Immunization Safety Review: Vaccines and Autism

Immunization to protect children and adults from infectious diseases is one of the greatest achievements of public health. Immunization is not without risks, however. It is well established, for example, that the oral polio vaccine on rare occasion has caused paralytic polio and that vaccines sometimes produce anaphylactic shock. Given the widespread use of vaccines, state mandates requiring vaccination of children for entry into school, college, or day care, and the importance of ensuring that trust in immunization programs is justified, it is essential that safety concerns receive assiduous attention.

The Immunization Safety Review Committee was established by the Institute of Medicine (IOM) to evaluate the evidence on possible causal associations between immunizations and certain adverse outcomes, and to then present conclusions and recommendations. The committee’s mandate also includes assessing the broader significance for society of these immunization safety issues.

This eighth report from the committee examines the hypothesis that vaccines, specifically the measles-mumps-rubella (MMR) vaccine and thimerosal-containing vaccines, are associated with autism.

THE CHARGE TO THE COMMITTEE

Challenges to the safety of immunizations are prominent in public and scientific debate. Given these persistent and growing concerns, the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) recog-



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Immunization Safety Review: Vaccines and Autism Immunization Safety Review: Vaccines and Autism Immunization to protect children and adults from infectious diseases is one of the greatest achievements of public health. Immunization is not without risks, however. It is well established, for example, that the oral polio vaccine on rare occasion has caused paralytic polio and that vaccines sometimes produce anaphylactic shock. Given the widespread use of vaccines, state mandates requiring vaccination of children for entry into school, college, or day care, and the importance of ensuring that trust in immunization programs is justified, it is essential that safety concerns receive assiduous attention. The Immunization Safety Review Committee was established by the Institute of Medicine (IOM) to evaluate the evidence on possible causal associations between immunizations and certain adverse outcomes, and to then present conclusions and recommendations. The committee’s mandate also includes assessing the broader significance for society of these immunization safety issues. This eighth report from the committee examines the hypothesis that vaccines, specifically the measles-mumps-rubella (MMR) vaccine and thimerosal-containing vaccines, are associated with autism. THE CHARGE TO THE COMMITTEE Challenges to the safety of immunizations are prominent in public and scientific debate. Given these persistent and growing concerns, the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) recog-

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Immunization Safety Review: Vaccines and Autism nized the need for an independent, expert group to address immunization safety in a timely and objective manner. The IOM has been involved in such issues since the 1970s. (A brief chronology can be found in Appendix D.) In 1999, because of IOM’s previous work and its access to independent scientific experts, CDC and NIH began a year of discussions with IOM to develop the Immunization Safety Review project, which would address both existing and emerging vaccine safety issues. The Immunization Safety Review Committee is responsible for examining a broad variety of immunization safety concerns. Committee members have expertise in pediatrics, neurology, immunology, internal medicine, infectious diseases, genetics, epidemiology, biostatistics, risk perception and communication, decision analysis, public health, nursing, and ethics. While all of the committee members share the view that immunization is generally beneficial, none of them has a vested interest in the specific immunization safety issues that come before the group. Additional discussion of the committee composition can be found in the Foreword, written by Dr. Harvey Fineberg, President of the IOM. The committee was charged with examining up to three immunization safety hypotheses each year during the three-year study period (2001-2003). These hypotheses were selected by the Interagency Vaccine Group (IAVG), whose members represent several units of the Department of Health and Human Services: the CDC’s National Vaccine Program Office, National Immunization Program, and National Center for Infectious Diseases; the NIH’s National Institute of Allergy and Infectious Diseases; the Food and Drug Administration (FDA); the Health Resources and Services Administration’s National Vaccine Injury Compensation Program; and the Centers for Medicare & Medicaid Services. The IAVG includes representation from the Department of Defense and the Agency for International Development as well. The committee has issued seven previous reports on vaccine safety issues over the three-year study period (2001-2003). This eighth and final report from the committee examines the hypothesis that vaccines, specifically the MMR vaccine and thimerosal-containing vaccines (TCVs), cause autism. In its first two reports that were published in 2001, the committee examined the hypothesized causal association between the MMR vaccine and autism and TCVs and neurodevelopmental disorders (NDDs), respectively. The IAVG asked the committee to revisit the hypothesized causal association between vaccines and autism in its final report in order to update its conclusions and recommendations based on the significant number of studies that have been undertaken in the last three years. For each topic, the Immunization Safety Review Committee reviews relevant literature and submissions by interested parties, holds an open scientific meeting, and directly follows the open meeting with a one- to two-day closed meeting to formulate its conclusions and recommendations. The committee’s

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Immunization Safety Review: Vaccines and Autism findings are released to the public in a brief consensus report 60 to 90 days after its meeting. The committee is charged with assessing both the scientific evidence regarding the hypotheses under review and the significance of the issues for society. The scientific assessment has two components: (1) an examination of the epidemiologic and clinical evidence regarding a possible causal relationship between exposure to the vaccine and the adverse event; and (2) an examination of theory, and of experimental or observational evidence from in vitro, animal, or human studies, regarding biological mechanisms that might be relevant to the hypothesis. The significance assessment addresses such considerations as the burden of the health risks associated with the adverse event as well as with the vaccine-preventable disease. Other considerations may include the perceived intensity of public or professional concern, and the feasibility of additional research to help resolve scientific uncertainty regarding causality. The findings of the scientific and significance assessments underlie the committee’s recommendations regarding the public health response to the issue. In particular, the committee addresses any needs for a review of immunization policy, for current and future research, and for effective communication strategies. See Figure 1 for a schematic representation of the committee’s charge. THE STUDY PROCESS The committee held an initial organizational meeting in January 2001. CDC and NIH presented the committee’s charge at the meeting, and the committee then conducted a general review of immunization safety concerns. At this meeting, the committee also determined the basic methodology to be used for assessing causality in the hypotheses to be considered in its subsequent deliberations. A website (www.iom.edu/imsafety) and a listserv were created to provide public access to information about the committee’s work and to facilitate communication with the committee. The conclusions and recommendations of the committee’s reports thus far (see Box 1) are summarized in Appendix A. For its evaluation of the questions concerning vaccines and autism, the committee held an open scientific meeting in February 2004 to hear presentations on issues germane to the topic (see Appendix B). Many of these presentations are available in electronic form (audio files and slides) on the project website. In addition, the committee reviewed an extensive collection of material, primarily from the published, peer-reviewed scientific and medical literature. The committee also commissioned a paper on autism and the immune system. A list of the

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Immunization Safety Review: Vaccines and Autism FIGURE 1 Committee charge.

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Immunization Safety Review: Vaccines and Autism BOX 1 Previous Reports of the Immunization Safety Review Committee Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism (IOM, 2001a) Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders (IOM, 2001b) Immunization Safety Review: Multiple Immunizations and Immune Dysfunction (IOM, 2002b) Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders (IOM, 2002a) Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer (IOM, 2002c) Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy (IOM, 2003) Immunization Safety Review: Influenza Vaccines and Neurological Complications (IOM, 2004) materials reviewed by the committee, including many items not cited in this report, can be found on the project’s website. THE FRAMEWORK FOR SCIENTIFIC ASSESSMENT Causality The Immunization Safety Review Committee has adopted the framework for assessing causality developed by previous IOM committees (IOM, 1991, 1994a,b) convened under the congressional mandate of P.L. 99-660 to address questions of immunization safety. The categories of causal conclusions used by the committee are as follows: No evidence Evidence is inadequate to accept or reject a causal relationship Evidence favors rejection of a causal relationship Evidence favors acceptance of a causal relationship Evidence establishes a causal relationship Assessments begin from a position of neutrality regarding the specific immunization safety hypothesis under review. That is, there is no presumption that a specific vaccine (or vaccine component) does or does not cause the adverse event in question. The weight of the available clinical and epidemiologic evi-

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Immunization Safety Review: Vaccines and Autism dence determines whether it is possible to shift from that neutral position to a finding for causality (“the evidence favors acceptance of a causal relationship”) or against causality (“the evidence favors rejection of a causal relationship”). The committee does not conclude that the vaccine does not cause the adverse event merely because the evidence is inadequate to support causality. Instead, it maintains a neutral position, concluding that the “evidence is inadequate to accept or reject a causal relationship.” Although no firm rules establish the amount of evidence or the quality of the evidence required to support a specific category of causality conclusion, the committee uses standard epidemiologic criteria to guide its decisions. The most definitive category is “establishes causality,” which is reserved for those relationships in which the causal link is unequivocal, as with the oral polio vaccine and vaccine-associated paralytic polio or with anaphylactic reactions to vaccine administration (IOM 1991, 1994a). The next category, “favors acceptance” of a causal relationship, reflects evidence that is strong and generally convincing, although not firm enough to be described as unequivocal or established. “Favors rejection” is the strongest category in the negative direction. (The category of “establishes no causal relationship” is not used because it is virtually impossible to prove the absence of a relationship with the same surety that is possible in establishing the presence of one.) If the evidence is not reasonably convincing either in support of or against causality, the category “inadequate to accept or reject a causal relationship” is used. Evidence that is sparse, conflicting, of weak quality, or merely suggestive—whether toward or away from causality—falls into this category. Under these circumstances, some authors of similar assessments use phrases such as “the evidence does not presently support a causal association.” The committee believes, however, that such language does not make the important distinction between evidence indicating that a relationship does not exist (category 3) and evidence that is indeterminate with regard to causality (category 2). The category of “no evidence” is reserved for those cases in which there is a complete absence of clinical or epidemiologic evidence. The sources of evidence considered by the committee in its assessment of causality include epidemiologic and clinical studies directly addressing the question at hand. That is, the data are specifically related to the effects of the vaccine(s) under review and the adverse health outcome(s) under review—in this report, the MMR vaccine and thimerosal-containing vaccines and the risk of autism. Epidemiologic studies carry the most weight in a causality assessment. These studies measure health-related exposures and outcomes in a defined set of subjects and use that information to make inferences about the nature and strength of associations between such exposures and outcomes in the overall population from which the study sample was drawn. Epidemiologic studies can be categorized as observational or experimental (clinical trial), and as uncontrolled or

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Immunization Safety Review: Vaccines and Autism controlled. Among these categories, experimental studies generally have the advantage of random assignment to exposures and are therefore the most influential in assessing causality. Uncontrolled observational studies are important but are generally considered less definitive than controlled observational studies. Ecological studies are another category of epidemiological studies that use populations or groups of people, rather than individuals, as the units of analysis (Last et al., 1995). Because the joint distribution of the study factors(s) and disease within each group is unknown in ecological studies, it is difficult to make any causal inferences regarding the association between an exposure and disease at the individual level (Kleinbaum et al., 1982). The committee also separates those studies that analyze data from passive reporting systems into a separate category. Case reports and case series are generally inadequate by themselves to establish causality. Despite the limitations of case reports, the causality argument for at least one vaccine-related adverse event (the relationship between vaccines containing tetanus toxoid and Guillain-Barré syndrome) was strengthened most by a single, well-documented case report on recurrence of the adverse event following readministration of the vaccine, a situation referred to as a “rechallenge” (IOM, 1994a). Biological Mechanisms The committee’s causality assessments must be guided by an understanding of relevant biological processes. Therefore the committee’s scientific assessment includes consideration of biological mechanisms by which immunizations might cause an adverse event. The evidence reviewed comes from human, animal, and in vitro studies of biological or pathophysiological processes relevant to the question before the committee. This kind of review was referred to in previous reports of this committee on vaccines and autism (IOM, 2001a,b) and others (IOM, 1991, 1994a) as an assessment of the “biological plausibility” of a causal relationship. The use of “biologic mechanisms” in lieu of “biologic plausibility” was introduced in the committee’s third report (IOM, 2002b). The committee shifted its terminology for several reasons. First, an agreed upon hierarchy of evidence required for assessments of biological plausibility does not exist, nor does an associated terminology (Weed and Hursting, 1998). Second, the committee noted that the term biological plausibility is associated with a particular set of guidelines (sometimes referred to as the Bradford Hill criteria) for causal inference from epidemiological evidence (Hill, 1965). In that context, an assessment of the biological plausibility of an association demonstrated by epidemiological analysis is meant to ensure that such an association is consistent with current biological knowledge. Evidence regarding biological plausibility, however, can never prove causality. It is also meant to guard against attributions of causality to biologically implausible statistical associations that

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Immunization Safety Review: Vaccines and Autism might result from studies that have not adequately accounted for important variables.1 Third, the committee understands that some readers of its reports are confused by what might be perceived as contradictory findings. Although the committee has previously stated that biological plausibility can range across a spectrum, readers sometimes regard the term with a degree of certainty or precision the committee never intended. When other evidence of causality is available, biological plausibility adds an additional piece of supportive evidence. However, in the absence of other evidence pointing to a causal relationship, use of the term biological plausibility, as ingrained in the language of causal inference, seems to add confusion. Thus the committee concluded in its third report (IOM, 2002b) that for future reports, the lack of clarity in the phrase “biological plausibility” warranted the adoption of new terminology and a new approach to its discussion of biological data. The committee decided to review evidence regarding “biological mechanisms” that might be consistent with the proposed relationship between a vaccine exposure and given adverse events. The biological mechanisms section of the report is written distinct from any argument regarding the causality of such relationships. This is not meant to imply that current understanding of biological processes does not shape or guide assessments of causality. When convincing statistical or clinical evidence of causality is available, biological data add support. This committee, however, is often faced with a set of circumstances in which the epidemiological evidence is judged inadequate to accept or reject a causal association between a vaccine exposure and an adverse event of concern. It is then left with the task of examining proposed or conceivable biological mechanisms that might be operating if an epidemiologically sound association could be shown between vaccine exposure and an adverse event. Identification of sound mechanisms could influence the development of an appropriate research agenda and give support to policymakers, as decisions frequently must be made in situations of incomplete information regarding causality. Finally, there is often value in understanding and pursuing possible biological mechanisms even if the epidemiological evidence suggests a 1   For example, although a strong statistical relationship might exist between a woman’s risk of breast cancer and the number of bathrooms in her home, there is no mechanism based on knowledge of cancer biology that could indicate the relationship is causal. Rather, the number of bathrooms is associated with socioeconomic status, which is associated with such factors as diet that can be linked mechanistically to cancer biology. The biological implausibility of an association between the number of bathrooms in a house and the risk of breast cancer weakens the argument for a causal relationship. In other cases, a review of the biological plausibility of an association might add reassurance that the epidemiological findings point toward or reflect causality. Occasionally an epidemiological observation has been explained by a reasonable biological mechanism that, on further investigation, appeared not to be relevant for the pathophysiology.

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Immunization Safety Review: Vaccines and Autism lack of a causal association. New epidemiological studies could lead one to revise a previous causality assessment thus giving sound biological mechanisms more prominence in future assessments. Also, a review of biological data could give support to the negative causality assessment or could cause one to reconsider or pursue the epidemiological findings further. However, absent evidence of a statistical association, or convincing clinical evidence, biological mechanisms cannot be invoked to prove causality. The committee has established three general categories of evidence on biological mechanisms: Theoretical. A reasonable mechanism can be hypothesized that is commensurate with scientific knowledge and does not contradict known physical and biological principles, but has not been demonstrated in whole or in part in humans or animal models. Postulated mechanisms by which a vaccine might cause a specific adverse event but for which no coherent theory exists would not qualify for this category. Thus, “theoretical” is not a default category, but one that requires thoughtful and biologically meaningful suppositions. Experimental. A mechanism can be shown to operate in in vitro systems, animals, or humans. But experimental evidence often describes mechanisms that represent only a portion of the pathological process required for expression of disease. Showing that multiple portions of a process operate in reasonable experimental models strengthens the case that the mechanisms could possibly result in disease in humans, but it cannot establish proof. Some experimental evidence is derived under highly contrived conditions. For example, achieving the results of interest may require extensive manipulation of the genetics of an animal system, or in vivo or in vitro exposures to a vaccine component that are extreme in terms of dose, route, or duration. Other experimental evidence is derived under less contrived conditions. For example, a compelling animal or in vitro model might demonstrate a pathologic process analogous to human disease when a vaccine antigen is administered under conditions similar to human use. Experimental evidence can also come from studies in humans. In any case, biological evidence is distinct from the epidemiologic evidence obtained from randomized controlled trials and other population-based studies that are the basis for the causality assessment. Evidence that the mechanism results in known disease in humans. For example, a wild-type infection causes the adverse health effect associated with the vaccine, or another vaccine has been demonstrated to cause the same adverse effect by the same or a similar mechanism. Data from population-based studies of the risk of adverse outcomes following vaccination constitute evidence regarding causality, not biological mechanisms. If the committee identifies evidence of biological mechanisms that could be operating, it offers a summary judgment of that body of evidence as weak, mod-

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Immunization Safety Review: Vaccines and Autism erate, or strong. Although the committee tends to judge biological evidence in humans as “stronger” than biological evidence from highly contrived animal models or in vitro systems, the summary judgment of the strength of the evidence also depends on the quantity (e.g., number of studies or number of subjects in a study) and quality (e.g., the nature of the experimental system or study design) of the evidence. Obviously, the conclusions drawn from this review depend both on the specific data and scientific judgment. To ensure that its own summary judgment is defensible, the committee aims to be as explicit as possible regarding the strengths and limitations of the biological data. The committee’s examination of biological mechanisms reflects its opinion that available information on possible biological explanations for a relationship between immunization and an adverse event should influence the design of epidemiologic studies and analyses. Similarly, the consideration of confounders and effect modifiers is essential in epidemiologic studies and depends on an understanding of the biological phenomena that could underlie or explain the observed statistical relationship. The identification of sound biological mechanisms can also guide the development of an appropriate research agenda and aid policymakers, who frequently must make decisions without having definitive information regarding causality. In addition, investigating and understanding possible biological mechanisms is often of value even if the available epidemiologic evidence suggests the absence of a causal association. A review of biological data could give support to the negative causality assessment, for example, or it could prompt a reconsideration or further investigation of the epidemiologic findings. If new epidemiologic studies were to question the existing causality assessment, the biological data could gain prominence in the new assessments. Published and Unpublished Data Published reports carry the most weight in the committee’s assessment because their methods and findings are laid out in enough detail to be assessed. Furthermore, those published works that undergo a rigorous peer review are subject to comment and criticism by the entire scientific community. Thus the committee generally cannot rely heavily on unpublished data in making its scientific assessments (regarding either causality or biological mechanisms) because they usually lack the commentary and criticism provided by peer review and must therefore be interpreted with caution. The committee also relies on editorial and peer-review procedures to ensure the disclosure of potential conflicts of interest that might be related to sources of funding of the research studies. The committee does not itself investigate the sources of funding of the published research reports it reviews, nor do funding sources influence the committee’s interpretation of the evidence. Unpublished data and other reports that have not undergone peer review do

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Immunization Safety Review: Vaccines and Autism have value, however, and are often considered by the committee. They might be used, for example, in support of a body of published, peer-reviewed literature with similar findings. If the committee concluded that the unpublished data were well described, had been obtained using sound methodology, and presented very clear results, the committee could report, with sufficient caveats in the discussion, how the unpublished data fit with the entire body of published literature. Only in extraordinary circumstances, however, could an unpublished study refute a body of published literature. The Immunization Safety Review Committee’s scope of work includes consideration of clinical topics for which high-quality experimental studies are rarely available. Although many other panels making clinical recommendations using evidence-based methods are able to require that randomized trials be available to reach strong conclusions, the IOM committee was convened specifically to assess topics that are of immediate concern yet for which data may just be emerging. Given the unique nature of this project, therefore, the committee deemed it important to review and consider as much information as possible, including unpublished reports. The committee does not perform primary or secondary analyses of unpublished data, however. In reviewing unpublished material, the committee applies generally accepted standards for assessing the quality of scientific evidence, as described above. (All unpublished data reviewed by the committee and cited in this report are available—in the form reviewed by the committee—through the public access files of the National Academies. For a summary of these submissions, see Appendix E. Information about the public access files is available at 202-334-3543 or www.national-academies.org/publicaccess.) UNDER REVIEW: VACCINES AND AUTISM In this report, the committee examines the hypothesis of whether or not the MMR vaccine and the use of vaccines containing the preservative thimerosal can cause autism. The IOM has issued two previous reports examining the role of vaccines in autism. The first report, which reviewed the hypothesized causal association between the MMR vaccine and autism (IOM, 2001a), the committee concluded that the evidence at the time favored rejection of a causal relationship at the population level between MMR vaccine and autism. The committee’s conclusion did not exclude the possibility that MMR could contribute to autism in small number of children, given that the epidemiological studies lacked sufficient precision to assess rare occurrences. Thus it was possible that epidemiological studies would not detect a relationship between autism and MMR vaccination in a subset of the population with a genetic predisposition to autism. The biological models for an association between MMR and autism were not established, but nevertheless were not disproved. In a subsequent report, the committee reviewed the hypothesized link be-

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Immunization Safety Review: Vaccines and Autism that the magnitude of concern in the general population is uncertain. However, the committee concludes that because autism can be such a devastating disease, any speculation that links vaccines and autism means that this is a significant issue. There are many examples in medicine of disorders defined by a constellation of symptoms that have multiple etiologies, and autism is likely to be among them. Determining a specific cause in the individual is impossible unless the etiology is known and there is a biological marker. Determining causality with population-based methods such as epidemiological analyses requires either a well-defined at-risk population or a large effect in the general population. Absent biomarkers, well-defined risk factors, or large effect sizes, the committee cannot rule out, based on the epidemiological evidence, the possibility that vaccines contribute to autism in some small subset or very unusual circumstances. However, there is currently no evidence to support this hypothesis either. As we have learned more about the causes of autism, some cases have been reclassified as other conditions—for example, Rett’s syndrome. Additional etiologies are likely to be identified. However, as of yet, the vast majority of cases with autism cannot be consistently and accurately subclassified. Thus, if there is a subset of individuals with autism syndrome triggered by exposure to vaccines, our ability to find it is very limited in the absence of a biological marker. The committee has yet to see any convincing evidence that supports the theory that vaccines are associated with an increase in the risk of autism, either to the population at large or to subsets of children with autism. Although this area of inquiry is interesting, it is only theoretical. However, interactions between genetic susceptibility and environmental triggers are being studied across a broad spectrum of disorders, the cause of which is not understood. Different expressions of the ASD spectrum could arise from the same or different exposures. These relationships could be a source of important new understanding of this family of disorders. While the committee strongly supports targeted research that focuses on better understanding the disease of autism, from a public health perspective the committee does not consider a significant investment in studies of the theoretical vaccine-autism connection to be useful at this time. The nature of the debate about vaccine safety now includes a theory that genetic susceptibility makes vaccinations risky for some people, which calls into question the appropriateness of a public health, or universal, vaccination strategy.43 However, the benefits of 43   There are, of course, populations at risk for some very specific vaccine adverse events. For example, people with severe immunosuppression are at risk for developing vaccine-associated paralytic polio and the inactivated vaccine has long been recommended for those people. However, the current debate implicates as yet undefined susceptibilities (not proven to exist) to a host of serious and less well-defined adverse outcomes, such as neuroimmunological brain damage.

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Immunization Safety Review: Vaccines and Autism vaccination are proven and the hypothesis of susceptible populations is presently speculative. Using an unsubstantiated hypothesis to question the safety of vaccination and the ethical behavior of those governmental agencies and scientists who advocate for vaccination could lead to widespread rejection of vaccines and inevitable increases in incidences of serious infectious diseases like measles, whooping cough, and Hib bacterial meningitis. The committee urges that research on autism focus more broadly on the disorder’s causes and treatments for it. Thus, the committee recommends a public health response that fully supports an array of vaccine safety activities. In addition the committee recommends that available funding for autism research be channeled to the most promising areas. The committee emphasizes that confidence in the safety of vaccines is essential to an effective immunization program—one that provides maximum protection against vaccine-preventable diseases with the safest vaccines possible. Questions about vaccine safety must be addressed responsibly by public health officials, health professionals, and vaccine manufacturers. Although the hypotheses related to vaccines and autism will remain highly salient to some individuals, (parents, physicians, and researchers), this concern must be balanced against the broader benefit of the current vaccine program for all children. RECOMMENDATIONS FOR PUBLIC HEALTH RESPONSE Specific recommendations regarding policy review, epidemiologic research and surveillance, and communication follow. The committee also revisits and discusses many of the recommendations of its two previous reports on vaccines and autism (IOM, 2001a,b). Policy Review At this time, the committee does not recommend a policy review of the licensure of MMR vaccine or of the current schedule and recommendations for the administration of the MMR vaccine. At this time, the committee does not recommend a policy review of the current schedule and recommendations for the administration of routine childhood vaccines based on hypotheses regarding thimerosal and autism. At the time of the committee’s previous report on thimerosal and NDDs (IOM, 2001b), several universally recommended vaccines contained thimerosal. In that report the committee recommended that appropriate professional societies and government agencies give full consideration to removing thimerosal from vaccines administered to infants, children, or pregnant women in the United States. Currently, thimerosal has in fact been removed from all universally recommended childhood vaccines except influenza. A thimerosal-free preservative influenza vaccine exists, however, and is available for use in infants, children, and pregnant

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Immunization Safety Review: Vaccines and Autism women. There are a few vaccines with thimerosal (e.g., Td) that infants and young children44 could be exposed to, but only under very special circumstances. The committee also recommended in its prior report that the appropriate professional societies and government agencies review their policies on the non-vaccine biological and pharmaceutical products that contain thimerosal and are used in infants, children, and pregnant women. The committee’s recommendation reflected concern about total mercury burden and potential risk of certain NDDs. The committee believes that these ongoing reviews are important and should continue. At the same time, the committee recognizes that many other countries, particularly developing countries, must rely on multidose vaccine vials that use thimerosal as a preservative. Because thimerosal is an antibacterial agent that has been highly successful in preventing field contamination, its removal from multidose vials would increase the risk of bacterial infection leading to toxic shock syndrome or death. The option of using single dose vaccines, which do not require thimerosal, is not feasible for some countries because of limits in the production of single-dose vaccines and lack of infrastructure for the transportation and storage of single-dose vials in a cold-chain system. While the United States chose to eliminate thimerosal from routine childhood vaccines as a precautionary measure and because it was feasible, the committee recognizes that other countries have different constraints and other factors; their own assessments of the risks and benefits may lead those countries to reach different conclusions regarding the thimerosal content of their vaccines. Given the lack of direct evidence for a biological mechanism and the fact that all well-designed epidemiological studies provide evidence of no association between thimerosal and autism, the committee recommends that cost-benefit assessments regarding the use of thimerosal-containing versus thimerosal-free vaccines and other biological or pharmaceutical products, whether in the United States or other countries, should not include autism as a potential risk. Surveillance and Epidemiologic Research The committee reaffirms its previous recommendation to use standard and accepted case definitions and assessment protocols for ASD to enhance the precision and comparability of results from surveillance, epidemiological studies, and biological investigations. Studies should also address the heterogeneity in the etiology of ASD and the spectrum of clinical presentation. The committee reaffirms its previous recommendation to conduct clinical and epidemiological studies of sufficient rigor to identify risk factors and biological markers of ASD in order to better understand genetic or environmental causes of ASD. 44   Td is recommended for children 12-18, but it is conceivable that some infants and young children could receive Td in lieu of DTaP.

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Immunization Safety Review: Vaccines and Autism Autism is a complex disease with unknown etiology. A number of research studies are being conducted to examine that etiology, as well as brain structure and function, developmental course, epidemiology, and treatment. To evaluate and compare these current and future studies, accepted and consistent case-definition and assessment protocols are critical. Currently, adverse events associated with vaccines are monitored through several mechanisms, including the pre-and postlicensure studies undertaken by vaccine manufacturers, the VAERS, and the CDC’s large-linked database (LLDB). Surveillance of adverse events related to vaccines is important and should be strengthened in several ways: The committee recommends that standardized case definitions for adverse events be adopted. The committee notes that the lack of standardized case definition for adverse events following vaccination is a recurring concern for the committee and for all who study immunization safety. The committee thus encourages the work recently begun by the Brighton Collaboration to develop, through an international consensus process, a set of standard definitions for adverse events (brightoncollaboration.org), as well as the work of the newly established Clinical Immunization Safety Assessment centers (www.cdc.gov/programs/immun8.htm). The committee recommends that formal guidelines or criteria be developed for using VAERS data to study adverse events. VAERS, the national passive surveillance system administered by CDC and FDA, monitors adverse events following immunization through reports from health care providers, manufacturers, and the public. Reports to VAERS indicate a temporal, but not necessarily causal, relationship between an adverse event and a vaccine. Furthermore, because VAERS data come from a passive reporting system, they are subject to a variety of limitations, including underreporting of adverse events and lack of a representative control group. Although VAERS is of limited utility in assessing causality, it has served as an early warning system for potential adverse events from vaccination (for example, in the case of intussusception and rotavirus vaccine) and as a useful tool for generating hypotheses on vaccine safety that can be investigated in more structured epidemiological studies. Formal guidelines for analyzing these data for studying adverse events are needed, however, to avoid promulgation of misinformation. The committee recommends the continued use of large-linked databases, active surveillance, and other tools to evaluate potential vaccine-related adverse events. The VSD project, which was initiated in 1990 as a partnership between CDC and eight large HMOs, is another example of LLDB that is used to monitor vaccine safety. The VSD includes information which covers more than six million people on all vaccines administered within the study population and includes information on vaccine type, vaccination date, concurrent vaccinations, the manufacturer, lot number, and injection site. Data from medical records are then monitored for potential adverse events resulting from immuniza-

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Immunization Safety Review: Vaccines and Autism tion. The VSD project has been used, for example, on investigations of adverse events from thimerosal and other hypotheses (http://www.cdc.gov/nip/vacsafe/default.htm#VSD). The committee supports the development of Clinical Immunization Safety Assessment (CISA) centers to improve understanding of adverse events at the individual level. While these mechanisms exist for reporting adverse events and conducting epidemiological studies, until recently no coordinated facilities existed in the U.S. to investigate or manage adverse events on an individual level. CISA centers are a new initiative designed to improve the scientific understanding of vaccine safety at the individual patient level. These centers are a collaboration between CDC and clinical academic centers across the United States that are sources of clinical expertise in evaluating and treating adverse events following immunization. CISA centers will serve as an intermediate step between passive reporting (i.e., providing information on individual cases of adverse events with no or minimal follow-up) and more rigorous epidemiological investigations into vaccine safety, such as the use of LLDBs, clinical trials, and case-control or cohort studies. These centers will systematically evaluate cases of adverse events reported to VAERS, and selected cases will undergo enhanced follow-up and targeted clinical evaluation to better understand the mechanism(s) and risk factors involved. These evaluations will be used to develop clinical protocols and patient management guidelines that can be used by all health care providers. The CISAs will also evaluate groups of patients with similar adverse events, using a standard protocol, in order to elucidate the mechanism(s) by which unusual or severe adverse reactions occur. Through such evaluation, genetic or other risk factors that predispose individuals to these reactions may be determined. The committee wishes to comment on several of the other recommendations it made in its 2001 report on MMR and autism. First, the committee recommended exploring whether exposure to MMR vaccine is a risk factor for ASD in a small number of children. To date, no convincing evidence of a clearly defined subgroup with susceptibility to MMR-induced ASD has been identified. However, genomics and proteonomics could reveal in the future whether or not any genetic susceptibility to vaccine-induced autism exists. The committee also recommended targeted investigations of whether measles vaccine-strain virus is present in the intestines of some children with ASD. The committee recommended this research because the findings most salient in the public debate over the hypothesized relationship between MMR vaccine and ASD is the case series reported in 1998 (Wakefield et al., 1998). The committee understands that researchers from Columbia University and CDC are currently working with researchers from the original reporting lab to study this issue and that results will be forthcoming. In addition, in the previous report (IOM, 2001a), the committee recommended studying the possible effects of different MMR

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Immunization Safety Review: Vaccines and Autism immunization exposures. For example, the committee noted that studies might enroll children whose families have chosen not to have them receive the MMR vaccine. To date, this type of study has been difficult to do with sufficiently large numbers. One alternative strategy would be to conduct trials in which the MMR vaccine is delayed among some children, so that it does not coincide with administration of TCVs. This option introduces ethical concerns about having insufficient vaccine coverage in the population for herd immunity and about leaving individual children unprotected against measles, mumps, and rubella, diseases which can cause serious complications and are widely prevalent throughout the world. Many of the epidemiological research recommendations of the committee’s 2001 report on thimerosal and NDDs are either under way or have been completed. Researchers have undertaken a number of case-control studies examining the potential link between NDDs and TCVs, epidemiological studies comparing the incidence and prevalence of NDDs before and after the removal of thimerosal from vaccines, and studies of neurodevelopmental outcomes of children from other countries who did not receive thimerosal-containing doses of DTaP. Insofar as monitoring of ASD occurs, one area of complementary research that the committee continues to recommend is surveillance of ASD as exposure to thimerosal declines. Any research in this area should be conducted with critical attention to case definition, diagnostic criteria, and other factors (for example, data collection procedures and definitions of autism in the special education system) that could affect prevalence estimates of ASD. As noted above, thimerosal has been removed from routine childhood vaccines as a precautionary measure. If TCVs are the primary cause for the rise in ASD, as some have argued, then one would expect to see a sharp decline in the incidence of ASD as thimerosal is removed from vaccines and other biological/pharmaceutical products and exposure declines. If rates of ASD continue to increase following the removal of thimerosal, however, then TCVs could not be the primary cause and research efforts on ASD should be redirected to other potential etiological mechanisms. Individuals may be exposed to inorganic mercury and mercurial compounds through a variety of sources, including dental amalgams, environmental or occupational exposure, and the consumption of seafood and fish. Based on the literature and presentations at the committee meetings, little is known about the levels of background exposure to mercury in the population. One recent study found that approximately 8 percent of women had concentrations higher than the EPA’s recommended reference dose (Schober et al., 2003), suggesting that at least some proportion of the population is at risk for mercury toxicity. The committee recommends increased efforts to quantify the level of prenatal and postnatal exposure to thimerosal and other forms of mercury in infants, children, and pregnant women.

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Immunization Safety Review: Vaccines and Autism Clinical Studies The committee heard from some parents of children with ASD who have chosen to rely on chelation therapy as a treatment. Some reported that unaffected siblings of children with ASD have been chelated as well. The committee saw no scientific evidence, however, that chelation is an effective therapy for ASD or is even indicated in these circumstances. Chelation therapy is currently indicated only for high-dose, acute mercury poisonings. Even in these cases, however, chelation therapy has not been established to improve renal or nervous system symptoms of chronic mercury toxicity (Sandborgh Englund et al., 1994) and has had no effect on cognitive function when used for excretion of another heavy metal—lead (Rogan et al., 2001). Because it is unlikely to remove mercury from the brain, chelation is useful only immediately after exposure and before damage has occurred (Evans, 1998). Moreover, chelation therapy has serious risks; for example, some chelation therapies might cause the release of mercury from softtissue stores, thus leading to increased exposure of the nervous system to mercury (Wentz, 2000). Because chelation therapy has potentially serious risks, the committee recommends that it be used only in carefully controlled research settings with appropriate oversight by Institutional Review Boards protecting the interests of the children who participate. Communication Many parents described to the committee their concerns about the MMR vaccine and thimerosal use in vaccines. Many expressed their frustration and difficulties in making informed decisions about vaccination of their children as their level of trust in the government, media, and science in general has declined. One such example of communication problems that led to controversy and animosity over vaccine safety issues was the VSD research regarding TCVs and NDDs. Because of the importance and difficulty of maintaining mutual trust, a model that focuses on increasing public participation in risk decisionmaking is likely to make that process more democratic and improve the relevance and quality of the technical analysis (Slovic, 1999). Such participative processes may not necessarily lead to increased acceptability of risk policies, but may lead to higher quality decision-making processes (Arvai, 2003). However, better risk-benefit communication requires attention to the needs of both the scientific and public communities. Many scientists need to develop a more comprehensive understanding of what risk-benefit communication entails and the rich knowledge base that can be used to design strategic communication programs. Appreciating that risk-benefit communication requires two-way exchanges of information and opinions (NRC, 1989) and working from a larger frame of communication methods, scientists will be able to work more effectively with the public to address vaccine-related issues. A mix of information,

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Immunization Safety Review: Vaccines and Autism dissemination, education services, and community-based dialogues are probably needed (NRC, 1989). To address these goals, the committee looked at existing programs that promote dialogue between various stakeholders around issues where science, research, and policy intersect. One innovative model is Project LEAD® developed by the National Breast Cancer Coalition (NBCC), a grassroots advocacy group (Dickersin et al., 2001; Hinestrosa, 2001). This program promotes open communication and exchange of information between consumers, scientists, researchers, and policymakers. It is multifaceted in that it combines both didactic and interactive learning activities with goals such as improving understanding of research, influencing legislation and policy, and conducting outreach. A key tenet of this program is to ensure that breast-cancer activists play an integral role in policy and research decisions, given their unique and critical perspectives on the issues. Scientists also gained a better understanding of advocates’ perspectives on the issues and learned from them how to better communicate their findings. (More information can be found by going to the NBCC website at http://www.natlbcc.org/andclickingonProjectLEAD.) Similarly, the Committee on the Public Understanding of Science (COPUS) was created in 1985 by the British Association, the Royal Institution, and the Royal Society to support and encourage ways of increasing public understanding and access to scientific literature in the United Kingdom. The COPUS Grant Schemes, begun in 1987, are funded and administered by the Royal Society to encourage small-scale science communication activities. The 2003/2004 COPUS Grant Schemes in particular are designed to make science, engineering, and technology available to a broad range of public audiences and to improve communication between scientific communities, professionals, and public audiences about funding priorities. (More information can be found at http://www.copus.org.uk/.) Another potential model might be the IOM’s Vaccine Safety Forum, which was established in 1995 to examine critical issues and discuss methods for improving the safety of vaccines and vaccination programs. Members of the forum included parents or consumer groups with an interest in immunization, individuals representing vaccine manufacturers, physicians, officials from federal agencies responsible for regulating vaccines and implementing vaccine policies, and academic researchers with expertise in vaccine-related issues. The Forum provided an opportunity to convene individuals from a variety of government, academic, industry, and citizen groups for regular and open dialogue. The objective was to identify key issues rather than to resolve them (IOM, Vaccine Safety Forum Workshop Summary). The committee recommends developing programs to increase public participation in vaccine safety research and policy decisions and to enhance the skills and willingness of scientists and government officials to engage in constructive dialogue with the public about research findings and their im-

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Immunization Safety Review: Vaccines and Autism plications for policy development. Programs such as Project LEAD®, COPUS Grant Schemes, or the IOM Vaccine Safety Forum may serve as useful models. Any proposed program should be easily accessible to the public and should involve a wide range of individuals. Additionally, ways to rebuild trust between scientists, professionals, media, and government should be explored. SUMMARY This eighth and final report of the Immunization Safety Review Committee examines the hypothesis that vaccines, specifically the measles-mumps-rubella (MMR) vaccine and thimerosal-containing vaccines, are causally associated with autism. The committee reviewed the extant published and unpublished epidemiological studies regarding causality and studies of potential biologic mechanisms by which these immunizations might cause autism. The committee concludes that the body of epidemiological evidence favors rejection of a causal relationship between the MMR vaccine and autism. The committee also concludes that the body of epidemiological evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism. The committee further finds that potential biological mechanisms for vaccine-induced autism that have been generated to date are theoretical only. The committee does not recommend a policy review of the current schedule and recommendations for the administration of either the MMR vaccine or thimerosal-containing vaccines. The committee recommends a public health response that fully supports an array of vaccine safety activities. In addition, the committee recommends that available funding for autism research be channeled to the most promising areas. The committee makes additional recommendations regarding surveillance and epidemiological research, clinical studies, and communication related to these vaccine safety concerns. Please see Box 2 for a summary of all conclusions and recommendations.

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Immunization Safety Review: Vaccines and Autism BOX 2 Committee Conclusions and Recommendations SCIENTIFIC ASSESSMENT Causality Conclusions The committee concludes that the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism. The committee concludes that the evidence favors rejection of a causal relationship between MMR vaccine and autism. Biological Mechanisms Conclusions In the absence of experimental or human evidence that vaccination (either the MMR vaccine or the preservative thimerosal) affects metabolic, developmental, immune, or other physiological or molecular mechanisms that are causally related to the development of autism, the committee concludes that the hypotheses generated to date are theoretical only. SIGNIFICANCE ASSESSMENT The committee concludes that because autism can be such a devastating disease, any speculation that links vaccines and autism means that this is a significant issue. PUBLIC HEALTH RESPONSE RECOMMENDATIONS The committee recommends a public health response that fully supports an array of vaccine safety activities. In addition the committee recommends that available funding for autism research be channeled to the most promising areas. Policy Review At this time, the committee does not recommend a policy review of the licensure of MMR vaccine or of the current schedule and recommendations for the administration of the MMR vaccine. At this time, the committee does not recommend a policy review of the current schedule and recommendations for the administration of routine childhood vaccines based on hypotheses regarding thimerosal and autism. Given the lack of direct evidence for a biological mechanism and the fact that all well-designed epidemiological studies provide evidence of no association between thimerosal and autism, the committee recommends that cost-benefit assessments regarding the use of thimerosal-containing versus thimerosal-free vaccines and other biological or pharmaceutical products, whether in the United States or other countries, should not include autism as a potential risk. Surveillance and Epidemiologic Research The committee reaffirms its previous recommendation to use standard and accepted case definitions and assessment protocols for ASD to enhance the pre

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Immunization Safety Review: Vaccines and Autism cision and comparability of results from surveillance, epidemiological studies, and biological investigations. Studies should also address the heterogeneity in the etiology of ASD and the spectrum of clinical presentation. The committee reaffirms its previous recommendation to conduct clinical and epidemiological studies of sufficient rigor to identify risk factors and biological markers of ASD in order to better understand genetic or environmental causes of ASD. Surveillance of adverse events related to vaccines is important and should be strengthened in several ways: The committee recommends that standardized case definitions for adverse events be adopted. The committee recommends that formal guidelines or criteria be developed for using VAERS data to study adverse events. The committee recommends the continued use of large-linked databases, active surveillance, and other tools to evaluate potential vaccine-related adverse events. The committee supports the development of Clinical Immunization Safety Assessment (CISA) centers to improve understanding of adverse events at the individual level. One area of complementary research that the committee continues to recommend is surveillance of ASD as exposure to thimerosal declines. The committee recommends increased efforts to quantify the level of prenatal and postnatal exposure to thimerosal and other forms of mercury in infants, children, and pregnant women. Clinical Studies Because chelation therapy has potentially serious risks, the committee recommends that it be used only in carefully-controlled research settings with appropriate oversight by Institutional Review Boards protecting the interests of the children who participate. Communication Better risk-benefit communication requires attention to the needs of both the scientific community and public communities. Many scientists need to develop a more comprehensive understanding of what risk-benefit communication entails and the rich knowledge base that can be used to design strategic communication programs. Thus, the committee recommends developing programs to increase public participation in vaccine safety research and policy decisions and to enhance the skills and willingness of scientists and government officials to engage in constructive dialogue with the public about research findings and their implications for policy development.