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6 Methodological Approaches to Studying Health Outcomes Associated with the Current Immunization Schedule: Options, Feasibility, Ethical Issues, and Priorities The current immunization schedule recommended by the Advisory Committee on Immunization Practices (ACIP) was developed after con- sideration of the safety and effectiveness of the component vaccines and the burden of the infectious diseases on the population targeted by each vaccine. The Food and Drug Administration’s (FDA’s) current protocol for approval of new vaccines requires an evaluation of the effect of admin- istration of a new vaccine along with other vaccines within the preexist- ing schedule. Therefore, the burden of disease and evidence of adequate immunogenicity when vaccines are administered together with existing recommended vaccines are established at the time of FDA approval and development of a recommendation by the ACIP. Although the committee’s review of the available scientific evidence revealed that no potential adverse health outcomes that may occur after immunization with the recommended immunization schedule rose to a level of concern or biological plausibility sufficient to justify a strong recommendation for immediate study, the com- mittee was asked to recommend methodological approaches that could be implemented should the need arise. To fulfill its appointed charge, the committee deliberated on five distinct topics to meet the requirements of its statement of task: (1) factors that should be used to determine that new research is needed; (2) major stake- holder concerns that the committee identified; (3) epidemiological evidence on the health effects of the current schedule; (4) major stakeholder concerns and available epidemiological evidence recast into testable research ques- tions; and (5) possible research approaches to address priority research questions. 99

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100 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY CONSIDERATIONS TO DETERMINE NEED FOR INITIATION OF NEW STUDIES As discussed in Chapter 5, the committee noted that limited published data do not provide evidence that the recommended immunization schedule is associated with safety or health risks. Indeed, the available epidemiologi- cal data repeatedly indicate the health benefits associated with the recom- mended schedule (e.g., reduced infections and hospitalizations). To undertake new studies on the immunization schedule beyond analy- ses with existing data from surveillance systems, researchers will need to carefully consider the current evidence, both epidemiological and biologi- cal, that supports the plausibility of their hypotheses. The decision to initi- ate further studies should depend on the results of an evaluation of three considerations that the committee identified through its review of stake- holder concerns and scientific findings: 1. epidemiological evidence of potential adverse health outcomes associated with elements of the immunization schedule (such as postmarketing signals or indications of an elevated risk from ob- servational or experimental studies); 2. biological plausibility supporting hypotheses linking specific as- pects of the immunization schedule with particular adverse health outcomes; and 3. expressed concerns from some stakeholders about the immuniza- tion schedule’s safety, which should support efforts to evaluate the previous two considerations. Currently, the U.S. Department of Health and Human Services (HHS) considers these criteria before initiating new studies through the Vaccine Safety Datalink (VSD). As discussed in Chapter 3, the Vaccine Adverse Event Reporting System (VAERS) allows parents and providers to report suspected adverse events after immunization. If an association is suspected on the basis of these signals, medical experts in the Clinical Immuniza- tion Safety Assessment (CISA) Network evaluate the pathophysiological basis of the suspected event. Researchers may also conduct, using VSD, population-based epidemiological studies on the basis of signals reported through VAERS and conclusions about biological plausibility reported by the CISA Network. The committee concluded that stakeholder concerns have a role in guid- ing the research priorities of the Centers for Disease Control and Prevention (CDC), FDA, the National Institutes of Health, and the National Vaccine Program Office because they may point to potential research questions that need to be validated from their epidemiological signals and the plausibil-

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METHODOLOGICAL APPROACHES 101 ity of the suggested biological pathways. Given the safeguards already in place, stakeholder concerns alone are not sufficient reason to embark on costly clinical research, such as new randomized controlled trials (RCTs) or prospective cohort studies, without the existence of supporting signals or evidence of biological plausibility. Recommendation 6-1: The committee recommends that the Depart- ment of Health and Human Services incorporate study of the safety of the overall childhood immunization schedule into its processes for setting priorities for research, recognizing stakeholder concerns, and establishing the priorities on the basis of epidemiological evidence, biological plausibility, and feasibility. Animal Models Animal models play a critical role in preclinical studies during develop- ment of all medications, including vaccines (Kanesa-thasan et al., 2011). For example, rats and mice are used for investigations into fundamental basic science issues to establish ranges of dosing, to explore immunogenic- ity, and even to provide perspectives on some clinical outcomes. Studies of acute toxicity, tolerability, and causes of fever have been performed in guinea pigs and rabbits (Kanesa-thasan et al., 2011). Subsequent studies of safety may be carried out in rats or primates, as appropriate (Kanesa-thasan et al., 2011). Animal models may also be useful for studies exploring novel vaccines, the extent of interference with vaccine immunogenicity by concur- rently administered vaccines, and the bactericidal qualities of antibodies. In its review of the existing evidence of the immunization schedule and safety, the committee did not explicitly review mechanistic evidence for any health outcomes, such as case studies or existing animal models, and instead points to the excellent work of previous committees in their reviews of individual vaccines (IOM, 2002, 2012). However, various stakeholders expressed interest in the potential use of animal models, and the committee therefore also considered the potential of studies with animal models of disease to advance knowledge of the biological mechanisms by which the childhood immunization schedule might be associated with adverse events. To use animal models for the biological study of the recommended immunization schedule, however, many challenges must be overcome and limitations must be appreciated. For example, if one is interested in events that are purported to occur long after vaccine administration, such as asthma or food allergy, one must establish the generalizability of animal models of those diseases to the human context. Furthermore, spontaneously occurring models of diseases in animals would have to be developed before

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102 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY studies exploring the safety of the aggregate immunization schedule could be performed. To the committee’s knowledge, realistic animal models that could pro- vide information on the potential of long-term health outcomes of the full immunization schedule in humans are not available. Furthermore, an assessment of the long-term effects of multiple immunizations in, for example, rats 3 months after they receive those immunizations would not be applicable to humans because the onset of such chronic diseases takes years to arise in humans. An example of an animal model is the model of allergic hypersensitiv- ity to dust mites and Ascaris in monkeys, which has resulted in studies of asthma (Hogan et al., 1994). However, few such primate colonies with relevance to asthma in humans exist. Furthermore, the cost to establish and maintain a primate colony is extremely high, and the availability of allergic monkeys is therefore extremely limited. In the absence of animal models of the spontaneous onset of chronic diseases such as Guillain-Barré syndrome, studies of the effects of multiple vaccinations on aspects of airway hyperreactivity in mice or monkeys could be performed, but such studies would be limited in their ability to answer questions about the aggregate immunization schedule. The key limitation to the use of animal models for evaluation of the im- munization schedule therefore is not the availability of science or resources but the limited ability of models to produce results generalizable to the human experience. Given the committee’s recognition of the complexity of the immunization schedule, the importance of family history, the role of individual immunologic factors, and the complex interaction of immuniza- tion with the health care system, the committee determined that it would be more appropriate to focus future research efforts on human research rather than research involving animal models. In summary, it is not possible to recommend studies with animals to in- form the notion that the aggregate childhood immunization schedule results in the onset of chronic diseases. The committee also recognized the role of animal models in understanding neurological diseases, which have made important contributions to the understanding of disease processes that af- fect the brain in terms of structural or motor changes, such as seizures. In addition to the limitations described above in relation to chronic diseases, the study of neurological diseases such as autism has limited use for animal models since “no animal embodies the repertoire of behaviors seen in the human, and in particular, no animal has language equivalent to that of the human” (IOM, 2012, p. 86). Thus, there are sizable barriers in using ani- mal models to assess such neurological outcomes following administration of the childhood immunization schedule.

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METHODOLOGICAL APPROACHES 103 POTENTIAL RESEARCH QUESTIONS OF INTEREST The complexity of the current immunization schedule, which includes variables such as the number of doses, the age of administration, and the time between doses, permits the examination of a large number of potential research questions. Nevertheless, the committee noted a general lack of consistent and integrated theories of biological mechanisms or pathways that link specific elements of the immunization schedule to specific health conditions in the vaccinated child. Perhaps the most compelling hypothesis is that introduction of an excess of immune-stimulating agents into an immature or dysregulated immune system might result in a cascade of adverse immunological pro- cesses culminating in asthma, allergies, autoimmune disorders, and the like. Nevertheless, the biological evidence to support this line of reasoning was examined by an Institute of Medicine committee in 2002 as part of the Im- munization Safety Review series, and that examination found no more than weak justification for such a hypothesis (IOM, 2002). Likewise, the committee’s review of existing epidemiological studies of the immunization schedule was complicated by the effectively infinite num- ber of variations for delivery of the recommended childhood immunization schedule that could be investigated. The literature summarized in Chapter 5 reflects the range of approaches that have been used to characterize depar- tures from the recommended schedule, and no single approach prevailed across multiple investigations. The committee struggled in its efforts to identify research questions that could be posed to evaluate the health outcomes after immunization with the recommended childhood immunization schedule because of a lack of well- defined exposures and biologically plausible outcomes. Thus, the primary research questions of interest that the committee identified and that are listed below are broad and most likely too general to be readily translated into new research studies, unless biologically plausible hypotheses emerge. Among the many questions about the current immunization schedule that could be posed, the committee identified what it viewed to be the lead- ing research questions of interest on the basis of a review of stakeholder concerns. The committee parsed the phrase “this question” in Part 2 of the statement of task into four broad research questions. These questions are listed in Box 6-1. The committee identified other potential gaps in research on the larger health care delivery system and policy-setting procedures that influence parents’ knowledge of and decisions about their immunization choices for their children. For example, several stakeholders identified the need for ad- ditional research on effective provider-patient communications on the risks and benefits of vaccinations. Others suggested the value of addi­ional re- t

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104 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY BOX 6-1 Leading Research Questions of Interest to Select Stakeholders 1.  ow do child health outcomes compare between those who re- H ceive no vaccinations and those who receive the full currently recommended immunization schedule? 2.  ow do child health outcomes compare between (a) those who H receive the full currently recommended immunization schedule and (b) those who omit specific vaccines? 3.  children who receive the currently recommended immunization For schedule, do short- or long-term health outcomes differ for those who receive fewer immunizations per visit (e.g., when immuniza- tions are spread out over multiple occasions), or for those who receive their immunizations at later ages but still within the recom- mended ranges? 4.  o potentially susceptible subpopulations—for example, children D from families with a history of allergies or autoimmune diseases— who may experience adverse health consequences in association with immunization with the currently recommended immunization schedule exist? search on patient barriers to obtaining vaccinations. Although the commit- tee acknowledges that these subjects are of interest and indeed are merely two examples of a large number of potential questions about the system of delivery of the immunization schedule that research could evaluate (see Chapter 4), they are beyond the scope of this committee’s task. There- fore, the committee makes no recommendations regarding further research aimed at addressing such concerns; however, the committee encourages HHS to make continued efforts to identify populations facing barriers to immunization and consider stakeholder concerns on the safety, efficacy, and delivery of the immunization schedule and communication about the immunization schedule, as detailed in Recommendation 4-1. This chapter focuses on potential health benefits or concerns about the recommended schedule at the individual level (e.g., the vaccinated child) and population-level considerations, including monitoring of community immunity (also called “herd immunity,” which is the indirect protection af- forded to unimmunized individuals, e.g., infants too young to be vaccinated against pertussis when a sufficient fraction of the population is vaccinated), that are necessary for study of the recommended immunization schedule.

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METHODOLOGICAL APPROACHES 105 The next section focuses on research questions that directly address the individual health benefits and risks of the recommended immuniza- tion schedule for the vaccinated child and describes a number of research approaches that could be pursued. The chapter then highlights the critical point that the consequences of individual vaccination choices can be con- sidered only in light of the level of immunization in the larger population, to which the individual is invariably linked. The committee recognized the vital importance of considering the population health impacts of any studies of the childhood immunization schedule. As the immunization schedule exists within a complex system consisting of individual-level protection and community immunity, studies that require any variations to the immunization schedule may have a pro- found impact on broader population health. After the discussion of meth- ods to study individual health outcomes, the committee describes methods to monitor and maintain community immunity. GENERAL RESEARCH APPROACHES TO ADDRESS PRIMARY RESEARCH QUESTIONS OF INTEREST Each of the primary research questions of interest to stakeholders con- cerned about the safety of the immunization schedule described in Box 6-1 could be investigated by a range of study methods that vary considerably according to their cost, feasibility, and ethical propriety. At the one end are secondary analyses of existing data sets that could be initiated immediately; at the other end are primary research efforts involving the collection of new data, most notably, large, new RCTs. This section describes the range of research approaches that could be pursued to investigate the leading questions of interest, with attention given to each approach’s potential according to cost, feasibility, and anticipated scientific yield and utility. The research strategies broadly include • initiation of new RCTs, • initiation of new observational studies, and • secondary analyses of data from current vaccine safety surveillance systems in the United States (such as VSD) and comparable inter- national systems. Each of these approaches has some potential to advance knowledge of the four primary research questions identified. The following sections discuss the strengths, limitations, cost, and feasibility of each approach.

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106 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY Randomized Controlled Trials It is widely acknowledged that when it is possible to randomize study participants, the RCT is the preferred design for evaluating the effective- ness and safety of health interventions. Data obtained from RCTs are often touted as the “gold standard” for clinical evidence, and results from a properly conducted clinical trial are considered to be of superior quality and reliability to evidence from most observational studies. The committee deliberately considered the form that an RCT of the immunization schedule could take and explored whether such a design would be both ethical and practical. The critical advantage of the RCT is its ability to randomly assign par- ticipants to follow one of two or more different immunization schedules. Such a design would enable researchers to be reasonably certain that any observed difference in outcomes would be free of bias that could result from unequal allocation to treatment groups and would create reasonably comparable groups. The outcomes observed in a well-conducted RCT thus should accurately reflect an actual causal effect of treatment rather than results that could arise from population differences (Friedman et al., 2010). Although it is well established that vaccines prevent a vast burden of disease among immunized as well as unimmunized or underimmunized peo- ple via community immunity, data suggest that some children continue to receive no vaccinations. One could argue that it would be ethical to recruit this population to an RCT comparing a group that receives the standard vaccination schedule with a group that receives no immunization. Because participants would be randomly placed in one of these study arms, at least half of the participating children, who otherwise would receive no vaccina- tion, would receive all or part of the recommended immunization schedule. The other half would receive no benefit, except for a possible improvement in community immunity that would increase their chances of avoiding vaccine-preventable diseases. They would also avoid any hypothetical risk of receiving immunizations according to the ACIP-recommended schedule. The committee considered and rejected this logic on the basis that any child, even the child of a parent who staunchly rejects vaccination, who is randomized to a no-vaccination arm is essentially consigned to an elevated risk of severe illness and even possible death should the child contract a vaccine-preventable disease. Moreover, should a child in the no-vaccination arm contract a preventable disease, the risk to other unprotected people in the community would increase. Randomization of such a child would also place the child’s pediatrician in the position of having to go against profes- sional medical guidelines. Likewise, parents of intentionally unvaccinated children are unlikely to allow their children to be randomized to receive vaccines. Similarly, the committee believes that any study stipulating that

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METHODOLOGICAL APPROACHES 107 some children receive less than the recommended immunization schedule would not be ethical. The ethics of human experimentation always trump scientific and other considerations, and no study that needlessly endangers children is acceptable. As the committee did not find evidence to suggest that the current schedule is unsafe, the committee concludes that any RCT comparing the current schedule with an alternative schedule that does not provide full and timely coverage of all the currently recommended vaccines would offer an unacceptable risk of vaccine-preventable diseases in indi- viduals and in the population. The committee believes that it may be ethical to use the RCT design to evaluate the third research question, which seeks to determine how health outcomes differ for those who receive the full recommended schedule in unconventional ways. A potential schedule that might be feasible as a comparative intervention is one that would disperse the vaccinations within the recommended window so that children are visiting their health care providers more often but receiving fewer doses at each visit. An example of such a study would be one that compares the health of infants who receive their five immunizations at the 4-month visit during one encounter with a health care provider with the health of infants who receive the same immunizations after age 4 months over the course of five separate visits. Because such a dispersed vaccination schedule would require an increased number of visits, often in rapid succession over a period of a few weeks, such a study would add substantial costs to both parents and providers and, moreover, may be unacceptable to insurers if its effectiveness—measured as a decreased rate of adverse outcomes—is negligible. Although it is unobjec- tionable ethically, the committee considered the time and financial strains resulting from immunization on a dispersed schedule to be too prohibitively costly to recommend pursuing this line of research and, thus, does not endorse this method as a feasible option for studying the recommended immunization schedule. Certain segments of the population, including premature infants, chil- dren born into families with histories of autoimmune disease, and children with genetic traits not yet identified that confer an increased chance of developing diseases having autoimmune features, could be vulnerable both to putative harmful effects of vaccination and, conversely, to the absence of protection from vaccine-preventable diseases should they not be vaccinated. The benefits of immunization to such possibly vulnerable populations could surpass those to children in nonvulnerable groups, allowing them to avoid vaccine-preventable diseases that, although mild for others, could be severe for them. One might hypothesize, however, that the risk of a severe adverse effect of immunization is elevated in this group if, for example, administra- tion of several vaccines causes an immune overload that precipitates the onset of an immunological disease.

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108 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY If observational data suggest that a particular element of the schedule is associated with a particular adverse outcome in an identifiable subgroup, it could be ethical to conduct a randomized trial of the schedule with such a population, if such a trial does not require some children to receive a reduced schedule that would put them at risk for vaccine-preventable dis- ease. However, as both the potential risks and the benefits are elevated and, moreover, the research community does not currently have a sound idea of the magnitudes of those risks and benefits, it is premature to propose RCTs to evaluate differences in outcomes between these hypothesized groups. General Feasibility Issues As detailed in Chapter 3, RCTs to evaluate the introduction of in- dividual vaccinations are conducted within the context of the currently recommended childhood immunization schedule. The committee found no evidence that a trial has ever been conducted to evaluate the entire immu- nization schedule, for example, to compare administration of the recom- mended schedule of vaccines with administration of an alternative schedule. To conduct such a trial would require careful consideration of multiple factors. For instance, it has been established that some vaccines are associ- ated with fevers, febrile convulsions, anaphylaxis, and other syndromes, which in some cases are similar to the symptoms of the diseases that they are intended to prevent. These adverse reactions are mostly rare. For ex- ample, febrile seizures occur for only 1 of every 3,000 measles, mumps, and rubella (MMR) vaccine doses (IOM, 2012), but a sufficiently large study of the safety of a schedule that omits or delays MMR would likely show an increased risk of seizures in the group receiving the regular doses of MMR. Unless researchers somehow accounted for the occurrence of the more seri- ous preventable diseases, it may appear that nonvaccination is “safer” in this respect. To further complicate matters, the rare unvaccinated child in an otherwise heavily vaccinated area will benefit from community immunity and may thus appear to have done better than his or her peers, some of whom will develop adverse effects, such as fever. Because vaccination in the United States essentially begins at birth, an RCT of the immunization schedule would have to randomize children either before birth or shortly thereafter. In addition to the many practical difficulties that this raises, randomization before birth means that the trial cannot be conducted solely through interactions with child health care providers, as pregnant women will typically be seeing a pregnancy care provider in the months preceding delivery. Such a trial would also require parents to adhere to their child’s assigned schedule for at least 6 years and to avoid catch-up immunizations in the years that follow to evaluate hy- pothesized long-term health outcomes, all of which would likely add up to

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METHODOLOGICAL APPROACHES 109 an impractically long study commitment, likely much longer than 10 years. Compliance with this study protocol may prove difficult for parents over this length of time. Clinical trials commonly mask participants and evaluators to the iden- tity of the randomized treatments to prevent bias in the evaluation of treat- ment effects. In an RCT comparing the recommended schedule with an alternative schedule, masking of subjects would involve administration of placebo injections at the recommended vaccination times (for the alterna- tive arm) and at the alternative times (for the recommended arm). Such a scheme would be cumbersome and difficult to implement, potentially caus- ing errors in treatment administration and discouraging good compliance. It would also be unacceptable to parents, who would object to their children being repeatedly injected. One key limitation of RCTs, which was discussed in Chapter 2 in the context of RCTs already performed to evaluate vaccine safety, is that they generally require large sample sizes to have adequate power. The power critically depends on the incidence rate of the adverse outcome in question. For example, a 90 percent power to detect a halving of the rate of an ad- verse event that occurs in 8 percent of children would require a relatively small sample size, likely no more than 2,000 participants. With disorders that are less common, for example, those that occur in only 1 percent of a population, one would need about 15,000 subjects to achieve a 90 percent power of detection. For events that occur very rarely, for example, in 0.25 percent of children, a trial would need upward of 50,000 participants to have the same level of power. Given the weak biological justification for the association of the immunization schedule with any adverse outcome, an RCT would have to include tens or hundreds of thousands of participants to be powered to look for a range of outcomes simultaneously, including those that are very rare (see Appendix D). Only if observational studies suggest specific hypotheses to address could researchers use smaller sample sizes in follow-on RCTs. Given the large number of participants that would be required, the cost of such tri- als would also be prohibitive. Tens of millions of dollars would likely be required to adequately study the identified hypotheses. A federal investment in an RCT of the immunization schedule would therefore be infeasible, and unless further epidemiological evidence of safety problems from ob- servational studies reveals a safety problem, such an investment could be considered wasteful. Overall, the committee recognizes the value of the RCT in provid- ing definitive data on the potential effects of the immunization schedule on adverse outcomes and asserts that the RCT should have a role in the overall research program on the safety of the schedule. Even though RCTs on individual and combination vaccines are part of the federal research

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116 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY Finally, it might be conceivable to conduct direct assessments of sub- groups of interest (e.g., those who receive no vaccinations and a comparable group that receives the full immunization schedule). This option is discussed further below, but it is more feasible to study children who have had incom- plete immunizations by a specified age than to identify children considered vaccine refusals because the population which falls into the latter category is generally very small. Extending the Length of Follow-Up of VSD Patients A limitation of VSD is that it includes data only from individuals in the nine participating health plans. Families with young children may move and switch health plans, resulting in limited follow-up information after their immunizations. This shortcoming is largely overcome in comparable systems in Scandinavia and the United Kingdom because of their universal health care systems and patient registries that contain information on medi- cal services received from primary care providers. The use of strategies to collect health care utilization data through EHRs or provider reports after a participant has left the original health plan may warrant consideration. Increasing the Number and Variety of VSD Participants With an annual birth cohort of more than 100,000 participants, the total number of children monitored through VSD is substantial. However, national estimates derived from a representative sample of all U.S. children, including those in public health plans, suggest that less than 1 percent of children receive no vaccines. Data from VSD (Jason Glanz, University of Colorado–Denver, personal communication) suggest that the number of unvaccinated children within VSD is generally consistent with national values. Approximately 1.23 percent of children participating in VSD had no vaccinations recorded by age 1 year, and 1 percent of children had no vaccinations recorded by age 2 years. These estimates are limited to children who were born between 2004 and 2008 and who had a minimum period of enrollment in VSD of 12 months and a maximum enrollment of 36 months. It is not clear how commonly other variations of the recommended immu- nization schedule occur among the children in VSD. In addition, the diversity of the participants represented in VSD is limited by the fact that managed care organizations in the Southwest and rural South are not currently among the managed care organizations par- ticipating in VSD. Furthermore, because VSD does not now include any public insurance plans, its population has fewer low-income and minority individuals than the number in the U.S. population as a whole. Options to broaden the diversity of VSD participants would enhance the utility of this

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METHODOLOGICAL APPROACHES 117 system to address the primary research questions of interest and increase the generalizability of research results. Further discussion would be required to assess the feasibility and cost of such efforts. The committee noted that although VSD represents the most promising system for investigating outcomes after immunization with the recommended childhood immunization schedule, other resources discussed in Chapter 3, such as VAERS, the National Immunization Survey, and im- munization information systems, are highly valued resources for monitoring vaccine safety and coverage as well. The Post-Licensure Rapid Immuniza- tion Safety Monitoring (PRISM) program, which has been used to evaluate vaccine safety in a larger cohort than the VSD, may have the capability to monitor rare adverse events potentially associated with the childhood immunization schedule. However, the data are not yet well-characterized. Analyses of comparable international immunization surveillance sys- tems in countries including Denmark, the United Kingdom, and Canada have historically been better suited for these purposes for the reasons described below. Although consideration of international immunization surveillance systems was not central to the committee’s task, analyses in Denmark, the United Kingdom, Canada, and other countries also hold considerable promise for advancing knowledge about the health outcomes associated with the immunization schedule. First, as discussed in Chapter 3, these countries often collect and maintain full immunization histories for the entire population, greatly increasing the total sample size and the num- ber of children immunized with less common combinations of vaccines (in- cluding no vaccines). Second, many of these countries have comprehensive health and educational registries permitting linkage to longer-term and less severe child outcomes. Third, these systems include a richer set of variables on sociodemographic characteristics and family history, permitting analyses of potentially susceptible subpopulations. The committee considered but does not recommend cross-national comparisons because of the potential bias and lack of generalizability from results that must account for different environments, vaccine antigens, or immunization schedules. The U.S. population differs from the populations in other countries in important ways, including on the basis of genetics and health care history. Even vaccine efficacy can vary among populations, as has been demonstrated in separate studies of a Haemophilus influenzae type b conjugate vaccine in two different populations (Eskola et al., 1990; Ward et al., 1990). A cross-national comparison to study child health out- comes related to recommended childhood immunization schedules would require careful and extensive consideration of the possible covariates, many of which may not be known at this time. Ecological comparisons may be useful for monitoring disease trends and detecting epidemiological sig- nals; however, the information gathered from such studies could not be

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118 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY extrapolated to inferences of individual risk of adverse events related to each immunization schedule, and thus would not be useful for shaping U.S. immunization policy. The major limitations of U.S. surveillance systems to address the pri- mary research questions identified in this report are (1) the potentially limited number of families included in these systems who will have used the major alternative immunization schedules of interest; (2) potentially high rates of migration from the participating health care organizations, resulting in varying and often short-term follow-up after vaccination; (3) limits on how much information on less severe health outcomes is collected from participating children; and (4) limited ancillary information routinely collected about participating children, such as premature birth or a family history of allergies. Despite these limitations, VSD is currently the best available system for the study of the safety of the immunization schedule in the United States and holds tremendous promise for advancement, including the potential for future prospective cohort studies. Furthermore, continuing to move toward the increased use of EHRs (as encouraged by federal funding), which are what allow VSD to capture and link large amounts of immunization and health data on children, will help the United States establish richer data sets that are more comparable to those in other high- income countries. To further enhance the data collected by VSD, the system should strive to obtain complete demographic information to strengthen its functions and generalizability to the whole U.S. population. Secondary analyses with data from other existing databases similar to VSD would be feasible, ethi- cal, and a lower-cost approach to investigating the research questions that the committee identified, including research on alternative immunization schedules. To date, the data obtained from VSD have already been used to study health outcomes of children with incomplete immunizations or who may follow alternative schedules, as described above. In addition, the VSD system has a large enough proportion of unvaccinated children to inves- tigate differences in health outcomes of unvaccinated and vaccinated chil- dren. Increased efforts to collect information on individual medical histories could lead to a fruitful source of data for studying which populations are potentially susceptible to vaccine adverse events. The committee recognizes that the currently funded managed care organizations’ commitment to VSD studies needs to remain high to continue and build upon existing efforts. Additionally, VSD’s utility will be expanded with the addition of more de- tailed demographic data and family medical histories. Recommendation 6-3: The committee recommends that the Depart- ment of Health and Human Services (HHS) and its partners continue to

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METHODOLOGICAL APPROACHES 119 fund and support the Vaccine Safety Datalink project to study the safety of the recommended immunization schedule. Furthermore, HHS should consider expanding the collaboration with new health plan members and enhancing the data to improve its utility and generalizability. METHODS TO MONITOR COMMUNITY IMMUNITY AND MEASURE POPULATION-LEVEL IMPACTS OF STUDIES OF THE IMMUNIZATION SCHEDULE If large numbers of children avoided immunization, community immu- nity would be eroded and this protective effect would disappear for those who are not or who cannot be fully vaccinated. Thus, any analysis of vac- cine safety data needs to consider the community immunity aspect of the milieu in which the study is conducted. Such complications would affect both clinical trials and observational studies. Consideration of Population Impacts of Alternative Schedules Attempts to quantify the relative safety of contrasting immunization schedules need to take into account at least two separate health outcomes: (1) adverse events related to the administration of specific vaccines and the overall immunization schedule, and (2) the respective impacts of alterna- tive schedules on the circulation of vaccine-preventable diseases and the consequent adverse outcomes associated with infection. Secondary effects (such as longer waiting times and the greater cost of care if more visits are needed for immunization) and potential medical errors in provider offices accustomed to the routine schedule would also have to be measured. Previously, high-profile analyses have focused on calculation of the number of serious reactions either per vaccine or over the immunization schedule compared with the per child risk of hospitalization associated with vaccine-preventable diseases (Sears, 2011). Although such analyses are intuitively appealing, they overlook the intimate association between immu- nization and age-specific disease incidence. Specifically, any shifts in the im- munization schedule that lead to a net increase in the time spent vulnerable to these diseases will inevitably increase the circulation of these pathogens. The population-level impacts of such an outcome will be a simultaneous rise in the incidence of the affected infectious diseases and a reduction in the age at which they are contracted. Thus, not only is the risk of exposure to vaccine-preventable diseases increased but so is the likely severity of infec- tion, which may be most acute in younger children (Heiniger et al., 1997). A clear manifestation of the dual impact of immunization on the inci- dence and age distribution of vaccine-preventable diseases has been docu- mented in Sweden, where the pertussis vaccine was removed from the

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120 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY national pediatric immunization schedule in 1979 because of concerns over the reactogenicity of the whole-cell vaccine (Gangarosa et al., 1998; Romanus et al., 1987). After a 17-year hiatus, the acellular pertussis vaccine was added to the immunization schedule in 1996 (Carlsson and Trollfors, 2009). Analyses of age-stratified incidence reports highlighted both a sharp decline in the incidence and a marked increase in the age distribution of per- tussis cases as a result of the resumption of immunization against pertussis (Rohani et al., 2010). Importantly, Swedish data also illustrate the concept of community immunity. A pattern similar to that seen in Sweden has been observed in England and Wales, where declines in the uptake of MMR after controversy insti- gated by a subsequently retracted paper questioning the vaccine’s safety were associated with a rise in measles notifications and a shift in the inci- dence of measles toward younger age groups (Jansen et al., 2003). Predicting Changes to Community Immunity As outlined in the commissioned paper (see Appendix D), a variety of designs may be used to compare the safety of alternative schedules. It is, unfortunately, difficult predict the long-term population-level consequences of disease transmission as a result of changes to the immunization schedule. It is possible, however, to use mathematical and computational models to predict the impacts of changes in the administration of any one specific vaccine on the incidence of the infectious disease affected by that vaccine. This process involves three distinct steps: model formulation, parameter- ization, and model validation. These and other elements of the models are described below. Model Formulation The development of a disease-specific transmission model begins with determination of the model structure and key processes, which are informed by the known immunology and epidemiology of the system. For instance, a loss of immunity may be a necessary ingredient for a model of pertussis transmission, whereas a latent carrier stage may be appropriate for varicella (Anderson and May, 1992; Keeling and Rohani, 2008). The model also needs to explicitly consider age-dependent heterogeneities in contact rates, susceptibility to complications, and reporting. A number of age-specific models have been proposed for many of the key childhood infections, including measles (Anderson and May, 1992; Schenzle, 1984), pertussis (Hethcote, 1998; Rohani et al., 2010), Strepto- coccus pneumoniae infection (Cobey and Lipsitch, 2012), rubella (Metcalf et al., 2011), and chickenpox (Ferguson et al., 1996).

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METHODOLOGICAL APPROACHES 121 Parameterization and Model Validation The usefulness of any model and the reliability of its predictions de- pend on its veracity. Thus, models need to be carefully based on ground truths, a process that is made particularly challenging for high-dimensional age-structured models because a fundamental challenge to the effective pa- rameterization of age-specific models is determination of the appropriate patterns of contact by age. It is fortunate that recent studies have addressed this problem, and detailed information on the typically age-stratified pat- terns of contact in the United States (Del Valle et al., 2007) and a number of European countries (Mossong et al., 2008) is now available. Synthesis of this information together with historical incidence data to formulate validated transmission models is made possible by the use of modern infer- ence techniques, including sequential Monte Carlo methods for hypothesis testing (Ionides et al., 2006). An example is the age-structured pertussis model developed by Rohani et al. (2010) and parameterized with data from incidence reports from Sweden. Data Needs The production of fully validated transmission models requires access to age-specific incidence reports. This is often a critical bottleneck in such an endeavor, as public health agencies (e.g., CDC) do not routinely pro- vide such complete data via, for instance, the National Notifiable Diseases Surveillance System (Goldwyn and Rohani, 2012). When detailed incidence reports, stratified by age, county, and immunization status (e.g., through the Supplementary Pertussis Surveillance System), do become available, requests for access to such data are not always granted in a timely manner, and may be answered with the provision of data that was not obtained us- ing the best-available methods (Thacker et al., 2012). Quantifying Uncertainty and Sensitivity The predictions of any formal modeling analyses need to be evaluated within the context of their inherent variability and should be subject to extensive sensitivity analyses (Blower, 2000). Uncertainty in predictions can be quantified by use of a wide array of rigorous probabilistic approaches to model execution, whereby the system of equations is translated into a Markov chain process (Gibson and Bruck, 2000; Gillespie, 1977; Keeling and Rohani, 2008). Such an approach would permit a detailed situational analysis, whereby the model could provide policy makers with information on the most likely (i.e., the median) outcome, for example, the size of the focal vaccine-preventable disease outbreak given a specific change in the

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122 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY immunization schedule. This approach would also provide information about extreme outcomes or the 95th percentile of predicted outbreak sizes (Park et al., 2009; Rohani et al., 2009). Examination of sensitivity involves extensive repetition of the model simulation as a critical parameter of in- terest (e.g., the efficacy of the first dose of diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed administered at 3 months of age) is systematically varied. The development, appropriate parameterization, and scrutiny of mech- anistic transmission models have been adopted by a number of governmen- tal agencies, and this process has been influential for determination of the implementation of specific immunization practices in countries such as the United Kingdom. In 2002, for example, Edmunds et al. used an approach similar to that outlined here to examine the potential cost-effectiveness of introduction of an acellular pertussis booster vaccine to the schedule in England and Wales (Edmunds et al., 2002). Similarly, Jit et al. (2008) car- ried out extensive analyses of detailed transmission models to inform the policy decision of the government of the United Kingdom on the effective- ness of routine vaccination of 12-year-old schoolgirls against human papil- lomavirus. Other examples include identification of the optimal targeting of age groups to contain the influenza pandemic (Medlock and Galvani, 2009), as well as pinpointing the most effective immunization schedule for meningococcal serogroup C (Trotter and Edmunds, 2006). CONCLUSIONS The committee deliberated on many potential research approaches and worked to determine which were feasible, ethical, and cost-effective. The commissioned paper in Appendix D helped identify methods that could be considered. Many questions can be answered by use of the methods described above, although they are not currently well integrated. Chapter 7 summarizes the committee’s judgment on its statement of task. Setting of priorities for research will be challenging. For example, the committee does not recommend a study comparing the recommended immunization schedule and no immunization at this time because a high- quality randomized trial is not ethical and a prospective observational study could be complex, lengthy, and expensive and would potentially provide inconclusive results about key health outcomes after immuniza- tion. Thus, the committee proposes establishment of a process for setting priorities incorporating epidemiological and other evidence (on the basis of ­ ormal systematic reviews), biological plausibility, feasibility, and stake- f holder concerns.

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