immunizations has been, and could continue to be, of societal significance in terms of parental worries, potential health burdens, and future challenges for immunization policy-making.

RECOMMENDATIONS FOR PUBLIC HEALTH RESPONSE

With government and professional recommendations calling for young children to receive increasing numbers of immunizations, it is important to respond to concerns about possible increases in risk of allergic or autoimmune diseases. Although the committee’s review favors rejection of a causal association between multiple immunizations and type 1 diabetes or risk of infection, and the review is inconclusive for asthma, the biological evidence does provide weak support for increased risk of allergy and for autoimmunity and strong support for increased risk of infection (see Table 6 for a summary). The committee was not able to address more than one autoimmune disease and one specific allergic disease in this report. The generalizability of the epidemiological evidence and the causality assessments to every possible type of exposure to multiple immunizations and every type of immune dysfunction is not clear. In addition, the burden of autoimmune and allergic diseases is great. Investigating whether associations indeed exist poses difficult scientific challenges, and relevant epidemiological evidence remains limited. Several important scientific and policy issues, therefore, deserve further public health attention.

Policy Review

The nature of the childhood immunization schedule is likely to change in response to such factors as the development of new vaccines and utilization of novel delivery systems. Changing perceptions of disease risks—derived from antibiotic resistance, threats of bioterrorism, or (re)emerging infectious diseases—could also lead to wider use of existing vaccines not currently included in the immunization schedule. As the array of available vaccines and disease targets expands, the current emphasis on universal recommendations and state mandates for vaccine use should be reassessed (Feudtner and Marcuse, 2001). The committee recommends that state and federal vaccine policymakers consider a broader and more explicit strategy for developing recommendations for the use of vaccines.

Such a strategy should include consideration of a range of perspectives (e.g., those of individuals, families, organizations, society) regarding the benefits, risks, and ethical implications of vaccine use and immunization policies. Priorities can be expected to differ among those diverse perspectives, and policymakers must consider how to achieve an equitable balance (Feudtner and Marcuse, 2001).



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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction immunizations has been, and could continue to be, of societal significance in terms of parental worries, potential health burdens, and future challenges for immunization policy-making. RECOMMENDATIONS FOR PUBLIC HEALTH RESPONSE With government and professional recommendations calling for young children to receive increasing numbers of immunizations, it is important to respond to concerns about possible increases in risk of allergic or autoimmune diseases. Although the committee’s review favors rejection of a causal association between multiple immunizations and type 1 diabetes or risk of infection, and the review is inconclusive for asthma, the biological evidence does provide weak support for increased risk of allergy and for autoimmunity and strong support for increased risk of infection (see Table 6 for a summary). The committee was not able to address more than one autoimmune disease and one specific allergic disease in this report. The generalizability of the epidemiological evidence and the causality assessments to every possible type of exposure to multiple immunizations and every type of immune dysfunction is not clear. In addition, the burden of autoimmune and allergic diseases is great. Investigating whether associations indeed exist poses difficult scientific challenges, and relevant epidemiological evidence remains limited. Several important scientific and policy issues, therefore, deserve further public health attention. Policy Review The nature of the childhood immunization schedule is likely to change in response to such factors as the development of new vaccines and utilization of novel delivery systems. Changing perceptions of disease risks—derived from antibiotic resistance, threats of bioterrorism, or (re)emerging infectious diseases—could also lead to wider use of existing vaccines not currently included in the immunization schedule. As the array of available vaccines and disease targets expands, the current emphasis on universal recommendations and state mandates for vaccine use should be reassessed (Feudtner and Marcuse, 2001). The committee recommends that state and federal vaccine policymakers consider a broader and more explicit strategy for developing recommendations for the use of vaccines. Such a strategy should include consideration of a range of perspectives (e.g., those of individuals, families, organizations, society) regarding the benefits, risks, and ethical implications of vaccine use and immunization policies. Priorities can be expected to differ among those diverse perspectives, and policymakers must consider how to achieve an equitable balance (Feudtner and Marcuse, 2001).

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction As part of that exercise, the committee also encourages state and federal immunization policymakers to include a discussion of state mandates for vaccine use. The committee is encouraged by an activity, tentatively called the “Workgroup on Public Health Options for Implementing Vaccine Recommendations,” currently underway by the National Vaccine Advisory Committee (NVAC) of the National Vaccine Program Office (NVPO). The exact nature of that activity—its scope, timetable, and authority to initiate action—are not clear, but it appears to be an important first step toward this dialogue. The committee hopes that this important activity remains a priority for NVPO and NVAC, even as other timely vaccine-related issues influence the agenda. Such issues require long-term planning and evaluation; a reactive response to the next schedule addition will be much less effective than a proactive assessment and strategy development across the board. As part of this overall effort, the committee encourages an exploration of the merits of accommodating requests for alternative vaccine dosing schedules and the development of appropriate clinical guidance for any such alternatives. A more flexible schedule might allow for a reduction in the number of vaccines administered at one time. Such a change would respond to some concerns about multiple immunizations; but it could also have disadvantages, such as requiring more health care visits, that might contribute to lower rates of immunization coverage in the population and consequent increases in morbidity and mortality. In addition, such a change would require extensive communication with healthcare providers and health plans in order that appropriate immunizations occur and are compensated as much as they are for the “traditional” schedule. A more flexible schedule might also permit innovative epidemiological research that currently is difficult because of the homogenous immunization schedules now extant in the United States. If more flexible schedules do gain acceptance, policymakers must ensure that those options are equally available to children who receive immunizations in public clinics and those who are served by private providers. By issuing the recommendation listed above, the committee does not intend to signal concern about health consequences of the multiple immunizations in the recommended childhood immunization schedule. In fact, the committee does not recommend a policy review—by the CDC’s Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics’ Committee on Infectious Diseases, and the American Academy of Family Physicians—of the current recommended childhood immunization schedule on the basis of concerns about immune system dysfunction. Similarly, the committee does not recommend a policy review by the Food and Drug Administration’s Vaccines and Related Biologic Products Advisory Committee of any currently licensed vaccines on the basis of concerns about immune system dysfunction. The committee’s review of evidence regarding multiple immunizations and immune system dysfunction provides no basis for recommending

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction reconsideration at this time of the current childhood immunization schedule or of any specific vaccine. Research The committee concluded that the findings available from epidemiological sources and consideration of possible biological mechanisms—which were deemed weak—do not at this time warrant specialized studies of possible associations between multiple immunizations and immune system dysfunction. Instead, the committee encourages epidemiological studies conducted within the framework of ongoing research and surveillance programs on allergy, autoimmune disease, and vaccine safety; it also encourages additional basic research on the immune system and on allergy and autoimmune diseases. Epidemiological Studies The committee emphasizes the need for continuing surveillance of vaccine recipients and possible adverse events. Changes in the immunization schedule may present opportunities to study whether or not the incidence of adverse health outcomes also changes. However, one of the challenges in addressing concerns about multiple immunizations is identification of appropriate and adequately sized study populations; allergy or autoimmune diseases have complex risk factors and potentially long intervals between vaccine exposure and diagnosis. Several vaccine-related data resources already exist, including the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and state and local immunization registries. The committee recommends exploring the feasibility of using existing vaccine surveillance systems, alone or in combination, to study safety questions related to asthma and other important allergic disorders, as well as to study type 1 diabetes and other important autoimmune diseases. In addition, surveillance of autoimmune diseases and allergic disorders should be strengthened. Despite the routine diagnosis of asthma, finding a widely accepted definition for the disease has been problematic (Samet 1987, Toelle et al., 1997). The absence of a universally accepted definition of asthma makes it difficult to determine a consistent operational definition for epidemiological studies (IOM, 2000). Disease registries and long-term research programs that identify individuals with these diseases, or with known genetic risk factors, could be an efficient means of finding subjects for either retrospective or prospective studies of possible vaccine-related risks. The committee recommends exploring the use of such cohorts for research on possible vaccine-related disease risks. Furthermore, the committee recommends that disease registries and research programs for autoimmune and allergic disorders routinely collect

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction immunization histories as part of their study protocols. The committee is encouraged to see that the Diabetes Autoimmunity Study in the Young (DAISY), which includes cohorts drawn from the general population and from siblings and offspring of persons with IDDM, is already including immunizations as a routinely monitored variable. Basic and Clinical Science Research on the developing human immune system, especially in relation to vaccines, is limited. Studies of animal models are essential to advancing knowledge of the immune system, but those studies have limits because of important differences between humans and animals. Thus, the committee recommends continued research on the development of the human infant immune system. A better understanding of the development of the human immune system is needed as a basis for improved understanding of infants’ response to vaccines and other environmental exposures. In addition, the committee encourages collaborative activities, such as NIAID/NICHD workshops and initiatives, that help the research community synthesize the results of individual research efforts. The inclusion of vaccinologists and vaccine safety researchers in these efforts is encouraged. Genetic factors are known to be an important source of variability in the responses of the human immune system and in the risks of allergic or autoimmune disease. But understanding of the complex interactions among genetic variables, as well as of the interactions between those variables and environmental exposures (including vaccines and wild-type viral and bacterial agents), remains incomplete. The committee endorses current research efforts aimed at identifying genetic variability in human immune system development and immune system responsiveness as a way to gain a better understanding of genetic susceptibility to vaccine-based adverse events. For some autoimmune and allergic disorders, surrogate biological markers of disease or disease risk have been identified. In particular, in individuals at risk for type I diabetes, the development of multiple autoantibodies to GAD65 (glutamic acid decarboxylase), IA-2 (protein tyrosine phosphatase-like molecule), and insulin correlate strongly with later development of overt type I diabetes (Notkins and Lernmark, 2001). However, there are to date no other surrogate markers that have sufficient predictive power to be useful in monitoring risk for other autoimmune diseases in children receiving routine immunizations (Leslie et al., 2001). For allergic disorders, the clinical history of allergic diseases should be collected in follow-up evaluations, and the feasibility of specific tests for atopy considered. Studies of the normal development of the immune system in conjunction with surrogate markers of autoimmune and allergic disease and a cohort analysis of autoimmune and allergic disease could be carried out not only in the United States but in infants in a less developed country. Such a compari-

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction son might more clearly define how an earlier and more intense exposure to microbes might influence the maturation process and alter the proposed impact of immunizations on allergy and autoimmune disease. In theory, collecting data on known markers in the course of vaccine research and testing would present an opportunity to study the prevalence of such markers before and after immunization. Similarly, it might also be possible to study whether the prior presence of a marker was associated with differences in the response to a vaccine. The committee recommends exploring the feasibility of collecting data on surrogate markers for type I diabetes and clinical history of allergic diseases in the vaccine testing and licensing process. Such data might also be useful in vaccine-related studies in high-risk cohorts, such as those in the DAISY study. The committee recommends exploring surrogates for type I diabetes and clinical history of allergic diseases in existing cohort studies of variations in the immunization schedule. Communication Along with the increasingly complex immunization schedule has come a dramatic increase in the complexity of vaccine safety issues, and it appears that some people have redefined their conceptions of the related risks and benefits. The focus seems to have shifted from whether children will get a disease if they are not vaccinated to whether children will experience temporary or potentially longer-term adverse events if they are vaccinated (McPhilips and Marcuse, 2001). The committee is not convinced, however, that available reports on such attitudes provide an adequate scientific basis for understanding either these changes in perception or the groups that are experiencing them. Reports from population-based telephone surveys, for example, typically provide information about what people think, but such surveys rarely can probe adequately about why respondents think the way they do. More information is needed in order to develop effective risk-benefit communication strategies on immunization and vaccine safety. A deeper understanding of why and how people make decisions as they do is needed, but relying on impressions, assumptions, or any single research method (e.g., survey, focus group, mental modeling, decision analysis) will be too limited. Therefore, the committee recommends that an appropriate panel of multidisciplinary experts be convened by the Department of Health and Human Services. It would develop a comprehensive research strategy for knowledge leading to the optimal design and evaluation of vaccine risk-benefit communication approaches. By communication approaches, the committee is not referring to communication tools, such as vaccine information statements, lists of frequently asked questions (FAQs), or websites. Instead, the committee intends that this panel consider a larger definition of risk-benefit communication goals and strategies. In addition, this multidisciplinary panel