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Immunization Safety Review: Influenza Vaccines and Neurological Complications Immunization to protect children and adults 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 on rare occasion has caused paralytic polio and that vaccines sometimes produce anaphylactic shock. Given the widespread use of vaccines, state mandates requir- ing 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 Insti- tute of Medicine (IOM) to evaluate the evidence on possible causal associations between immunizations and certain adverse outcomes, and to then present con- clusions and recommendations. The committee's mandate also includes assessing the broader significance for society of these immunization safety issues. This seventh report from the committee examines the hypothesis that influ- enza vaccines are associated with an increased risk of neurological complica- tions, particularly Guillain-Barre syndrome (GBS) and multiple sclerosis (MS). THE CHARGE TO THE COMMITTEE Challenges to the safety of immunizations are prominent in public and scien- tific 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 23

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24 IMMUNIZATION SAFETY REVIEW been involved in such issues since the 1970s. (A brief chronology can be found in Appendix C.) In 1999, because of IOM's previous work and its access to inde- pendent scientific experts, CDC and NIH began a year of discussions with IOM to develop the Immunization Safety Review project, which would address both emerging and existing vaccine safety issues. The Immunization Safety Review Committee is responsible for examining a broad variety of immunization safety concerns. Committee members have exper- tise in pediatrics, neurology, immunology, internal medicine, infectious diseases, genetics, epidemiology, biostatistics, risk perception and communication, deci- sion 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 is charged with examining up to three immunization safety hypotheses each year during the three-year study period (2001-2003~. These hypotheses are selected by the Interagency Vaccine Group (IAVG), whose mem- bers 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; the Health Resources and Services Administration's National Vaccine Injury Compensation Program; and the Centers for Medicare and Medicaid Services (formerly the Health Care Financing Administration). The IAVG includes representation from the Depart- ment of Defense and the Agency for International Development as well. 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 1- to 2-day closed meeting to formulate its conclusions and recommendations. The committee's 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 regard- ing 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 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 both the vaccine-preventable disease and 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 causality.

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS 25 The findings of the scientific and significance assessments provide the basis for the committee's recommendations regarding the public health response to the issue. In particular, the committee addresses any needs for a review of immuniza- tion 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 initial meeting, the committee also determined the basic methodology to be used for assessing causality in 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 communica- tion 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 question concerning influenza vaccines and neuro- logical complications, the committee held an open scientific meeting in March 2003 (see Appendix B) to hear presentations on issues germane to the topic. These presentations are available in electronic form (audio files and slides) on the project website (www.iom.edu/imsafety). In addition, the committee reviewed an extensive collection of material, primarily from the published, peer-reviewed scientific and medical literature. A list of the materials reviewed by the com- mittee, 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: 1. No evidence 2. Evidence is inadequate to accept or reject a causal relationship 3. Evidence favors rejection of a causal relationship 4. Evidence favors acceptance of a causal relationship 5. Evidence establishes a causal relationship.

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS 27 Assessments begin from a position of neutrality regarding the specific immu- nization 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 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 against causality ("the evidence favors rejection of a causal relationship". The com- mittee 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 epidemiologic criteria to guide its decisions. The most definitive category is "establishes causality," which is reserved for those relation- ships 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.)

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28 IMMUNIZATION SAFETY REVIEW 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 sugges- tive 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 ques- tion at hand. That is, the data are specifically related to the effects of the vaccines under review and the adverse health outcomes) under review in this report, the effects of influenza vaccination on the risk of neurological complications. Epidemiologic studies carry the most weight in a causality assessment. These studies measure health-related exposures and outcomes in a defined set of sub- jects 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 catego- rized as observational or experimental (clinical trial) and as uncontrolled (descriptive) or controlled (analytic). Among the various study designs, experi- mental studies generally have the advantage of random assignment to exposures and are therefore the most influential in assessing causality. Uncontrolled obser- vational studies are important but are generally considered less definitive than controlled studies. In uncontrolled observational studies, where observations are made over time, confounding factors such as changing case definitions or improv- ing 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 estab- lish 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-Barre 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, 1994a). Biological Mechanisms The committee's causality assessments must be guided by an understanding of relevant biological processes. Therefore the committee's scientific assessment

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS 29 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. When convincing statistical or clinical evidence of causality is available, biological data add support. But this committee is often faced with circumstances in which the epidemiologic 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 a vaccine exposure and an adverse event. The biological data alone cannot be invoked as proof of causality, however. The committee has established three general categories of evidence on bio- logical mechanisms: 1. Theoretical. A reasonable mechanism can be hypothesized that is com- mensurate 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. 2. 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 experi- mental models strengthens the case that the mechanisms could possibly result in disease in humans. 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 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 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. 1For a discussion of the evolution of the terminology concerning biological mechanisms, see the committee's earlier reports (TOM, 2001a,b, 2002a,b).

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30 IMMUNIZATION SAFETY REVIEW 3. Evidence that the mechanism results in known disease in humans. For example, the wild-type infection causes the adverse health outcome associated with the vaccine, 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 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, 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 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 judg- ment 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 epi- demiologic studies and analyses. Similarly, the consideration of confounders and effect modifiers is essential in epidemiologic studies and depends on an under- standing 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 policy- makers, who frequently must make decisions without having definitive informa- tion 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. In general,

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS 31 the committee 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 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 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 discus- sion, 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 con- sideration 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 of any kind 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 sec- ondary 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. Informa- tion about the public access files is available at 202-334-3543 or www.national- academies . org/publicacces s . ~ UNDER REVIEW: INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS The Immunization Safety Review Committee was asked to examine the hypothesis that a causal relationship might exist between receipt of influenza vaccines and neurological complications. In the United States, concern about such adverse neurological events is most prominently linked to cases of Guillain-

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32 IMMUNIZATION SAFETY REVIEW Barre syndrome (GBS) that occurred following the administration of influenza vaccine to between 40-45 million people in the 1976 National Influenza Immuni- zation Program (CDC, 2003c; Langmuir et al., 1984~. This federally funded immunization program was aimed at averting the possibility of an outbreak of a type of influenza "swine flu" thought to be related to the virus that caused a massive global epidemic in 1918-1919. Although production of a vaccine was slowed by technical problems as well as by negotia- tions between the government and manufacturers over the purchase contracts and liability protections, ultimately, the production, distribution, and administration of the swine influenza vaccine was successfully implemented. However, the vaccination program was halted in December 1976 when no pandemic was evi- dent and after more than 500 cases of GBS were reported among U.S. vaccinees, which appeared to be associated with the vaccine (Kitch et al., 1999~. When a CDC-sponsored study showed a statistically significant association between vaccination and an increase in the risk of GBS during the 10 weeks following vaccination, the federal government agreed to accept liability for all cases of GBS with onset falling within this period (Kitch et al., l999~. More than $90 million was paid by the government to cover claims on these cases. The large scale of the program and the administration of vaccine within a narrow time window offered an opportunity to identify a vaccine-related event as rare as GBS. The detection of such a rare and unexpected event such as the association of the vaccine with GBS was facilitated by the large number of doses of vaccine admin- istered in a narrow time window. The program also demonstrated the role of resource-intensive surveillance for rare adverse events and the significance of liability concerns, both for the government and vaccine manufacturers. The committee's review of the evidence concerning risks that might be associated with influenza vaccines had to take into account a distinctive feature of the vaccine: its formulation changes from year to year to reflect changes in the strains of influenza virus circulating in the population. As a result, the question before the committee actually concerns many different influenza vaccines rather than a single, consistent product used over many years. In terms of the neurologi- cal outcomes of concern, GBS is the most widely cited. Other outcomes con- sidered by the committee are multiple sclerosis (MS) and optic neuritis. Key features of influenza, influenza viruses, and influenza vaccines are described below, followed by brief overviews of these outcomes. Influenza and Influenza Vaccines Influenza Influenza is an acute and highly contagious viral respiratory disease that occurs worldwide. Up to 20 percent of the population may be infected in a single year (Palese and Garcia-Sastre, 2002~. Although some infections are subclinical,

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS 33 influenza is responsible for substantial morbidity and mortality. The elderly, young children, and persons with chronic cardiac or pulmonary diseases are generally at greatest risk for fatal complications (Dolin, 2001~. In the United States alone, the disease is now estimated to contribute to an average of 36,000 deaths each year, a toll that has risen as the population has aged (Thompson et al., 2003). The incidence of influenza peaks during the winter months in temperate zones, but infections occur year-round in the tropics (Dolin, 2001~. The extent and severity of influenza infections can vary widely from year to year. The disease frequently reaches epidemic levels and periodically becomes pandemic- referring to high levels of infection worldwide that are not necessarily associated with an unusually severe form of the disease (Kilbourne and Arden, 1999~. The 1918-1919 pandemic, however, resulted in the deaths of an estimated 500,000 persons in the United States and 20 to 50 million persons worldwide, including large numbers of young adults (CDC, 2002a). The influenza viruses infect the respiratory epithelium. Onset of illness is often abrupt, with systemic symptoms that include fever, chills, headache, myalgias and respiratory signs such as cough and sore throat. In uncomplicated cases, acute illness typically resolves over 2 to 5 days. Recovery may be complete within a week, but some patients experience persistent weakness or lassitude (Dolin, 2001~. Treatment generally consists of symptomatic therapy, such as acetaminophen for headache, myalgia or fever. Antiviral drugs may also be effec- tive if therapy is started within 48 hours of the onset of illness (Dolin, 2001~. Many of the influenza-related deaths result from complications, the most common being secondary bacterial pneumonia (e.g., Streptococcus pneumonias, Haemophilus in;fluenzae, or Staphylococcus aureus). Primary viral pneumonia is less common but has a high fatality rate. Influenza can also exacerbate chronic pulmonary conditions or contribute to a general deterioration in cardiac or pul- monary function, especially in the elderly or persons with chronic illness. Other complications sometimes seen include myositis, rhabdomyolysis, and myoglobi- nuria (Dolin, 2001; Hilleman, 2002~. A temporal association between neurological complications such as encephalitis, transverse myelitis, and GBS has also been reported (Dolin, 2001~. Encephalitis/ encephalopathy has been reported as a complication primarily of influenza type A (H3N2) infections in Japanese children, although a causal relationship has not been proven (Morishima et al., 2002; Sugaya, 2002~. Others have reported smaller num- bers of cases of encephalitis associated with influenza B infections in children in the United States and elsewhere (Newland et al., 2003~. The CDC (2003a) has recently requested information to try to identify additional cases of acute encephalopathy that may have occurred in children with influenza since January 1998. Factors that have been proposed as possibly accounting for the complications observed in the Japanese children include genetic characteristics in the Japanese population, infection with a particularly virulent viral strain, and regional differ-

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136 IMMUNIZATION SAFETY REVIEW The FDA recently approved a live attenuated intranasal influenza vaccine for use in the United States. The vaccine uses a cold-adapted influenza virus master strain into which the HA and NA genes of the current, circulating strains are incorporated. The vaccine is delivered intranasally and proliferates in the upper airways, where it stimulates mucosal antibodies and T-cell responses. The use of a cold adapted master strain means that replication of the live virus in the vaccine is restricted to the upper respiratory tract of humans because the vaccine-strain virus is unable to reproduce in the higher-temperature environment of the lower respiratory tract. Cold adaptation was achieved by propagation of the wild-type virus in chicken kidney cells at progressively lower temperatures to identify stable mutants that could grow at 25C (Maassab and Bryant, 1999~. A primary concern about a live-virus influenza vaccine is the possibility that the vaccine-strain viruses could undergo genetic reassortment with nonhuman (e.g., avian or swine) strains and give rise to new, virulent strains to which the population would be susceptible (Beyer et al., 2002; Pfleiderer et al., 2001~. This theoretical concern has not been borne out in clinical studies, and similar vac- cines given to tens of millions of children in Russia have not produced any clinical evidence of live attenuated vaccines reverting to virulence (Belshe et al., 2002; Cha et al., 2000~. Research related to killed-virus vaccines is also continuing. For example, efforts are being made to develop techniques to grow influenza virus in mamma- lian cell culture instead of eggs (Halperin et al., 2002~. Other studies are looking at the influenza virus's M2 protein as a possible vaccine antigen that could eliminate the need to formulate a new vaccine each year to respond to the antigenic drift or shift in the circulating viruses. M2 is highly conserved antigeni- cally, and antibodies to M2 have been shown to be protective in mice (Neirynck et al., 1999~. There is also interest in developing a DNA vaccine, and studies immunizing mice with recombinant plasmids bearing coding sequences for selected HA, NP, or M proteins have been promising (Fu et al., 1999; Okuda et al., 2001~. Another approach to influenza vaccination involves using Escherichia cold heat-labile toxin as an adjuvant, complexed with lecithin vesicles, to improve the immunogenicity of the inactivated trivalent vaccine (Palese and Garcia-Sastre, 2002~. These "virosomal" vaccine preparations are given intranasally.l2 12One virosomal influenza vaccine licensed for use in Switzerland in 2000 was withdrawn a year later because of unresolved concerns about an association between the vaccine and Bell's palsy (temporary facial paralysis) (Berna Biotech, 2002). The committee did not examine this vaccine because it was not used in the United States, it is no longer available in Switzerland, and no pub- lished study is available.

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS Influenza Immunization Risk-Benefit Communication 137 Factors that affect people's understanding of health risks and the options to reduce those risks include, for example, personal attributes (e.g., age, gender, ethnicity, etc.), beliefs about the disease and potential control options, attitudes about the sources of those controls, the risk and benefits attributed to the con- trols, and the trade-offs among the controls. In addition, heuristics, as well as societal and decision contexts, matter in vaccine decision making (e.g., Leask and Chapman, 1998; Bostrom, 1997~. Although the impacts of these factors on vaccine decisions are not well understood and may vary somewhat by type of vaccine, it is clear that no one factor acts alone. Both individual and contextual factors are important to the individual's final decision about whether to get vac- cinated or not. It is well known, however, that people often lack knowledge about disease processes and the safety and effectiveness of vaccines, and usually do not know what critical information they are lacking. Individuals may also underestimate the risk of the disease and overestimate risks of the vaccine and their own abilities to avoid getting the disease (e.g., Bostrom, 1997; Fischhoff et al, 2000~. In developing a risk communication strategy for a specific health decision, it is important then to know what key pieces are missing from people's cognitive frameworks about the decision and related issues, what they need to know to complete and/or correct their understandings, and what factors and contexts strengthen their abilities to make effective and personally meaningful decisions. As noted by Bostrom (1997), there are several health behavior models and theories that can be applied to vaccination issues. To date there has not been a compre- hensive effort to organize current knowledge and evaluate these models and theories using the results for various populations. Knowledge of the key factors that predict and/or influence influenza vaccination decisions remains constrained, thereby limiting the basis on which sound risk communication strategies can be designed. A more comprehensive and cohesive understanding is needed to iden- tify what elements are crucial to people's decision processes, how they relate those and tangential elements, what they include and/or relate incorrectly in their decision processes, and what elements they emphasize or de-emphasize inappro- priately. Risk communication efforts will remain less than ideal as long as they are not based on a full, fundamental picture of what people believe they know, what they see as valid and rational control options, what they believe the conse- quences of those options are, why they view vaccine issues as they do, and how they assess the trade-offs between the options. Influenza vaccination rates typically fall short of national goals, particularly among susceptible subpopulations such as the elderly and disadvantaged. Several studies have been conducted recently to develop insights into the barriers and incentives that may affect immunization rates (CDC, 1999; CDC, 2003b; Zimmerman et al., 2003b). Societal contexts, influences of the mass media, and cognitive and motivational biases have been investigated.

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138 IMMUNIZATION SAFETY REVIEW People who were more likely to receive the influenza vaccine were found in these studies to be more likely to believe that: Getting vaccinated is a wise decision, a good habit. The recommendations of their doctors, relatives, or friends are important. The vaccine is effective in preventing influenza. Medicare will cover the costs. Avoiding getting influenza is important. They are at risk for getting the disease. Unvaccinated people will contract influenza. People who did not get vaccinated had beliefs that differed from those who became vaccinated. Some of the key beliefs among non-vaccinees were: They are not at risk for influenza. The vaccine is not for them; it is for old, weak, or sick people. The vaccine causes influenza. The vaccine causes side effects. They had bad reactions to influenza vaccinations in the past. They do not need to be vaccinated. The vaccine will not prevent influenza. Potential vaccine recipients have been found to have incomplete or incorrect knowledge about: The nature of influenza as a disease process (e.g., some believe it is part of spectrum of diseases that begins with the common cold and ends with pneu- monia), the severity of the complications that may arise from influenza, the degree to which individual actions (e.g., hand washing, taking vita- mins, etc.) can reduce the risk of getting the disease, the unique role of the vaccine as a preventive measure, and the health impacts and side effects related to the influenza vaccine. in several studies, the most important source of vaccination information has been found to be health care providers, but physicians do not always recommend that their elderly patients receive the influenza vaccine, either in conjunction with or without the pneumococcal vaccine (CDC, 1999; CDC, 2003b; Zimmerman et al., 2003 a,b). Zimmerman and colleagues (2003a) studied the beliefs and attitudes of the same elderly people in vaccine supply-rich and supply-limited periods. They found shifts in the participants' attitudes and contexts. For example, during the vaccine shortage period the participants reported more doubts and concerns about

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS 139 the vaccine (including safety, efficacy, and side effects issues); declines in physicians' and friends' recommendations to get vaccinated; less concern about unvaccinated people getting ill; and fewer concerns that other family members would contract influenza if one person got it. These changes may have led potential vaccinees to further underestimate the risk of getting influenza and thus their need for vaccination. CDC (2003b) also examined physicians' views about the influenza and pneu- mococcal vaccines. The participating physicians saw these vaccinations as an important patient service, demonstrated that they were knowledgeable about the vaccines, and said they wanted more involvement of their office managers in promoting the vaccinations. However, the physicians had little knowledge of the costs of the vaccinations and believed that people who were in the habit of visiting a doctor were more likely to be vaccinated. These recent studies show that modifications to current influenza risk communication programs would be beneficial. People need more appropriate contexts; information that is relevant to their cultural, societal, and personal circumstances; and materials in a language they can understand. An effective communication strategy must not only simplify and summarize key information, but also ensure that the needs of a variety of at-risk populations are met. Fre- quently, this must be done through carefully tailored methods and messages for each group. Conclusions Influenza vaccine is an essential tool for reducing the substantial burden of morbidity and mortality associated with influenza infections each year. Not only is the yearly disease toll high, but the prospect of an influenza pandemic is a serious concern to many. Because the vaccine is used so widely, and may be recommended for regular administration to young children, the possibility of vaccine-related adverse events must be given serious consideration. But although it is important to fully understand any risk for GBS or other neurological compli- cation that might be associated with influenza vaccination, it is also important that this be appropriately weighed against the sizable burden of illness associated with influenza infections. In its scientific assessment, the committee found support for a causal asso- ciation between the vaccine used in 1976 and GBS. But it found no support for an association with relapses of MS, and inconclusive evidence regarding influenza vaccines used in other years and other neurological conditions. The committee found no evidence bearing on a causal relationship between influenza vaccines and demyelinating neurological disorders in children aged 6-23 months. GBS is a serious condition, but it is rare and the additional risk related to vaccination in 1976 translated into fewer than 6 cases per million vaccinee (Langmuir et al., 1984~. By contrast, influenza contributes to an annual average of 13.8 deaths per

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140 IMMUNIZATION SAFETY REVIEW 100,000 (36,000 deaths, majority are 65 years of age or older) and to an annual excess of 49 pneumonia and influenza related hospitalizations per 100,000 (114,000 hospitalizations) (Thompson et al., 2003; Simonsen et al., 2000~. RECOMMENDATIONS FOR PUBLIC HEALTH RESPONSE The committee's charge includes making recommendations regarding a broad range of actions, including potential policy reviews, research needs, and changes in communication to the public and to health care providers about issues of vaccine safety. Policy Review Despite evidence favoring a causal association between GBS and the influ- enza vaccines used in 1976, the committee sees no evidence regarding more recent influenza vaccines that would warrant a review of current influenza immu- nization policies. Vaccination against influenza remains an essential component of efforts to reduce the substantial morbidity and mortality associated with influ- enza infections. The committee does not recommend a policy review of the recommenda- tions for influenza vaccination by any of the national or federal vaccine advisory bodies on the basis of concerns about neurological complications. Current and future immunization policies should continue to reflect the benefits of influenza vaccination. Research The evidence reviewed by the committee does not support a causal associa- tion between influenza vaccines and MS relapses and is inconclusive on some other outcomes, but it does support an association between GBS and the influ- enza vaccines used in 1976 (i.e., whole- and split-virus products formulated as monovalent or bivalent vaccines). Although the 1976 vaccines are no longer in use, experience with them should not be ignored because the mechanism by which they contributed to GBS remains unclear. With a vaccine as widely used as influenza vaccine, the committee considers it important to pursue research and research-related activities aimed at ensuring that any risk of GBS or other neuro- logical complications is minimized. Surveillance and Epidemiologic Studies Influenza vaccine is not only widely used but is recommended for even wider use than is routinely achieved. In addition, there are expectations that recommended use will be extended to include all children aged 6-23 months.

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS 141 Even though use of the vaccine generally appears to pose minimal risk of adverse neurological events, the strong association between the 1976 vaccine and GBS points to the need for appropriate vigilance through adequate surveillance systems and for better tools to support studies of rare adverse events. Currently, ACIP recommends annual influenza vaccination for any person aged 6 months or older who is at increased risk for complications from influenza (CDC, 2003d). The 2002 ACIP recommendations note that "because young, otherwise healthy children are at increased risk for influenza-related hospitaliza- tions, influenza vaccination of healthy children aged 6-23 months is encouraged when feasible" (CDC,2003d). But the ACIP, the American Academy of Pediatrics, and the American Academy of Family Physicians recognize that a full recom- mendation for annual vaccinations of all children aged 6-23 months cannot be made until certain issues are addressed (CDC, 2003d). Important among these is educating parents and providers regarding the impact of influenza infections in children and the risks and benefits of vaccination. Routine vaccination of chil- dren, some of whom may require two doses of vaccine within a season, will require the development of strategic plans to ensure efficient delivery of services within a limited time each year. Issues regarding vaccination costs and reim- bursement policies must also be addressed. A recommendation for annual vacci- nations of all children aged 6-23 months could be made in the near future (CDC, 2003d). In preparation for this change in influenza immunization practices, the committee recommends increased surveillance of adverse events associated with influenza vaccination of children, with particular attentiveness to detecting and assessing potential neurological complications. Enhanced sur- veillance should be in place before an ACIP recommendation is implemented for universal annual influenza vaccination of young children. Better methods are needed to identify and assess risks for rare outcomes such as the neurological complications considered in this report. The scale of the 1976 vaccination program almost 45 million people vaccinated within 2.5 months- helped make detection of the link with GBS feasible. CDC's Vaccine Safety Datalink program offers a valuable means of assembling systematic population- based data on vaccination and medical histories. Nevertheless, it may not cover a large enough population to successfully investigate concerns about some rare adverse events. Moreover, in the context of influenza vaccines, which are still given primarily to adults, the committee learned at its March 2003 meeting that only three of the participating HMOs have funding to collect data on adults. For the vaccines routinely administered to older adults, primarily the influenza and pneumococcal vaccines, Medicare databases may prove to be useful resources for exploratory analyses. A new project to use Medicare data for this purpose was described at that meeting (Burwen, 2003~. The committee recommends efforts to develop techniques for the detection and evaluation of rare adverse events and encourages the use of administrative databases and the standardization of immunization records as part of this effort.

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142 Basic and Clinical Sciences IMMUNIZATION SAFETY REVIEW Despite advances over the past 25 years in the broad understanding of the pathogenesis of autoimmune diseases and of GBS in particular, the exact mecha- nisms by which the 1976 influenza vaccines precipitated this adverse outcome remain unknown. To gain a better understanding of these mechanisms, the com- mittee sees a need for additional basic and clinical research on influenza viruses, the composition and immunological properties of the 1976 vaccine, immunologi- cal responses to vaccines in general, and host characteristics that may affect susceptibility to adverse events. There is a need to better understand the immunological responses in recipi- ents of the 1976 swine influenza vaccine who experienced GBS. One avenue of inquiry should be the pathogenesis of influenza viruses in general and the swine influenza strain (A/New Jersey/76) in particular to learn whether and how strains might differ in their ability or predisposition to produce neurological injury. The committee supports ongoing research aimed at better understanding the pathogenesis of influenza and encourages efforts to anticipate which strains might be more neurologically active. Although, the 1976 influenza vaccines were produced under atypical condi- tions, with the four manufacturers given less time than usual while being asked to produce much larger quantities than in previous years, there is no evidence that the speed of manufacture or volume of production produced lapses that could have led to a faulty vaccine. Even though the viral strain was first identified less than 8 months before vaccination began, about 150 million doses of vaccine were ultimately manufactured (Dowdle, 1997~. The increased risk of GBS associated with the 1976 swine influenza vaccines appeared consistent for vaccine from the four different manufacturers, for the monovalent and bivalent vaccines, and for the whole- and split-virus vaccines. The consistency of the risk across the sources and types of vaccine argues against, but does not rule out, problems related to the manufacturing process. Issues that might be investigated include whether there was something atypical about the nonviral components of the swine influenza vaccines and, if so, identifying it and determining whether it can be controlled. The use of eggs to produce vaccine-strain influenza virus suggests the possi- bility that unrecognized antigens might have been present in the 1976 vaccine. C. jejuni infection is a recognized risk factor for GBS, possibly acting through molecular mimicry, and C. jejuni commonly infects chickens. Although the com- mittee concluded that molecular mimicry is only theoretically possible as an immune mechanism by which influenza vaccines may cause GBS, the evidence that C. jejuni antigens can trigger GBS is strong, and the possibility cannot be excluded that C. jejuni antigens were present in swine influenza vaccines from all four manufacturers of the 1976 swine influenza vaccines. Although stocks of the 1976 vaccine are unlikely available, the committee recommends that if samples of the influenza vaccines used in 1976 are available, they should be

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS 143 analyzed for the presence of C. jejuni antigens, NS1 or NS2 proteins, or other possible contaminants. The 1976 vaccines should be compared with current and other historical influenza vaccines. Studies in animals (Hjorth et al., 1984; Ziegler et al., 1983) have provided at least some basis for considering bystander activation as a potential mechanism by which influenza vaccines could cause GBS or related neurological complications. Under contrived experimental conditions, influenza vaccines had adjuvant prop- erties in the presence of neural antigens. But whether an immune system mecha- nism of this sort played any role in vaccine-related cases of GBS remains far from clear. As it did in a previous report (IOM, 2002a), the committee recommends continued research using animal and in vitro models, as well as with humans, on the mechanisms of immune-mediated neurological diseases that might be associated with exposure to vaccines. Genetic factors are known to be an important source of variability in the responses of the human immune system and in the risks of autoimmune disease. The encephalitis/encephalopathy observed as a complication of influenza illness in Japanese children, but only very rarely reported in the United States, suggests the possibility that a genetic factor may be involved in neurological complica- tions of influenza illness. Indications of selective susceptibility to GBS following infection with C. jejuni also appear to point to differences in genetic or other host factors, some of which might be relevant as well to examination of mechanisms of vaccine-related risk in 1976 or other years. At present, understanding of the complex interactions among genetic variables and environmental exposures, including vaccines and wild-type infectious organisms, remains incomplete. The committee recommends continued research efforts aimed at identifying genetic variability in human immune system responsiveness as a way to gain a better understanding of genetic susceptibility to vaccine-based adverse events. Communication It is important that modifications to influenza communication not be seen as independent activities; it is essential that revisions be integrated in an overarching risk management strategy (Bostrom, 1997~. While available studies have docu- mented important attitudes, gaps and errors in knowledge, in-depth research is needed to develop greater insights into why people have the cognitive limitations, attitudes, and beliefs they have about the influenza vaccine and related issues. This deeper knowledge is necessary to provide an appropriate basis for strength- ening risk-benefit communication within an overall risk reduction strategy. A broader framework for influenza vaccine issues is critical for substantial progress in vaccination rates to be achieved. A rigorous, systematic identification of the influences that affect experts' and subpopulations' views and decisions

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44 IMMUNIZATION SAFETY REVIEW about vaccines is an important step toward developing such a framework (Bostrom, 1997~. Despite the studies that have been conducted to date, a com- prehensive context has not yet been compiled for the influenza vaccine. The committee recommends that research be supported to conduct investiga- tions that would deepen and expand the knowledge available from existing studies and more effectively organize what is currently known from these and future projects. Comprehensive influence diagrams of expert and at-risk populations' views of the vaccine are needed to provide a broader context and reveal richer insights than are possible from a review of currently available studies. SUMMARY Infection with the influenza virus can have a serious effect on the health of people of all ages, although it is particularly worrisome for infants, the elderly, and people with underlying heart or lung problems. At least 35,000 people die in the United States every year from influenza infection. A vaccine exists (the "flu" shot) that can greatly decrease the impact of influenza. Because the strains of virus that are expected to cause serious illness and death are slightly different every year, the vaccine is also slightly different every year and it must be given every year, unlike other vaccines. The influenza vaccine that was used in 1976 for the expected "Swine Flu" epidemic (which never materialized) was associ- ated with cases of a nervous system condition called Guillain-Barre syndrome (GBS). Ever since that time, public health leaders, doctors and nurses, and the public have wondered whether every year's influenza vaccine can cause GBS or other similar conditions. The Immunization Safety Review committee reviewed the data on influenza vaccine and neurological conditions and concluded that the evidence favored acceptance of a causal relationship between the 1976 swine influenza vaccine and GBS in adults. The evidence about GBS for other years' influenza vaccines is not clear one way or the other (that is, the evidence is inadequate to accept or reject a causal relationship). The committee concluded that the evidence favored rejection of a causal relationship between influenza vaccines and exacerbation of multiple sclerosis. For the other neurological conditions studied, the committee concluded the evi- dence about the effects of influenza vaccine is inadequate to accept or reject a causal relationship. The committee also reviewed theories on how the influenza vaccine could damage the nervous system. The evidence was at most weak that the vaccine could act in humans in ways that could lead to these neurological problems. See Box 4 for a summary of all conclusions and recommendations.

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INFLUENZA VACCINES AND NEUROLOGICAL COMPLICATIONS 145

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146 IMMUNIZATION SAFETY REVIEW