger. Many stakeholders from federal, state and local agencies, health plans, hospitals, clinics, employers, health care providers and philanthropic organizations play key roles in the implementation and day-to-day operation of the United States J o u r n a l P r e -p r o o f immunization system. The complex infrastructure of laws, regulations, funding streams, and programs continues to be informed by a spectrum of diverse epidemiologic surveillance and studies. We now describe some key elements of the federal agencies and respective advisory committees that inform immunization policy development. The National Vaccine Program Office (NVPO), provides strategic leadership and coordination among Federal agencies and other stakeholders to help reduce the burden of preventable infectious diseases. 14 NVPO and National Vaccine Advisory Committee (NVAC) were established to comply with Section 2105 of the Public Health Service Act. 14,15 NVPO obtains advice from the National Vaccine Advisory Committee (NVAC), which recommends approaches to control and prevent human infectious diseases through vaccine development, and provides advice on prevention of adverse reactions to vaccines ( Figure 2 ). 14,15 One example of NVAC's key role was during and after the time of the major measles resurgence of the 1990s was when it issued a call for action to eliminate endemic measles in the United States by using epidemiological evidence to improve childhood vaccination along with simultaneous monitoring of burden of measles. Use of scientific evidence by NVAC and the Advisory Committee for Immunization Practices' (ACIPs') is a strong example of how epidemiology has contributed to the development of evidence-based national policy and has strengthened the immunization system in the United States. 13, 16, 17 This example is discussed later in the article. J o u r n a l P r e -p r o o f As mentioned earlier, in the United States, vaccine development is supported by a combination of public and private sector research. In the public sector, the Federal government through the United States Department of Defense, the National Institutes of Health, and other agencies within the Department of Health and Human Services (HHS) funds vaccine development. Vaccine manufacturers invest significantly in all phases of vaccine development. The FDA is the government regulatory agency that approves vaccines for commercial use. The sponsor of a vaccine submits the required documentation on safety, efficacy, and other aspects of the candidate vaccine to the FDA. Following internal reviews, the proposal is presented to the Vaccines and Related Biological Products Advisory Committee (VRBPAC) (Figure 2 ), which then makes recommendations for licensing and additional data requests based on this evidence. The FDA Administrator makes the decision to approve the candidate vaccine based on the recommendation of the advisory committee. If approved, a vaccine license is issued with specific indications, precautions and contraindications. 11 The Advisory Committee on Immunization Practices (ACIP), provides advice and guidance to the Director of the Centers for Disease Control and Prevention (CDC) regarding use of vaccines and related agents for control of vaccine-preventable diseases in the civilian population of the United States ( Figure 2 ). 12,13 Once a vaccine is licensed, and following a comprehensive review of the scientific evidence, the ACIP recommends vaccines for routine use and provides guidance on vaccine administration schedules likely to achieve the best levels of disease protection. years. 13, [18] [19] [20] The increased availability and recommendations for more childhood vaccines represent remarkable achievements of the maturing immunization system of the United States to prevent vaccine preventable diseases, but have contributed to growing concerns about vaccine safety acceptability. [19] [20] [21] [22] [23] The Community Preventive Services Task Force, established by HHS in 1996, develops guidance on community-based approaches to increase vaccination coverage based on available scientific evidence. 21, 24, 25 This taskforce has provided evidence-based guidance for effective community-based approaches to reach and sustain high vaccination coverage ( Figure 2 ). Effective strategies recommended include "multi-component" efforts such as combining health care system and community interventions together, use of client reminder/recall and provider reminder systems, use of client incentives, use home visits, and implementing state or local school immunization requirements for attendance. From this point on, we use the terms, "surveillance" and "monitoring" interchangeably to refer to the ongoing, systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health in contrast to "point in time" epidemiologic studies and outbreak investigation data use. 30 VPDs and reports national summaries of notifiable diseases, a regular feature in the MMWR. 31, 32 CDC also monitors sporadic, endemic, epidemic and pandemic disease incidence overall and among population sub-groups to target and improve disease prevention and control efforts, including national elimination and global eradication initiatives. The recognition that HPV and hepatitis B vaccines can prevent cancer, has led to the inclusion of cancer and more recently precancerous disease surveillance and registries as data sources for monitoring the impact of vaccines in reducing cervical and liver cancer, respectively. [33] [34] [35] [36] Since the 1990s, after the resurgence of measles, the National Immunization Survey (NIS) has been measuring immunization coverage at national and state levels using standardized methods. The NIS originally targeted children 19-35 months of age, but now includes adolescents in a module designated as NIS-teen. 37, 38 The NIS (preschool child) and NIS-teen are multi-modal telephone-based surveys of parents with provider verification of immunization records. The NIS has been essential in monitoring coverage for new vaccines as they are incorporated into the recommended immunization schedule. Ensuring the safety of vaccines is a key component of Table, those affected can apply for compensation through a streamlined process that avoids lengthy litigation. 42, 43 Immunization policy, practice, and epidemiology are necessarily intertwined. Epidemiology informs policy and strategies to be incorporated into immunization practice through a process J o u r n a l P r e -p r o o f that begins with the consideration of what diseases may be preventable by a vaccine and continues with the identification of evidence-based strategies to effectively ensure high immunization coverage and optimally control or eliminate VPDs. The development of childhood vaccines is preceded by collection and analysis of epidemiological data on the incidence of VPD-related conditions, disease morbidity and mortality, and evidence that infection confers protection against recurrence of the disease ( Figure 1 ). 44 A recent example of this process related to the severity of varicella disease including mortality among adults in the United States prior to development of the varicella vaccine. 45 Also, as we write during the current pandemic, we are seeing unprecedented international scientific efforts to respond to the widespread community transmission of the novel Coronavirus, SARS-CoV-2, and the resulting waves of suffering and death related to COVID-19. These field clinical trials provide efficacy data and additional safety data about candidate vaccines. 50, 51 These clinical trials are developed using rigorous epidemiologic methods, which include identifying the targeted trial population, randomization of participants to vaccination or placebo/alternative comparator groups, surveillance of the disease targeted by the vaccine, and monitoring of adverse events following vaccine administration. There are many examples of how epidemiologic evidence from VPD surveillance systems and outbreak investigation have contributed to better understanding of vaccine effectiveness and have led to changes in recommendations of vaccine administration. Following introduction of a new vaccine, it is necessary to measure its population effectiveness in reducing the incidence of the targeted condition. Results from ongoing surveillance of VPDs and studies of reported outbreaks also provide opportunities to investigate waning vaccine immunity, reduced vaccine effectiveness, and gaps in vaccination due to missed opportunities to vaccinate during clinical encounters and/or vaccine hesitancy. The contribution of epidemiologic studies is evident, for example, in the development of recommendations for pertussis vaccines. Studies of several pertussis outbreaks provided evidence that adults and adolescents were sources of disease transmission to young children, and that previously vaccinated adolescents were responsible for school outbreaks because of waning immunity. These findings led to additional child dose recommendations and the development of a new acellular vaccine booster recommended for adolescents and adults. [52] [53] [54] The evidence of both waning immunity and that vaccinated pregnant women were able to provide passive immunity to their developing fetuses, also led to recommendations for routine tetanus and influenza vaccination for pregnant women. 53, 54 Epidemiologic studies of measles outbreaks led to the recognition that measles vaccination before 12 months of age was associated with lower vaccine effectiveness. This was the basis for the ACIP recommendation that the first measles dose be administered on or after 12 months of age. 55 Similarly, evidence from outbreaks among college students and school children showed insufficient effectiveness of a single measles dose to provide herd immunity. This led to recommendations for two doses of measles vaccines, one at 12-15 months and a second at 4 to 6 years of age. 56, 57 Other examples include a study of pertussis risk relative to the receipt and time since vaccination of the fifth dose of diphtheria and tetanus toxoids, and acellular pertussis vaccine (DTaP) during an outbreak, 58 and the role of varicella surveillance leading to change in immunization schedule from a single varicella dose to a two-dose schedule. 59 Epidemiologic studies have been used to evaluate new, and untested outbreak control interventions, such as evaluating recommendations to health care providers to vaccinate children using CDC's minimum immunization intervals during pertussis outbreaks and to use a third vaccination, during recent upsurges in mumps outbreaks. 60 From 1989 to 1990, the United States experienced a major nationwide resurgence of measles, which was detected by CDC's measles surveillance. The response to these events perhaps provides the best case-study of how epidemiologic evidence has informed, refined, and redirected United States immunization policy and practice. Examination of reasons for the resurgence identified two kinds of outbreaks: (1) large outbreaks among unvaccinated preschoolaged children, mainly in large urban centers, and (2) smaller outbreaks among vaccinated children who, we know retrospectively, needed a second dose of a measles-containing vaccine. 64, 65 Additional analyses showed that unvaccinated preschool-aged outbreaks affected mostly young minority children in urban areas, with African American, Latino, and American Indian/Alaska Native children who contracted measles at rates three to 16 times higher than white children did. 2 The NVAC examined evidence that pointed to challenges in the United States immunization system that likely contributed to the measles resurgence and to low immunization coverage rates that were well below Healthy People 2000 objectives for preschool children. Low vaccination coverage was primarily attributed to barriers in access to vaccination services or to missed opportunities to vaccinate by health care providers. 65, 66 Cost of vaccine was a key risk factor for uninsured or underinsured children. 67 Studies indicated that children visiting health care providers did not always receive all the recommended vaccines they were due, suggesting that missed opportunities to vaccinate were also important risk factors. 16,17,65-67 NVAC's report concluded that immunization services needed to be enhanced and expanded. To guide efforts to increase vaccination rates, the report recommended that a national, standardized surveillance system to track age-appropriate immunization coverage across jurisdictions was necessary. 68 This led to the creation of the National Immunization Survey to track the uptake of new childhood vaccines and monitor vaccination rates among young children 19-35 months of J o u r n a l P r e -p r o o f age to guide initiatives to more completely vaccinate these children with all recommended vaccines. 37, [69] [70] [71] [72] [73] The key NVAC findings and recommendations were published in 1991, in what is now considered a report of historic significance. 74 The NVAC recommendations were embraced by policy makers and resulted in the 1992 launch of the Childhood Immunization Initiative (CII). 75 The CII, a presidential initiative, included several key elements: (1) improving access to immunization services, (2) developing immunization information systems, (3) providing free vaccines to uninsured children (the Vaccines for Children Program), and (4) creating the National Immunization Program at CDC, now within the National Center for Immunization and Respiratory Diseases. Improved Access to Immunization Services improving access required addressing missed opportunities for immunizations. At the time, there were differences in recommendations between the ACIP, the American Academy of Pediatrics (AAP) and the American Academy of Family Practice (AAFP). A major accomplishment of the CII was harmonizing the childhood immunization schedule jointly endorsed by ACIP, AAP, and AAFP, revisions of which have become a well-established convention and practice standard since 1995. [19] [20] [21] To address missed opportunities, programs targeted health care providers to remind them to make every child's medical visit, including acute and chronic care visits, a vaccination visit. 76 Tools are now available to health care providers to help them assess and improve immunization practices and identify ways to eliminate missed opportunities for vaccination at their offices. Immunization Registries or Immunization Information Systems (IIS) Before the CII, most parents did not know the immunization status of their child. Use of completed immunization cards and access to scattered immunization records among child providers were very limited and there were no electronic medical records that would allow clinicians to accurately assess immunization status at every visit (something particularly difficult at emergency room visits). Immunization registries were developed to assist in the immunization assessment at each health J o u r n a l P r e -p r o o f care visit. 80 By the mid-1990s, provider-based and population-or community-based immunization registries, now called Immunization Information Systems (IIS), were created for use by health providers to address immunization record scatter across clinics. IIS are powerful and effective tools that provide timely access to immunization status at the point of care and have reduced missed opportunities by targeting under-vaccinated children for vaccination reminders and recalls, even before the introduction of electronic health record (EHR) systems. 81 72, [88] [89] [90] As new vaccines were added to the immunization schedule, the combined series have been expanded. 72 Table 1 includes a glossary of selected measures of vaccine completeness. 72, 89 The ACIP expansion of recommended vaccines to adolescents and adults led to upgrades of the NIS to specifically measure vaccination coverage for adolescents, including tetanus-diphtheriaacellular pertussis (Tdap) and meningococcal conjugate vaccine (MenACWY), by creating the NIS -Teen module in 2006. 38, 91, 92 In 2007, monitoring for human papillomavirus (HPV) vaccination was added. Like the original preschool child NIS, this NIS adolescent module includes provider-verified receipt of vaccines rather than relying on self-reported vaccination and provides data at state and selected local levels. Vaccination coverage among young children and adolescents is found in Figure 3 and Tables 2 and 3 . The end of the 20 th century and the subsequent decades of the 21 st century have witnessed further declines and the control of many VPDs. Polio has been eliminated from the Americas and most of the world and it is near eradication worldwide. Diseases like diphtheria, tetanus, measles, 99 In spite of the retraction, this article created major concerns among parents considering vaccinating their children and continues to affect vaccination coverage of the MMR vaccine. A large epidemiologic study in Denmark provided strong evidence of a lack of association between MMR and autism. 105 Similarly, a study in the United Kingdom did not find any association between MMR and autism. 106 The Institute of Medicine in the United States examined all available evidence and concluded that there was no evidence to link MMR vaccination and autism. 107 The consequences of the subsequently retracted Wakefield article include dramatic initial declines in MMR vaccination coverage in some countries. There were numerous resulting outbreaks of measles and mumps in the United Kingdom, France, and elsewhere. [107] [108] [109] [110] Surveillance documented that, in 2014, the United States experienced 667 cases in 27 states, the largest number of measles cases since endemic measles was eliminated in 2000. 111 125 NIS has also confirmed other study findings that suggest that those who intentionally delayed vaccination are significantly more likely to have heard or read unfavorable information about vaccines than parents who did not intentionally delay. 126 Additionally, parents who intentionally delayed due to vaccine safety or efficacy concerns were significantly more likely to seek information from the internet rather than from a health care provider compared with parents who delayed because of child illness. Differences by race have been documented in J o u r n a l P r e -p r o o f these analyses--the percentage of parents who intentionally delayed immunizations was highest among White, Non-Hispanics (28.1%), American Indian/Alaska Natives (26.6%), followed by Asians (17.2%), Hispanics (14.5%), and Blacks (12.4%). 126 Further analyses are needed to evaluate which parental, community and other characteristics and risk factors underlie these notable differences by racial/ethnic groups in childhood vaccine delays, for example examining how differences in historical experiences with VPDs and trust may influence vaccine decision making among different groups. Findings about intentional delays in immunization among some 2-year-old children and the ability of parents to claim religious or philosophical exemptions raise questions about the influence of the ease of parent claims in some states and higher state vaccination exemption rates. One study found that states enacting stricter exemption policies tend to have lower rates of exemptions. 120 In recent years, Congress and states, such as California, Vermont, Utah, Washington and Oregon, have passed or attempted to pass laws to modify or eliminate the use of non-medical exemptions. [127] [128] [129] [130] [131] [132] [133] [134] [135] These policy initiatives are being met with public controversy and opposition by nationally-organized and grassroots groups communicating vaccine safety, civil liberty, other concerns, and also anti-vaccine sentiments. [127] [128] [129] [130] [131] The legal viability and public health effectiveness of these more restrictive strategies remain to be determined. Early studies of California's non-medical exemption elimination show that, while non-medical exemptions declined, geographic clustering of these exemptions remained leaving populations of students at-risk for VPDs in a number of communities. [132] [133] [134] Epidemiological studies clearly play a key role in monitoring changing child immunization coverage, non-medical exemptions to school immunization requirements and other measures of vaccine hesitancy trends and the impact of policy changes and the interventions to address them. Another important immunization practice issue is addressing differences in VPD morbidity and disparities in vaccination coverage among special populations. Epidemiological studies proved to be particularly relevant when examining the impact of Haemophilus influenzae type b (Hib) and hepatitis A (HepA) vaccines on the American Indian/Alaska Native (AI/AN) population. 135 The introduction of the Hib vaccine significantly reduced Hib incidence in AI/AN children. Surveillance proved to be critical in demonstrating a greater response with the first dose of the polyribosylribitol phosphate conjugated to the meningococcal outer membrane protein (PRP-OMP)-containing Hib vaccines for AI/AN infants providing earlier protection. In fact, when Alaska switched from PRP-OMP to non-OMP vaccine during a vaccine shortage, AI/AN Hib incidence increased. 136, 137 Again, epidemiological evidence was important to guide immunization practice. Besides experiencing higher Hib disease incidence, AI/AN children historically had more than a five-fold higher incidence of HepA virus infection and were experiencing frequent large-scale outbreaks every 10-15 years. With the implementation of routine HepA vaccination in 1995 among high-risk populations (e.g., AI/ANs), disease incidence and outbreak disparities were completely eliminated. 135 As another special population, the Amish were the last group to experience a polio outbreak in the United States. In 2000, Pennsylvania noted an increase in Hib disease among Amish preschool children. An epidemiologic study of Hib carriage showed high levels of Hib carriage and low vaccination coverage among Amish households. A study among Amish parents who did J o u r n a l P r e -p r o o f not vaccinate their children found that only 25% identified personal-belief objections as a factor, 51% reported that vaccination was not a priority compared with other daily activities, and 73% would vaccinate children if offered locally. 138 These findings encouraged the state to target Hib vaccination programs to Amish communities and craft specific educational messages to Amish parents leading to a reduction in Hib disease in this special population. These examples show how public health used epidemiologic surveillance to document increases in disease incidence and disparities in vaccination coverage in special populations in order to respond with targeted interventions to address these problems and achieve disease prevention successes. Epidemiologists are improving their methods to track new vaccine uptake, especially for newer vaccines including the multi-dose human papillomavirus (HPV) vaccine to prevent cervical cancer and the Tdap booster for adolescents and adults. The HPV Vaccine Experience Epidemiologists have looked closely at the factors associated with rates of HPV vaccine initiation and completion to examine vaccine uptake and acceptance. 139 Observed differences pointed out that further research was needed to better understand population-specific barriers to completion of the HPV series. Monitoring HPV uptake, first among adolescent girls and later among adolescent boys, epidemiologists focused on identifying risk factors associated with low HPV vaccination.A 2009 telephone survey of mothers of 11-17-year-old girls found that the predominant perception was that their daughters were at low risk for HPV infections and HPV-related diseases. Findings also showed that mothers and their health care providers lacked sufficient knowledge about HPV disease and HPV vaccines. 139 Many mothers also reported that they believed that their daughters were currently too young to receive the HPV vaccine although receipt might be more acceptable at later ages. Also, mothers reported significant concerns about the long-term safety of these vaccines. The most commonly identified reasons for mothers accepting these vaccines for their daughters included: their perceptions that their daughters were at high risk for acquiring HPV; their beliefs that the vaccine had a favorable safety profile; their intentions to prevent cervical J o u r n a l P r e -p r o o f cancer among their daughters and protect them against cancer; their own personal experience with HPV infection or HPV-related diseases; and their recalling strong physician recommendations to vaccinate their daughters. 140 These findings have been shaping the messages and strategies to promote HPV vaccination with a stronger focus on the cancer prevention benefit of this vaccine. As in other countries, the impact of the COVID-19 pandemic on the United States immunization system and policies is starting to become apparent as COVID-19 continues to rapidly spread across communities. Since public health authorities across the United States have needed to urgently implement non-pharmaceutical public health disease containment measures (e.g., shelter-in-place, postponements of noncritical health care visits), early epidemiological studies are already documenting a dramatic decline in ordering and administration of childhood vaccines, VFC clinic capacity to vaccinate children, and immunization coverage rates for VPDs. [140] [141] [142] [143] [144] [145] [146] [147] Rapid development of new COVID-19 vaccines is an imperative because of the severe consequences of COVID-19 disease, which is disproportionately impacting people over 60 years of age, people with heart disease, diabetes, other chronic diseases, essential service workers and populations of color. [46] [47] [48] [49] However, as new vaccines for COVID-19 are being developed and tested, new reports also suggest the emergence of major challenges for new COVID-19 vaccination uptake. [148] [149] [150] Several reports state that that up to 33% percent of polled respondents were hesitant about accepting new COVID-19 vaccines when they become available. 149, 150 J o u r n a l P r e -p r o o f Previous epidemiological studies have shown that after vaccine supply chain disruptions and shortages have occurred, uptake of vaccine may slowly recover and could remain persistently lower than prior uptake well behind recommended target coverage rates when supplies become available. Re-engaging patients for clinical preventive services and increasing vaccination among people who have previously declined or fallen behind schedule during and after the COVID-19 crisis are critical strategies to prevent other VPD outbreaks, which could further strain our health care system, emergency response systems, and economy and, thus, slow economic and societal recovery from the pandemic. [143] [144] [145] 151 With delays in vaccinations, vaccine hesitancy and upcoming seasonal influenza transmission, during the pandemic, we face new challenges that risk losing historical achievements in individual and community health and new unknown risks of further preventable illnesses, disabilities and death. 116, [152] [153] [154] [155] Previous epidemiologic evidence suggests that by reducing the incidence of VPDs such as influenza and pneumococcal disease, we also would reduce burden on the health care facilities that are already under pressure in communities responding to the waves of COVID-19 outbreaks and community-wide transmission. Immunization policy makers, public health practitioners and health care providers must plan new immunization initiatives that include proactively and transparently gaining back the trust of an already skeptical public whose trust in public health and health care advice during this pandemic have been sorely tested. 116, [148] [149] [150] Epidemiologic surveillance, research and program evaluation will be essential nationally, regionally and within communities to guide needed interventions that successfully respond to these new public health challenges. More challenging is the ongoing need to develop new, specific vaccines for emerging diseases with high morbidity and mortality and rapid spread as real-time countermeasures, notable at the time of this writing during the COVID-19 pandemic. [46] [47] [48] [49] 148, 155 Especially challenging is that currently governments are usually the sole funding source for vaccine development unless commercial manufacturers offer to help and see financial and other incentives including the potential for more routine population-wide use. [46] [47] [48] [49] [155] [156] [157] To be ready to respond effectively to the eventuality of new, emergent vaccine-preventable outbreaks and community-wide biological attacks, policy makers, health officials, legislators and other stakeholders can work together to ensure that policies are in place to expedite development of new vaccines, ensure vaccine safety and efficacy, and determine appropriate resources in a timely fashion. Public/private partnerships can be developed to meet the demands for research and development of new vaccines and to establish capacity for production. Additional public health system capacity across all levels and communities could be enhanced and sustained in order to address mass vaccine distribution and administration by health care providers, vaccination monitoring, disease surveillance, and program and policy evaluations to meaningfully inform policy and program decisions in realtime. J o u r n a l P r e -p r o o f Uniform, quick, appropriate and timely reporting of disease cases and adverse events by physician offices, hospitals, laboratories, schools or other institutions such as child-care and correctional facilities can be more firmly established. Enhanced electronic reporting from electronic laboratory and health record systems, data analyses and information dissemination can be enhanced to function more rapidly in real-time. Rapid surveillance using electronic data is needed to provide more timely and accurate situational status assessments, target services and improve response time to public health emergencies. Epidemiologists can expand their use of methods from other public health disciplines, such as community-based participatory research, qualitative research, rapid-cycle quality improvement work and evaluation methods to better identify vaccine acceptance disparities and differences in perceptions, knowledge, attitudes, and beliefs among specific populations, including providers. Interventions that overcome the barriers and address the needs of special populations can be developed, implemented, evaluated and disseminated. Epidemiology remains essential for informing policy and programmatic practice decision making to prevent and respond to VPDs. Epidemiologic studies of the large United States measles resurgence identified major factors by further identifying determinants of low vaccination coverage. These efforts were crucial for focusing policies and programmatic strategies at national, state and local levels. Surveillance and epidemiologic research have also been essential in monitoring the impact of vaccinations on infectious disease incidence and vaccine acceptance J o u r n a l P r e -p r o o f by clinicians, parents and patients. While epidemiology has positively influenced changes in immunization policy and led to historic reductions in VPDs, the reduction of VPD incidence has created new challenges in our ability to help parents and providers understand why vaccines remain essential. Recent developments have led to public questioning of the value and risks of vaccinations while vaccine acceptance is high. 23, [94] [95] [96] 116, 126, 149, 150, 158 However, the nation must be vigilant in continuously measuring vaccine use, vaccine-preventable diseases, and vaccine safety, to avoid the trap of being victims to our own success. J o u r n a l P r e -p r o o f Table 3 . Vaccination coverage among adolescents ages 13-17 years, by race/ethnicity and selected vaccines and doses* 4 -National Immunization Survey -Teen, (NIS -Teen), United States, 2018 † 5 Vaccine-Preventable Disease Table Working G. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States Elimination of measles and of disparities in measles childhood vaccine coverage among racial and ethnic minority populations in the United States. The Journal of infectious diseases Centers for Disease Control and Prevention. Benefits from immunization during the vaccines for children program era -United States Ten great public health achievements--United States Ten great public health achievements--United States Economic evaluation of the routine childhood immunization program in the United States Office of the Associate Director for Policy and Strategy. Definition of Policy What is Policy? 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The New England journal of medicine >3 Polio: >1 MMR: >3 Hib: >3 HepB: >1 Varicella Abbreviations: DTP/DTaP = diphtheria and tetanus toxoids and whole cell pertussis vaccine or diphtheria and tetanus toxoids and acellular pertussis vaccine MMR = measles-mumps-rubella vaccine Hib = Haemophilus influenzae type b vaccine Hep B = hepatitis B vaccine; Varicella= varicella vaccine; and PCV = pneumococcal conjugate vaccine Abbreviations: DTP/DTaP = diphtheria and tetanus toxoids and whole cell pertussis vaccine or diphtheria and tetanus toxoids and acellular pertussis vaccine MMR = measles-mumps-rubella vaccine Hib = Haemophilus influenzae type b vaccine HepB = hepatitis B vaccine Varicella=varicella vaccine PCV = pneumococcal conjugate vaccine HepA = hepatitis A vaccine *Selected vaccines and dosages are in accordance with immunization objectives from Healthy People 2020 3 and follow the CDC's recommended immunization schedule for children and adolescents ages 18 years or younger 4 3:1:3*:3:1:4) includes ≥4 doses of DTaP, ≥3 doses of poliovirus vaccine, ≥1 dose of measles-containing vaccine, the full series of Hib (≥3 or ≥4 doses, depending on product type Figure 3. Vaccine coverage among preschool-aged children -United States Abbreviations: DTP/DTaP = diphtheria and tetanus toxoids and whole cell pertussis vaccine or diphtheria and tetanus toxoids and acellular pertussis vaccine MMR = measles-mumps-rubella vaccine Hib = Haemophilus influenzae type b vaccine Hep B = hepatitis B vaccine; Varicella= varicella vaccine PCV = pneumococcal conjugate vaccine RV = rotavirus vaccine Hep A = hepatitis A vaccine + From the United States Immunization Survey Note: No data are available for 1986-1990. Children in the United States Immunization Survey and National Health Interview Survey were ages 24-35 months Centers for Disease Control and Prevention. Coverage among children 19-35 months by State, HHS Region, and the United States National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13-17 Years -United States Centers for Disease C, Prevention. Benefits from immunization during the vaccines for children program era -United States Race/Ethnicity Non-Hispanic White *Selected vaccines and dosages are in accordance with immunization objectives from Healthy People 2020 and follow the CDC's recommended immunization schedule for children and adolescents aged 18 years or younger. 3, 4 **Includes those with >=3 doses, and those with 2 doses when the first HPV vaccine was initiated prior to age 15 years and there was at least five months minus four days between the first and second dose. ***Among adolescents with no history of varicella. † Numbers in parentheses refer to the number of doses of that vaccine being reported in this figure.