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Appendix A Committee Recommendations and Conclusions from Previous Reports MEASLES-MUMPS-RUBELLA VACCINE AND AUTISM Conclusions The committee concludes that the evidence favors rejection of a causal rela- tionship at the population level between measles-mumps-rubella (MMR) vaccine and autistic spectrum disorders (ASD). However, this conclusion does not ex- clude the possibility that MMR vaccine could contribute to ASD in a small number of children. The committee concludes that further research on the possible occurrence of ASD in a small number of children subsequent to MMR vaccination is warranted, and it has identified targeted research opportunities that could lead to firmer understanding of the relationship. Recommendations Public Health Response The committee recommends that the relationship between the MMR vaccine and autistic spectrum disorders receive continued attention. Policy Review The committee does not recommend a policy review at this time of the 155

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156 IMMUNIZATION SAFETY REVIEW licensure of MMR vaccine or of the current schedule and recommendations for administration of MMR vaccine. Research Regarding MMR and ASD The committee recommends the use of accepted and consistent case defini- tions and assessment protocols for ASD in order to enhance the precision and comparability of results from surveillance, epidemiological, and biological inves- tigations. The committee recommends the exploration of whether exposure to MMR vaccine is a risk factor for autistic spectrum disorder in a small number of children. The committee recommends the development of targeted investigations of whether or not measles vaccine-strain virus is present in the intestines of some children with ASD. The committee encourages all who submit reports to VAERS of any diag- nosis of ASD thought to be related to MMR vaccine to provide as much detail and as much documentation as possible. The committee recommends studying the possible effects of different MMR . . . mmun~zahon exposures. The committee recommends conducting further clinical and epidemiological studies of sufficient rigor to identify risk factors and biological markers of ASD in order to better understand genetic or environmental causes. Communications The committee recommends that government agencies and professional organizations, CDC and the Food and Drug Administration (FDA) in particular, review some of the most prominent forms of communication regarding the hypothesized relationship between MMR vaccine and ASD, including informa- tion they provide via the Internet and the ease with which Internet information can be accessed.

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APPENDIX A 157 THIMEROSAL-CONTAINING VACCINES AND NEURODEVELOPMENTAL DISORDERS Conclusions The committee concludes that although the hypothesis that exposure to thime- rosal-containing vaccines could be associated with neurodevelopmental disor- ders is not established and rests on indirect and incomplete information, primarily from analogies with methylmercury and levels of maximum mercury exposure from vaccines given in children, the hypothesis is biologically plausible. The committee also concludes that the evidence is inadequate to accept or reject a causal relationship between thimerosal exposures from childhood vac- cines and the neurodevelopmental disorders of autism, ADHD, and speech or language delay. Public Health Response Recommendations Policy Review and Analysis The committee recommends the use of the thimerosal-free DTaP, Hib, and hepatitis B vaccines in the United States, despite the fact that there might be remaining supplies of thimerosal-containing vaccine available. The committee recommends that full consideration be given by appropriate professional societies and government agencies to removing thimerosal from vaccines administered to infants, children, or pregnant women in the United States. The committee recommends that appropriate professional societies and gov- ernment agencies review their policies about the non-vaccine biological and pharmaceutical products that contain thimerosal and are used by infants, children, and pregnant women in the United States. The committee recommends that policy analyses be conducted that will inform these discussions in the future. The committee recommends a review and assessment of how public health policy decisions are made under uncertainty. The committee recommends a review of the strategies used to communicate rapid changes in vaccine policy, and it recommends research on how to improve those strategies. Public Health and Biomedical Research portfolio. The committee recommends a diverse public health and biomedical research

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158 Epidemiological Research IMMUNIZATION SAFETY REVIEW The committee recommends case-control studies examining the potential link between neurodevelopmental disorders and thimerosal-containing vaccines. The committee recommends further analysis of neurodevelopmental dis- orders in cohorts of children who did not receive thimerosal-containing doses as part of a clinical trial of DTaP vaccine. The committee recommends conducting epidemiological studies that com- pare the incidence and prevalence of neurodevelopmental disorders before and after the removal of thimerosal from vaccines. The committee recommends an increased effort to identify the primary sources and levels of prenatal and postnatal background exposure to thimerosal (e.g., Rho (D) Immune Globulin) and other forms of mercury (e.g., maternal consumption of fish) in infants, children, and pregnant women. Clinical Research The committee recommends research on how children, including those diag- nosed with neurodevelopmental disorders, metabolize and excrete metals par- ticularly mercury. The committee recommends continued research on theoretical modeling of ethylmercury exposures, including the incremental burden of thimerosal with background mercury exposure from other sources. The committee recommends careful, rigorous, and scientific investigations of chelation when used in children with neurodevelopmental disorders, especially autism. Basic Science Research The committee recommends research to identify a safe, effective, and inex- pensive alternative to thimerosal for countries that decide they need to switch from using thimerosal as a preservative. The committee recommends research in appropriate animal models on the neurodevelopmental effects of ethylmercury.

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APPENDIX A MULTIPLE IMMUNIZATIONS AND IMMUNE DYSFUNCTION Conclusions Scientific Assessment Causality Conclusions 159 The committee concludes that the epidemiological evidence favors rejection of a causal relationship between multiple immunizations and an increase in heterologous infection. The committee concludes that the epidemiological evidence favors rejection of a causal relationship between multiple immunizations and an increased risk of type 1 diabetes. The committee concludes that the epidemiological evidence is inadequate to accept or reject a causal relationship between multiple immunizations and increased risk of allergic disease, particularly asthma. Biological Mechanisms Conclusions Autoimmune Disease In the absence of experimental or human evidence regarding molecular mimicry or mercury-induced modification of any vaccine component to create an antigenic epitope capable of cross-reaction with self epitopes as a mechanism by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual's risk of autoimmunity, the committee con- cludes that these mechanisms are only theoretical. The committee concludes that there is weak evidence for bystander activa- tion, alone or in concert with molecular mimicry, as a mechanism by which multiple immunizations under the U.S. infant immunization schedule could pos- sibly influence an individual's risk of autoimmunity. In the absence of experimental or human evidence regarding loss of protec- tion against a homologous infection as a mechanism by which multiple immuni- zations under the U.S. infant immunization schedule could possibly influence an individual's risk of autoimmunity, the committee concludes that this mechanism is only theoretical. In the absence of experimental or human evidence regarding mechanisms related to the hygiene hypothesis as a means by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an indi- vidual's risk of autoimmunity, the committee concludes that this mechanism is only theoretical. Considering molecular mimicry, bystander activation, and impaired immuno- regulation collectively rather than individually, the committee concludes that

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160 IMMUNIZATION SAFETY REVIEW there is weak evidence for these mechanisms as means by which multiple immu- nizations under the U.S. infant immunization schedule could possibly influence an individual's risk of autoimmunity. Allergic Disease The committee concludes that there is weak evidence for bystander activa- tion as a mechanism by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual's risk of allergy. In the absence of experimental or human evidence regarding mechanisms related to the hygiene hypothesis as a means by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an indi- vidual's risk of allergy, the committee concludes that this mechanism is only theoretical. The committee concludes that there is weak evidence for the existence of any biological mechanisms, collectively or individually, by which multiple immuni- zations under the U.S. infant immunization schedule could possibly influence an individual's risk of allergy. Heterologous Infection The committee concludes that there is strong evidence for the existence of biological mechanisms by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual's risk for heterolo- gous infections. Significance Assessment The committee concludes that concern about multiple immunizations has been, and could continue to be, of societal significance in terms of parental worries, potential health burdens, and future challenges for immunization policy- making. Public Health Response Recommendations Policy Review The committee recommends that state and federal vaccine policymakers consider a broader and more explicit strategy for developing recommendations for the use of vaccines. The committee does not recommend a policy review by the CDC's Advi- sory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics' Committee on Infectious Diseases, and the American Academy of Family Physicians of the current recommended childhood immunization sched- ule on the basis of concerns about immune system dysfunction.

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APPENDIX A 161 The committee does not recommend a policy review by the Food and Drug Administration's Vaccines and Related Biologic Products Advisory Committee of any currently licensed vaccines on the basis of concerns about immune system dysfunction. Research Epidemiological Research The committee recommends exploring the feasibility of using existing vac- cine surveillance systems, alone or in combination, to study safety questions related to asthma and other important allergic disorders, as well as to type 1 diabetes and other important autoimmune diseases. The committee recommends exploring the use of cohorts for research on possible vaccine-related disease risks. Furthermore, the committee recommends that disease registries and research programs for autoimmune and allergic dis- orders routinely collect immunization histories as part of their study protocol. Basic Science and Clinical Research The committee recommends continued research on the development of the human infant immune system. The committee endorses current research efforts aimed at identifying genetic variability in human immune system development and immune system respon- siveness as a way to gain a better understanding of genetic susceptibility to vaccine-based adverse events. The committee recommends exploring the feasibility of collecting data on surrogate markers for autoimmune and allergic disorders in the vaccine testing and licensing process. The committee recommends exploring surrogates for allergy and auto- immunity in existing cohort studies of variations in the vaccine schedule. Communication The committee recommends that an appropriate panel of multidisciplinary experts be convened by the Department of Health and Human Services. It would develop a comprehensive research strategy for knowledge leading to the optimal design and evaluation of vaccine risk-benefit communication approaches.

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162 Causality Conclusions IMMUNIZATION SAFETY REVIEW HEPATITIS B VACCINE AND DEMYELINATING NEUROLOGICAL DISORDERS Scientific Assessment The committee concludes that the evidence favors rejection of a causal rela- tionship 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. 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. The committee concludes that there is weak evidence for biological mecha- nisms by which hepatitis B vaccination could possibly influence an individual's risk of the central or peripheral nervous system disorders of MS, first episode of CDD, ADEM, or optic neuritis, transverse myelitis, GBS, or 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.

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APPENDIX A 163 The committee recommends continued surveillance of hepatitis B disease and increased surveillance of secondary diseases such as cirrhosis and hepato- cellular 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 profes- sional organizations responsible for immunizations critically evaluate their communication services with increased understanding of, and input from, the intended user.

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164 Causality Conclusions IMMUNIZATION SAFETY REVIEW SV40 CONTAMINATION OF POLIO VACCINE AND CANCER Scientific Assessment The committee concludes that the evidence is inadequate to accept or reject a causal relationship between SV40-containing polio vaccines and cancer. Biological Mechanisms Conclusions The committee concludes that the biological evidence is strong that SV40 is a transforming virus. The committee concludes that the biological evidence is moderate that SV40 exposure could lead to cancer in humans under natural conditions. The committee concludes that the biological evidence is moderate that SV40 exposure from the polio vaccine is related to SV40 infection in humans. Significance Assessment The committee concludes that concerns about exposure to SV40 through inadvertent contamination of polio vaccines are significant because of the serious- ness of cancers as the possible adverse health outcomes and because of the continuing need to ensure and protect public trust in the nation's immunization program. Public Health Response Recommendations Policy Review The committee does not recommend a policy review of polio vaccine by any of the national or federal vaccine advisory bodies, on the basis of concerns about cancer risks that might be associated with exposure to SV40, because the vaccine in current use is free of SV40. Policy Analysis and Communication The committee recommends that the appropriate federal agencies develop a Vaccine Contamination Prevention and Response Plan. Research The committee recommends development of sensitive and specific serologic tests for SV40.

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APPENDIX A 165 The committee recommends the development and use of sensitive and spe- cific standardized techniques for SV40 detection. The committee recommends that once there is agreement in the scientific community as to the best detection methods and protocols, pre-1955 samples of human tissues should be assayed for presence or absence of SV40 in rigorous, multi-center studies. The committee recommends further study of the transmissibility of SV40 in humans. Until some of the technical issues are resolved, the committee does not recommend additional epidemiological studies of people potentially exposed to the contaminated polio vaccine.

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166 IMMUNIZATION SAFETY REVIEW VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY Scientific Assessment Causality Conclusions There is no basis for a change in the prior conclusions that the evidence favors rejection of a causal relationship between DTwP vaccine and SIDS. The evidence is inadequate to accept or reject a causal relationship between DTaP vaccine and SIDS. The evidence is inadequate to accept or reject causal relationships between SIDS and the individual vaccines, Hib, HepB, OPV, and IPV. The evidence favors rejection of a causal relationship between exposure to multiple vaccines and SIDS. The evidence is inadequate to accept or reject a causal relationship between exposure to multiple vaccines and sudden unexpected death in infancy, other than SIDS. The evidence favors acceptance of a causal relationship between diphtheria toxoid-and whole cell pertussis vaccine and death due to anaphylaxis in infants. The evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and neonatal death. Biological Mechanisms Conclusions In the absence of experimental or human evidence regarding the ability of common side effects of immunization, including fever and anorexia, to trigger sudden unexpected death in infants with underlying neuroregulatory abnormali- ties, the committee concludes that this mechanisms is only theoretical. In the absence of experimental or human evidence regarding the ability of common side effects of immunization, including fever and anorexia, to trigger an acute metabolic crisis in patients with inborn errors of metabolism, the committee concludes that this mechanism for vaccine-related sudden unexpected infant death is only theoretical. In the absence of experimental or human evidence demonstrating the ability of vaccines to stimulate an abnormal inflammatory response in the lung leading to sudden unexpected infant death, the committee concludes that this mechanism is only theoretical. The committee concludes that immediate type I hypersensitivity reactions to vaccines can cause SUDI within 24 hours of vaccine administration. Although a type I hypersensitivity reaction leading to death could possibly be missed both clinically and at post-mortem examination, and therefore misdiagnosed as SIDS, the committee concludes that this possibility is only theoretical.

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APPENDIX A Policy Review 167 Public Health Response Recommendations The committee does not recommend a policy review of the recommended childhood vaccination schedule by any of the national or federal vaccine advisory bodies on the basis of concerns about sudden unexpected death in infancy. Surveillance and Epidemiological Studies results. The committee urges prompt publication of all Vaccine Safety Datalink Basic and Clinical Science The committee recommends continued research on the etiology and pathology of SIDS. The committee recommends that a comprehensive postmortem workup, including a metabolic analysis, be done on all infants who die suddenly and unexpectedly. The committee encourages efforts by Centers for Disease Control and Pre- vention, American Academy of Pediatrics, and others to promote the develop- ment and consistent use throughout the United States of national guidelines for investigation, diagnosis, and reporting of SIDS cases. The committee recommends the development of standard definitions and guidance for diagnosis and reporting of SUDI for research purposes.