Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders

Immunization to protect infants and children from many 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 can on rare occasion cause paralytic polio, that some influenza vaccines have been associated with a risk of Guillain-Barré syndrome, and that vaccines sometimes produce anaphylactic shock. Given the widespread use of vaccines, state mandates requiring vaccination of children for entry into school 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.

In this fourth report in a series, the committee examines the hypothesis that the hepatitis B vaccine increases the risk for demyelinating disorders of the central or peripheral nervous systems, including multiple sclerosis (MS) and Guillain-Barré syndrome (GBS).

THE CHARGE TO THE COMMITTEE

Since the mid-1990s, challenges to the safety of immunizations seem to have gained prominence in public and scientific debate. Given these persistent and growing concerns about immunization safety, the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) recognized 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 C.) In 1999, as a



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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders Immunization to protect infants and children from many 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 can on rare occasion cause paralytic polio, that some influenza vaccines have been associated with a risk of Guillain-Barré syndrome, and that vaccines sometimes produce anaphylactic shock. Given the widespread use of vaccines, state mandates requiring vaccination of children for entry into school 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. In this fourth report in a series, the committee examines the hypothesis that the hepatitis B vaccine increases the risk for demyelinating disorders of the central or peripheral nervous systems, including multiple sclerosis (MS) and Guillain-Barré syndrome (GBS). THE CHARGE TO THE COMMITTEE Since the mid-1990s, challenges to the safety of immunizations seem to have gained prominence in public and scientific debate. Given these persistent and growing concerns about immunization safety, the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) recognized 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 C.) In 1999, as a

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders result 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 to address vaccine safety issues both existing and emerging. 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 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. Kenneth Shine, President of the IOM. The committee is charged with examining three immunization safety hypotheses each year during the three-year study period (2001–2003). These hypotheses are selected by the Interagency Vaccine Group, whose members represent several units of the Department of Health and Human Services (DHHS)— the National Vaccine Program Office, the National Immunization Program, and the National Center for Infectious Diseases at the CDC, the National Institute for Allergy and Infectious Diseases at the NIH, the Food and Drug Administration (FDA), the National Vaccine Injury Compensation Program at the Health Resources and Services Administration (HRSA), and the Centers for Medicare and Medicaid Services (CMS, formerly the Health Care Financing Administration)—and the Department of Defense and the Agency for International Development. 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 findings are released to the public in a brief consensus report 60–90 days after its meeting. For each hypothesis to be examined, the committee assesses both the scientific evidence and the significance of the issue for society. The scientific assessment has two components: an examination of the epidemiological and clinical evidence regarding a possible causal relationship between the vaccine and the adverse event, and an examination of theory and experimental evidence from human or animal 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 vaccine-preventable disease and with the adverse event. Other considerations may include the perceived intensity of public or professional concern, or the feasibility of additional research to help resolve scientific uncertainty regarding causal associations.

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders The findings of the scientific and significance assessments provide the basis for the committee’s recommendations regarding the public health response on the issue. In particular, the committee addresses needs for immunization policy review, current and future research, and 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 conducted a general review of immunization safety concerns and determined its methodology for assessing causality. This approach would be used for the hypotheses to be considered at subsequent meetings. 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 first three reports—Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism (IOM, 2001a), Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders (IOM, 2001b), and Immunization Safety Review: Multiple Immunizations and Immune Dysfunction (IOM, 2002)— are summarized in Appendix A. For its evaluation of the hypothesis on hepatitis B vaccine and demyelinating neurological disorders, the committee first commissioned a background paper; its purposes were to review current understanding of the biological mechanisms thought to be involved in MS and other demyelinating disorders, and to analyze the relationship of those mechanisms to the putative role of hepatitis B vaccine in such disorders. The committee also held an open scientific meeting in March 2002 (see Appendix B) for presentations on issues germane to the topic. The commissioned paper and all information presented to the committee at the open meeting can be viewed on the project website (www.iom.edu/imsafety). In addition, the committee reviewed an extensive collection of material from the published, peer-reviewed, scientific and medical literature. A reference list of materials reviewed by the committee, even if not cited in this report, can be found on its website.

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders THE FRAMEWORK FOR SCIENTIFIC ASSESSMENT Causality The Immunization Safety Review Committee has adopted the framework for assessing causality developed by its predecessors (convened by the IOM in 1991 and 1994 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 vaccine 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 epidemiological evidence 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 away from causality (“the evidence favors rejection of a causal relationship”). The committee does not conclude that the vaccine does not cause the adverse event merely if 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 epidemiological criteria to guide its decisions. The most definitive category is “establishes causality,” which is reserved for those relationships where the causal link is unequivocal, as with the oral polio vaccine and vaccine-associated paralytic polio or with anaphylactic reactions to vaccine administration. 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 its presence.

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders FIGURE 1 Committee Charge

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders 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 just suggestive either toward or away from causality falls into this category. 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 epidemiological evidence. The sources of evidence considered by the committee in its scientific assessment of causality include epidemiological and clinical studies directly addressing the question at hand. That is, the data relate to the effects of the vaccine(s) under review and the specific adverse health outcome(s) under review— in the case of this report, the effects of hepatitis B immunization on the risk for demyelinating neurological disorders. Epidemiological studies carry the most weight in a causality assessment; these studies measure health-related exposures and outcomes in a defined sample of subjects and make inferences about the nature and strength of associations between exposures and outcomes in the overall population from which the study sample was drawn. Epidemiological studies can be categorized as observational or experimental (clinical trial), and as uncontrolled (descriptive) or controlled (analytic). Among these various study designs, 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 studies. In uncontrolled observational studies where observations are made over time, confounding from factors such as changing case definitions or improving case detection may affect the apparent incidence and prevalence of the adverse outcomes studied. 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 re-administration of the vaccine, a situation referred to as a “rechallenge” (IOM, 1994).

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders Biological Mechanisms Terminology Evidence considered in the scientific assessment of biological mechanisms includes human, animal, and in vitro studies related to biological or pathophysiological processes by which immunizations could cause an adverse event. This kind of review has been referred to in previous reports of this committee (IOM, 2001a, 2001b) and others (IOM, 1991, 1994) as an assessment of the “biological plausibility” of a causal relationship. Although evidence regarding biological plausibility can never prove causality, the committee had previously described a spectrum of biological plausibility, ranging from not plausible to established. An agreed upon hierarchy of evidence required for assessments of biological plausibility does not exist, nor does an associated terminology (Weed and Hursting, 1998). The committee noted in its last report (IOM, 2002) that the term biological plausibility is a source of confusion on at least two fronts. First, it is associated with 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. It is also meant to guard against attributions of causality to biologically implausible statistical associations that might result from studies that have not adequately accounted for important variables. A review of the biological plausibility of an association might add reassurance that the epidemiological findings point toward or reflect causality. On occasion, however, an epidemiological observation has been attributed to an apparently reasonable biological mechanism that, on further investigation, appeared not to be relevant for the pathophysiology involved. 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. Even without epidemiological evidence, the identification of sound biological mechanisms could influence the development of an appropriate research agenda and give support for policymakers, who frequently must make decisions in situations of incomplete information regarding causality. In addition, there is often value in investigating and understanding possible biological mechanisms even if the available epidemiological evidence suggests the absence of a causal association. A review of biological data could give support to the negative causality assess-

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders ment, for example, or it could prompt a reconsideration or further investigation of the epidemiological findings. If new epidemiological studies were to question the existing causality assessment, the biological data could gain prominence in the new assessments. Second, the committee understands that some readers of its reports are confused by what are perceived as contradictions between the findings on causality and on biological plausibility. 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, data on biological mechanisms add 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 found that for the purpose of its 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. As it began doing in the report that immediately preceded this one (IOM, 2002), the committee will review evidence regarding “biological mechanisms” that might be consistent with the proposed relationship between a vaccine exposure and given adverse events. This assessment of the biological data is presented in a section of the report that is distinct from any argument regarding the causality of such relationships. This approach is not meant to imply that the current understanding of biological processes does not shape or guide the committee’s assessments of causality. In fact, the current thinking on a possible biological explanation for a relationship between immunization and an adverse event will influence the design of a good epidemiological analysis. The essential consideration of “confounders” in epidemiological studies depends on an understanding of the biological phenomena that could underlie or explain the observed statistical relationship. Only when important confounders are considered can a statistical observation be considered as evidence of causality. However, absent evidence of a statistical association, or convincing clinical evidence, biological mechanisms cannot be invoked as proof of causality. Categories of Evidence The committee has established three general categories of evidence on biological mechanisms: Theory only: A reasonable mechanism can be hypothesized that is commensurate with scientific knowledge and that does not contradict known physical and biological principles, but it has not been demonstrated in whole or in part in humans or in animal models. Postulated mechanisms by which a vac-

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders cine might cause a specific adverse event but for which no coherent theory exists would not meet the criteria for this category. Thus, “theoretical only” is not a default category, but one that requires thoughtful and biologically meaningful suppositions. Experimental evidence that the mechanism operates in animals, in vitro systems, or humans: Experimental evidence often describes effects on just one or a few of the steps in the pathological process required for expression of disease. Showing that multiple components of the theoretical pathways operate in reasonable experimental models increases confidence that the mechanisms could possibly result in disease in humans. The evidence can be 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 vaccine antigen 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 exists whereby administration of a vaccine antigen under conditions similar to human use results in a pathological process analogous to a human disease pathology. Mechanistic evidence also could come from studies in humans, but this is distinct from the evidence (about incidence of adverse events following immunization) that derives from randomized controlled trials or other population-based epidemiological studies, which contribute to the causality assessment. Evidence that the mechanism results in known disease in humans: For example, a wild-type infection causes the adverse health outcome, or another vaccine has been demonstrated to cause the same adverse outcome by the same or a similar mechanism. Data from population-based studies of the effects of the vaccine administration on the occurrence of the adverse outcomes under review are considered not as evidence regarding the biological mechanisms but as evidence regarding causality. If the committee identifies evidence of biological mechanisms that could be operational, it will offer a summary judgment of that body of evidence as weak, moderate, 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 strength of the evidence also depends on both 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 on both the specific data and on scientific judgment. To ensure that its own summary judgment is defensible, the committee intends to be as explicit as possible regarding the strengths and limitations of the biological data.

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders Published and Unpublished Data Published reports that have been subjected to a rigorous peer review process carry the most weight in the committee’s assessment. In general, the committee cannot rely heavily on unpublished data in making its scientific assessments (regarding either causality or biological mechanisms) because they have not undergone a formal review and must therefore be interpreted with caution. Immunization safety studies and other data reviewed by the committee are funded by a variety of sources—NIH, CDC, vaccine manufacturers, research advocacy organizations, or foundations. The committee relies on editorial and peer review procedures to ensure the disclosure of potential conflicts of interest that might be related to the source of funding for the research study. The committee does not investigate the source of funding of the published research reports it reviews, nor does the funding source influence the committee’s interpretation of the evidence. Unpublished data and other reports that have not undergone peer review do have value, however, and they are often considered by the committee; they might be used, for example, in support of a body of published 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 those 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 committee acknowledges that its approach differs from the state of the art for evidence-based reviews of clinical practices in medicine, which does not include consideration of unpublished or non-peer-reviewed information or of studies with flawed experimental designs (U.S. Preventive Services Task Force, 1996). However, the Immunization Safety Review Committee was convened specifically to assess topics that are often of immediate and intense concern. In some cases, the committee’s review will take place as data are only beginning to emerge. Thus, given the unique nature of this project, the committee decided that it was important to review and consider as much information as possible, including unpublished information. 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. Information about the public access files is available at 202–334–3543 or www.national-academies.org/publicaccess.)

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders UNDER REVIEW: HEPATITIS B VACCINE AND DEMYELINATING NEUROLOGICAL DISORDERS The Interagency Vaccine Group asked the Immunization Safety Review Committee to address the concern that the hepatitis B vaccine causes demyelinating neurological disorders. A plasma-derived vaccine was first marketed in the United States in the early 1980s, and it was supplanted later in the decade by vaccines produced with the aid of recombinant technology. Concern about the safety of the hepatitis B vaccine emerged with an analysis of the first three years of post-marketing surveillance reports on various demyelinating neurological disorders following administration of the plasma-derived vaccine. Those reports suggested a possible association with Guillain-Barré syndrome (GBS) (Shaw et al., 1988). In the early 1990s, a previous IOM committee concluded that the evidence was inadequate to accept or reject a causal relationship between hepatitis B vaccine and either GBS or a general category of central nervous system demyelinating diseases (IOM, 1994). Concern about the vaccine and neurological disorders has persisted, focusing most prominently on the possibility of a causal link with MS, a central nervous system demyelinating disease. Concerns were very salient in France recently and led to immunization policy change (as discussed in a subsequent section of the report). For this review, the committee addressed the relationship between hepatitis B vaccine and the following neurological diseases: the central nervous system (CNS) demyelinating diseases of MS (onset or relapse), acute disseminated encephalomyelitis (ADEM), optic neuritis, and transverse myelitis and the peripheral nervous system (PNS) demyelinating diseases of GBS and brachial neuritis. The committee chose to focus on these specific conditions because they are serious neurological disorders and known clinical entities. Published epidemiological studies and case reports investigating their association with hepatitis B vaccine are available, and a substantial body of literature exists on the pathophysiology of several of these conditions (e.g., MS, ADEM, and GBS). Key features of these diseases, and of hepatitis B infection and the hepatitis B vaccine, are described below. The committee recognizes that this report addresses only a portion of the full range of concerns about the hepatitis B vaccine. In particular, some members of the public believe that the hepatitis B vaccine, which is first administered to many infants within hours of birth, is associated with infant death. The death of any child—whether following immunization or a vaccine-preventable disease—is tragic, and the committee agrees that such deaths are of intense concern. However, in the context of the current review, it is not clear that the putative association in such infant deaths is with an immune-mediated neurological assault. The committee notes that the Interagency Group on Vaccines has dis-

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders tions of the extent of concern about immunizing infants and children against hepatitis B. Although concern about neurological disorders following immunization is justified on the basis of their total burden to individuals and to society and the known relationship of some vaccines to some neurological conditions, the benefits of hepatitis B vaccine in preventing liver disease are undeniable. However, because the benefits of hepatitis B vaccine are realized long after immunization, and because the population at highest risk of hepatitis B infection is in adolescents, young adults, and members of high-risk occupations, the universal newborn and infant immunization recommendation is difficult for some parents to understand. The theoretical risks of the vaccine are salient for them, but the known benefits are not. The committee concludes that concerns about the hepatitis B vaccine remain significant in the minds of some parents and workers who are required to take the vaccine because of occupational risk. RECOMMENDATIONS FOR PUBLIC HEALTH RESPONSE The scientific and policy issues considered by the committee lead to recommendations for targeted public health attention. The committee has found that although there is no evidence of increased risk of MS in adults following hepatitis B vaccination, the evidence is inconclusive in regard to risk for MS in infants and children. The evidence is also inconclusive for the other neurological diseases considered. However, because the hepatitis B vaccine is recommended by federal and national advisory bodies for use in infants and required by states for school entry and for employment in high-risk occupations (such as the health care field) and because the basis for the recommendation for universal immunization for infants and children is not fully understood by some parents and some health care providers, public health attention in the form of further research and improved communication is required. Policy Review The committee does not recommend a policy review of the hepatitis B vaccine by any of the national and federal vaccine advisory bodies, on the basis of concerns about demyelinating neurological disorders. Research Although the committee concluded that the epidemiological evidence is inadequate to accept or reject a causal relationship between the hepatitis B vaccine and most of the demyelinating disorders it reviewed, the committee found a

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders theoretical basis for the hypothesis when it considered biological mechanisms. The committee identified only indirect and scant evidence that relevant biological mechanisms could be operational. Because none of the evidence is specific to the hepatitis B vaccine, the summary judgment was that the evidence is weak. Given this, and the fact that the committee identified very little information about the possible effects of the vaccine on demyelinating disorders in infants and children, the committee recommends further research. Surveillance The committee emphasizes the need for continuing surveillance of vaccine recipients and possible adverse events. MS rarely appears in childhood but begins to appear in early adulthood (Noseworthy et al., 2000; Waubant and Stuve, 2002). The evidence that the onset of MS may appear a decade or more after exposure to a risk factor (environmental or microbial) raises the possibility that long-term follow-up might be needed to determine an effect on the rate of MS. Because the hepatitis B vaccine has been routinely administered to newborns and infants since 1991, surveillance of this exposed and aging group provides an opportunity to study its incidence of MS. The incidence of other central and peripheral nervous system disorders, such as optic neuritis, ADEM, GBS, brachial neuritis, and transverse myelitis should also be examined in this group. In addition, there should be continued surveillance of health workers who have received the vaccine. The committee recommends surveillance of MS and other central and peripheral nervous system demyelinating disorders, specifically in health care workers and those born since 1991. Surveillance of these outcomes would be strengthened by having standard diagnostic approaches and case definitions to permit epidemiologic investigations. 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. Specifically, the committee recommends the development of case definitions and guidance for diagnostic evaluation of the demyelinating disorders it has reviewed for purposes of improved vaccine adverse event surveillance and, when appropriate, causality assessment. The committee notes and 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 newly established Clinical Immunization Safety Assessment centers (www.cdc.gov/programs/immun8.htm). The committee has not reviewed these efforts in sufficient detail to recommend whether or not the entities behind them can or should assume the responsibility for this recommendation, or whether a distinct effort is needed.

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders Infection with the hepatitis B virus increases the risk of developing cirrhosis and hepatocellular carcinoma (El-Serag, 2001). Surveillance of these secondary outcomes of hepatitis B infection may provide a clearer understanding of the impact of the hepatitis B vaccination program. Continued surveillance of acute infections also remains important for the same reason. Furthermore, because hepatitis B infections can be asymptomatic, supplemental surveillance, such as the serological testing that has been conducted as part of the National Health and Nutrition Examination Survey, is needed for more accurate estimates of incidence and prevalence. Therefore, the committee recommends continued surveillance of hepatitis B disease and increased surveillance of secondary diseases, such as cirrhosis and hepatocellular carcinoma. Basic and Clinical Science The committee has not recommended large-scale epidemiological studies at this time to address concerns about the demyelinating conditions it has reviewed. But in recognition of its inability to reject causality for most of these conditions, and of the limited evidence regarding biological mechanisms, the committee recommends continued research in animal and in vitro models, as well as in humans, on the mechanisms of immune-mediated neurological disease possibly associated with exposure to vaccines. Communication The committee has continuing concerns that the public’s need for relevant information is not being effectively met. The committee again recommends that government agencies and professional organizations responsible for immunizations critically evaluate their communication services with increased understanding of and input from the intended users. It is important to ensure that the content and format of communication methods and tools are appropriate, readily accessible, and relevant to the public. SUMMARY Immunization advisory bodies recommend that all infants, adolescents, and high-risk adults receive the hepatitis B vaccine for protection from serious liver disease, including cirrhosis and hepatocellular carcinoma. These recommendations have been viewed skeptically by some because of concerns about the safety of the vaccine and because of a perception that hepatitis B infection is not a serious risk to the general population. The Immunization Safety Review Committee reviewed the evidence regarding the hypothesis that the hepatitis B

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders vaccine causes demyelinating neurological disorders, such as multiple sclerosis and Guillain-Barré syndrome. There is a theoretical basis for the hypothesis that vaccines, including the hepatitis B vaccine, could cause demyelinating disorders. A review of the scant and indirect evidence that relevant biological mechanisms could operate in humans in response to the hepatitis B vaccine to produce disease provides weak support for this theory. However, the committee found that the epidemiological evidence (i.e., from studies of vaccine-exposed populations and their control groups or of patients with these diseases and their control groups) favors rejection of a causal relationship between the hepatitis B vaccine in adults and multiple sclerosis. The evidence was inadequate to accept or reject a causal relationship between the hepatitis B vaccine and all other demyelinating conditions. Demyelinating disorders are often quite devastating, as are the conditions resulting from chronic hepatitis B infection. The committee found evidence that some parents and health care workers are skeptical about the vaccine more due to a perception that the vaccine is unnecessary, rather than due to a large concern about the safety of the vaccine. The committee is aware, however, that there are some people who very much object to the vaccine both on the basis of the perception that not all infants and children are at risk for hepatitis B infection and on the basis of concerns about its safety. Because of the lack of epidemiological data on conditions other than MS in adults, the committee recommends further attention in the form of research and communication. However, the committee does not recommend that national and federal vaccine advisory bodies review the hepatitis B vaccine on the basis of concerns about demyelinating disorders. See Box 2 for a summary of all conclusions and recommendations. BOX 2 Committee Conclusions and Recommendations SCIENTIFIC ASSESSMENT Causality Conclusions The committee concludes that the evidence favors rejection of a causal relationship between hepatitis B vaccine administered to adults and incident multiple sclerosis. The committee also concludes that the evidence favors rejection of a causal relationship between hepatitis B vaccine administered to adults and multiple sclerosis relapse. The committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and the first episode of a central nervous system demyelinating disorder. The committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and ADEM.

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders The committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and optic neuritis. The committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and transverse myelitis. The committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and GBS. The committee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and brachial neuritis. SIGNIFICANCE ASSESSMENT The committee concludes that concerns about the hepatitis B vaccine remain significant in the minds of some parents and workers who are required to take the vaccine because of occupational risk. PUBLIC HEALTH RESPONSE RECOMMENDATIONS Policy Review The committee does not recommend a policy review of the hepatitis B vaccine by any of the national and federal vaccine advisory bodies on the basis of concerns about demyelinating neurological disorders. The committee recommends continued surveillance of hepatitis B disease and increased surveillance of secondary diseases such as cirrhosis and hepatocellular carcinoma. Basic and Clinical Science The committee recommends continued research in animal and in vitro models, as well as in humans, on the mechanisms of immune-mediated neurological disease possibly associated with exposure to vaccines. Communication The committee again recommends that government agencies and professional organizations responsible for immunizations critically evaluate their communication services with increased understanding of, and input from, the intended users

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