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1 Introduction Vaccines have significantly contributed to worldwide reductions in morbidity and mortality by reducing the incidence of serious infectious diseases (IOM, 2012). Today, people all over the world experience the benefits of immunizations, beginning in infancy. Most adults in the United States have not witnessed firsthand the devastating illnesses against which vaccines offer protection, for example, polio, diphtheria, and Haemophilus influenzae meningitis. However, as the incidence of vaccine-preventable dis- ease has declined, many do not appreciate the potential of these diseases to reemerge, and the potential adverse effects of the vaccines themselves take on greater saliency among certain stakeholders. Indeed, vaccine safety con- cerns exist among a diverse range of individuals, institutions, and formal and informal networks worldwide. Healthy individuals are immunized with immunogenic materials that induce immunity to serious pathogens. A “schedule” is a tool that is used to ensure that the recommended immunizations are provided to shield both children and adults from disease when they are the most vulnerable. In the United States, schedules recommended by the U.S. Advisory Committee on Immunization Practices (ACIP) (schedules for children from birth to age 6 years, children and adolescents ages 7 through 18 years, and adults) are based on the immunogenicity of vaccines and the burden and timing of disease (CDC, 2011a). Each schedule is designed and updated yearly on the basis of new evidence (see Appendix A). This report focuses on the vaccines that protect young children under age 6 years against 14 different pathogens because that time period is when multiple inoculations are given (see Appendix A). 17

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18 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY Children may receive as many as 24 injections by 2 years of age and up to 5 injections in a single visit (see Appendix A). Immunization schedules vary around the world, however, with the variability being due in part to the different patterns of disease that exist globally (Lopalco et al., 2009; WHO, 2012). Additionally, levels of antigens and immunization timing and number differ. Some countries also have differing approaches to postmar- keting surveillance systems, as will be described in Chapter 3. Although the number of vaccinations recommended is greater than ever before, the vaccines used in the current immunization schedule actu- ally have fewer antigens (inactivated or dead viruses and bacteria, altered bacterial toxins, or altered bacterial toxins that cause disease and infection) because of developments in vaccine technology (Offit et al., 2002). For ex- ample, the vaccines to prevent whooping cough used before 1991 contained 3,000 different potentially antigenic proteins (IOM, 2002). From 1980 to 2000, the immunization schedule’s total number of antigens decreased by approximately 96 percent (from 3,041 to 123-126) (Offit et al., 2002). Ever since vaccines were introduced in the 18th century, questions and concerns about their safety have been voiced. However, the protection against feared, deadly diseases that vaccines offer encourages the majority of health care professionals and laypeople to support immunization (Stern and Markel, 2005). Although research on the adverse effects of individual vaccines is robust and a required part of the approval process by ACIP, questions about the safety of the entire recommended immunization sched- ule for children persist. Moreover, how safety is interpreted varies accord- ing to the severity of an adverse event and the benefit of the vaccine. For example, some might believe that one serious adverse event that occurs once in 1 million doses is “safe enough” compared with the benefit of prevention of serious disease, whereas others may consider that risk unacceptably high. As the number of recommended vaccines has increased in recent years, some parents and advocacy groups have expressed the concern that the im- munization schedule is too crowded and complex because of the increasing number of vaccines administered during the first 2 years of a child’s life (Offit et al., 2002). In addition to the complexity of vaccine delivery, some people have raised questions about the potential for adverse health out- comes as a consequence of the simultaneous or sequential administration of childhood vaccines (Gregson and Edelman, 2003). Even though the current childhood immunization schedule offers flexibility for administration of recommended vaccines (see Appendix A), some parents elect not to follow the recommended schedule (Dempsey et al., 2011). Analysis of current U.S. data shows that the vaccination rate among children entering kindergarten exceeds 90 percent for most recommended vaccines (CDC, 2012b). However, increases in the prevalence of delay or refusal of recommended vaccines have contributed to the emergence of

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INTRODUCTION 19 vaccine-preventable illnesses across the country. For example, measles and pertussis outbreaks have occurred in recent years in geographic areas with higher concentrations of unimmunized children (Felkin et al., 2000). States with easy procedures for granting exemptions were associated with a 90 percent higher incidence of pertussis in 2004 (Omer et al., 2006). Some vaccine-preventable diseases can be fatal and have caused morbidity and mortality in infants and people with compromised immune systems. The impacts on disease prevention that vaccines have had in the United States are illustrated in Table 1-1. Vaccinations—like all medical procedures—are neither 100 percent free of risk nor 100 percent effective. Vaccines, in rare cases, can cause ill- ness. Most children who experience an adverse reaction to immunization have a preexisting susceptibility. Some predispositions may be detectable prior to vaccination; others, at least with current technology and practice, are not (IOM, 2012, p. 82). The U.S. Department of Health and Human Services (HHS), through its agencies responsible for vaccine safety, supports such research and surveillance, including studies addressing concerns and fears over the current childhood immunization schedule. The system in the United States designed to ensure vaccine safety is detailed in Chapter 3. While immunization may be one of the greatest achievements in public health, the complex interactions among populations, health care systems, TABLE 1-1  Comparison of Pre-Vaccine Annual Incidence and Current Morbidity for Vaccine-Preventable Diseases 20th Century Annual Morbidity No. of Cases Percent Disease (No. of Cases)a Reported in 2011b Decrease Congenital rubella syndrome 152 0 100 Diphtheria 21,053 0 100 Haemophilus influenzae 20,000c 14d >99 (<5 years of age) Measles 530,217 220 >99 Mumps 162,344 404 >99 Pertussis 200,752 18,719 89 Polio (paralytic) 16,316 0 100 Rubella 47,745 4 >99 Smallpox 29,005 0 100 Tetanus 580 36 98 a SOURCE: Roush et al., 2007. b SOURCE: CDC, 2012a. c Estimated. d Haemophilus influenzae type b among children <5 years of age.

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20 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY families, children, and so forth that are affected by the immunization sched- ule cannot be ignored. STUDY BACKGROUND On June 2, 2009, the National Vaccine Advisory Committee (NVAC) reviewed the nation’s vaccine safety system and endorsed the recommenda- tion of the NVAC Safety Working Group for an external expert committee, such as a committee convened by the Institute of Medicine (IOM), “with broad expertise in research methodologies, study design, and the ethical conduct of research to consider the strengths and weaknesses, ethical issues and feasibility including timelines and cost of various study designs to ex- amine outcomes in unvaccinated, vaccine-delayed and vaccinated children and report back to the NVAC” (CDC, 2011b, p. 72). The recommendation by the NVAC Safety Working Group was based on a series of meetings and discussions on the U.S. childhood immuniza- tion schedule in which individuals raised concerns that the schedule could potentially harm children because of immunological or neurodevelopmental adverse effects. Furthermore, in the minds of some parents, concerns about potential harms outweigh the well-documented benefits of immunization for the prevention of morbidity and mortality, with the result being that their children are less than fully immunized (NVAC, 2009). After years of debate, some people continue to advocate for a study to compare health outcomes among vaccinated and unvaccinated children. The NVAC report stated that “the strongest study design, a randomized clinical trial that includes a study arm receiving no vaccine or vaccine not given in accord with the current recommended schedule, is not ethi- cal, would not pass Institutional Review Board (IRB) review, and cannot be done” (NVAC, 2009, p. 38). (Chapter 6 discusses some of the ethical considerations in detail.) Furthermore, it may be impossible to draw unbi- ased results from an observational study of this issue because of potential differences in baseline health and social characteristics of populations and subgroups. COMMITTEE ON THE ASSESSMENT OF STUDIES OF HEALTH OUTCOMES RELATED TO THE RECOMMENDED CHILDHOOD IMMUNIZATION SCHEDULE The National Vaccine Program Office of HHS asked the IOM to con- vene a diverse committee of experts in pediatrics, neurology, medical ethics, immunology, statistics, epidemiology, and public health to identify study designs feasible to address questions about the safety of the United States’ childhood immunization schedule. A 14-member committee was selected to

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INTRODUCTION 21 BOX 1-1 Statement of Task The Institute of Medicine will convene an expert committee to 1. Review scientific findings and stakeholder concerns related to the safety of the recommended childhood immunization schedule. 2. Identify potential research approaches, methodologies, and study designs that could inform this question, including an assessment of the potential strengths and limitations of each approach, meth- odology and design, as well as the financial and ethical feasibility of doing them. 3. Issue a report summarizing their findings. complete a study addressing the statement of task (see Box 1-1). The com- mittee’s charge was independent of the charges for previous IOM studies of vaccines, and committee members were carefully selected to avoid real or perceived biases or conflicts of interest. Strict criteria for membership prevented any members from having financial ties to vaccine manufactur- ers or their parent companies, previous service on federal vaccine advisory committees, or delivered expert testimony or written publications on issues of vaccine safety. Biographical sketches of the members of committee can be found in Appendix F. The committee’s charge is detailed in Box 1-1. COMMITTEE PROCESS To complete its charge, the committee held three information-gathering meetings in two different locations. Before the first meeting and through- out the committee’s deliberations, the committee gathered information on public perspectives and reviewed the scientific literature on the safety of the recommended childhood immunization schedule. At the public forums held in February, March, and May 2012, the committee heard presenta- tions from clinicians, representatives of U.S. federal and state agencies and public health agencies in other countries, vaccine safety researchers, advo- cacy groups, vaccine manufacturers, and methodological experts. During the public forums, the committee invited comments (both written and oral) from the general public and representatives from numerous organizations with an interest in vaccine safety. Additionally, the committee received and

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22 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY reviewed written correspondence from the public throughout the duration of the study. The committee held 5 deliberative meetings over 6 months between February and August 2012. To fully address its charge, the committee identified a consultant who prepared a commissioned paper on study de- signs that could be used to assess the safety of the immunization schedule (see Appendix D). The paper, written by Martin Kulldorff, was intended to provide methodological input to the committee, but the paper does not necessarily reflect the committee’s views or deliberations. To solicit stake- holders’ interest and feedback, a draft version of the commissioned paper was posted on the committee’s website on May 14, 2012, and comments on the paper were invited from the public. The comment period extended to May 31, 2012, and approximately 230 individuals provided written feedback. After a review of these comments and committee discussion, the committee requested revisions from the consultant. The commissioned paper was finalized on July 3, 2012, and again posted online for comment. The committee reviewed an additional 700 comments. PREVIOUS IOM VACCINE STUDIES Since the late 1970s, the IOM has conducted 60 studies on vaccina- tion (see Appendix G). Each IOM study has relied on scientific evidence as the basis for its findings, conclusions, and recommendations. Committee members reviewed the summaries of 18 IOM studies that focused on vac- cine safety. Reexaminations of safety are often prompted by new scientific findings and rising concerns usually in relationship to an individual vaccine and a possible adverse health outcome. However, the study of the present IOM committee is unique in that its focus is on the complete childhood immunization schedule. This report follows a series of eight reports on vaccine safety that ap- peared between 2001 and 2004. The eighth report in this series examined the evidence about a possible link between autism and vaccines. That examination of the evidence found no association. A striking element de- scribed in each of these IOM reports is society’s sustained interest in vac- cines (Fineberg, 2011). The 2012 IOM committee report Adverse Effects of Vaccines: Evidence and Causality examined 158 pairs of vaccines and putative adverse effects and was the IOM’s most recent study of vaccine safety (IOM, 2012). No evidence to support a link between a vaccine and adverse events was found for the majority of adverse events, but this was often due to the rarity of the adverse event and the lack of evidence in general to support or reject a causal link. However, the committee concluded that very few health prob- lems are caused by or are clearly associated with vaccines.

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INTRODUCTION 23 ORGANIZATION OF THE REPORT This report is organized into seven chapters and seven appendixes. Chapter 2 provides background on how vaccines are developed and recom- mended for U.S. children. Chapter 3 details existing surveillance and data systems for evaluating vaccine safety. Chapter 4 reports on the committee’s review of stakeholder concerns. Chapter 5 describes the methods used to perform and the results of a literature review on the scientific findings of studies of selected health outcomes and the recommended immunization schedule. Chapter 6 presents several methodological approaches for future studies. Chapter 7 summarizes the committee’s findings, conclusions, and recommendations. The appendixes include ACIP’s 2012 recommended im- munization schedule for children (Appendix A), a glossary (Appendix B), a list of acronyms used in this report (Appendix C), the commissioned paper by Martin Kulldorff (Appendix D), agendas from public meetings held by the committee (Appendix E), biographical sketches of the commit- tee members (Appendix F), and a chronological list of the IOM’s vaccine publications (Appendix G). REFERENCES CDC (Centers for Disease Control and Prevention). 2011a. General recommendations on immunization—recommendations of the Advisory Committee on Immunization Prac- tices (ACIP). MMWR Recommendations and Reports: Morbidity and Mortality Weekly Report 60(2):1-64. CDC. 2011b. Immunization Safety Office scientific agenda. Atlanta, GA: Immunization Safety Office, Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention. CDC. 2012a. Final 2011 reports of nationally notifiable diseases. Morbidity and Mortality Weekly Report 61(32):624-637. CDC. 2012b.Vaccination coverage among children in kindergarten—United States, 2011-12 school year. Morbidity and Mortality Weekly Report 61(33):647-652. Dempsey, A.F., S. Schaffer, D. Singer, A. Butchart, M. Davis, and G.L. Freed. 2011. Alter- native vaccination schedule preferences among parents of young children. Pediatrics 128(5):848-856. Felkin, D.R., D.C. Lezotte, R.F. Hamman, D.A. Salmon, R.T. Chen, and R.E. Hoffman. 2000. Individual and community risks of measles and pertussis associated with personal exemptions to immunization. Journal of the American Medical Association 284(24): 3145-3150. Fineberg, H.V. 2011. A perspective on vaccines: President’s address. Paper presented at Insti- tute of Medicine Annual Meeting, Washington, DC. Gregson, A.L., and R. Edelman. 2003. Does antigenic overload exist? The role of multiple im- munizations in infants Immunology and Allergy Clinics of North America 23(4):649-664. IOM (Institute of Medicine). 2002. Immunization safety review: Multiple immunizations and immune dysfunction. Washington, DC: National Academy Press. IOM. 2012. Adverse effects of vaccines. Washington, DC: The National Academies Press.

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24 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY Lopalco, P.L., H.G. de Carvalho, P. Kreidl, K. Leitmeyer, and J. Giesecke. 2009. Childhood vaccination schedules in Europe vary widely. Is this a problem? Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 52(11):1095-1098. NVAC (National Vaccine Advisory Committee). 2009. Recommendations on the Centers for Disease Control and Prevention Immunization Safety Office draft 5-year scientific agenda. Washington, DC: National Vaccine Advisory Committee. Offit, P.A., J. Quarles, M.A. Gerber, C.J. Hackett, E.K. Marcuse, T.R. Kollman, B.G. Gellin, and S. Landry. 2002. Addressing parents’ concerns: Do multiple vaccines overwhelm or weaken the infant’s immune system? Pediatrics 109(1):124-129. Omer, S.B., W.K. Pan, N.A. Halsey, S. Stokley, L.H. Moulton, A.M. Navar, M. Pierce, and D.A. Salmon. 2006. Nonmedical exemptions to school immunization requirements: Secular trends and association of state policies with pertussis incidence. Journal of the American Medical Association 296(14):1757-1763. Roush, S.W., T.V. Murphy, and Vaccine-Preventable Disease Table Working Group. 2007. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. Journal of the American Medical Association 298(18):2155-2163. Stern, A.M., and H. Markel. 2005. The history of vaccines and immunization: Familiar pat- terns, new challenges. Health Affairs 24(3):611-621. WHO (World Health Organization). 2012. Immunization, vaccines and biologicals. Ge- neva, Switzerland: World Health Organization. http://www.who.int/immunization/policy/ immunization_tables/en/index. html (accessed September 2012).