1

Executive Summary

"Our aim, therefore, must be to study these [complications] as fully as possible in the confident expectation that, as in other branches of science, knowledge will bring enlightenment" (Wilson, 1967).

Childhood immunization has been one of the foremost public health measures of the twentieth century. It has allowed control and prevention of many diseases from which morbidity and mortality can be staggering. Medical personnel in the United States currently rarely see a case of the infectious diseases against which the vaccines are directed. Yet, recent measles epidemics on college campuses and in inner cities suggest that vaccine-preventable disease is not to be ignored. The first health initiative of the immunization programs to boost vaccination rates in the United States, particularlyfor children under age 2 years.

BACKGROUND AND HISTORY

The public policy debate regarding immunization stretches beyond the question of how to meet the goals of universal immunization. Concern over the safety of pertussis vaccine was long-standing in Great Britain by the time of the 1982 airing in the United States of a documentary entitled "DPT: A Shot in the Dark (Coulter and Fisher, 1985). Concern has stretched to other vaccines and has spawned the formation of groups of interested citizens throughout the United States, for example, National Vaccine Information Center/Dissatisfied Parents Together, Determined Parents to Stop Hurting Our Tots, Concerned Health Professionals and Others, and Parents



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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 1 Executive Summary "Our aim, therefore, must be to study these [complications] as fully as possible in the confident expectation that, as in other branches of science, knowledge will bring enlightenment" (Wilson, 1967). Childhood immunization has been one of the foremost public health measures of the twentieth century. It has allowed control and prevention of many diseases from which morbidity and mortality can be staggering. Medical personnel in the United States currently rarely see a case of the infectious diseases against which the vaccines are directed. Yet, recent measles epidemics on college campuses and in inner cities suggest that vaccine-preventable disease is not to be ignored. The first health initiative of the immunization programs to boost vaccination rates in the United States, particularlyfor children under age 2 years. BACKGROUND AND HISTORY The public policy debate regarding immunization stretches beyond the question of how to meet the goals of universal immunization. Concern over the safety of pertussis vaccine was long-standing in Great Britain by the time of the 1982 airing in the United States of a documentary entitled "DPT: A Shot in the Dark (Coulter and Fisher, 1985). Concern has stretched to other vaccines and has spawned the formation of groups of interested citizens throughout the United States, for example, National Vaccine Information Center/Dissatisfied Parents Together, Determined Parents to Stop Hurting Our Tots, Concerned Health Professionals and Others, and Parents

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Concerned About the Safety of Vaccines. More articles and books have been published (e.g., Counter, 1990; Miller, 1992) to alert the public to the potential risks of vaccination. In 1986, the US. Congress passed the National Childhood Vaccine Injury Act (NCVIA; P.L. 99-660) in response to worries about the safety of currently licensed childhood vaccines and in response to the economic pressures that were threatening the integrity of childhood immunization programs. The litigation costs associated with claims of damage from vaccines had forced several companies to end their vaccine research and development programs as well as to stop producing already licensed vaccines. The NCVIA was an attempt to encourage and ensure vaccine production by creating a no-fault compensation program (the National Vaccine Injury Compensation Program) as a required first resort for those who believed that they or their children had been injured by certain vaccines. The need for a compensation program had long been recognized, and several groups had proposed possible mechanisms for compensating people believed to be injured by vaccination (Institute of Medicine, 1985; Office of Technology Assessment, 1980). This program was envisioned to alleviate, but not completely eliminate, manufacturer liability and encourage research and development of more and safer vaccines. The compensation program is administered by the federal government and is financed by an excise tax on the sale of vaccines covered by the program (Iglehart, 1987; Mariner, 1992). In addition to establishing the compensation program, the NCVIA set forth other vaccine-related efforts to be carried out by the U.S. Department of Health and Human Services, including mandatory reporting of specific adverse events following childhood immunizations against diphtheria, tetanus, pertussis, measles, mumps, rubella, and polio (see box entitled The Vaccine Injury Table in Chapter 10); voluntary reporting of any reaction to any immunization to the Vaccine Adverse Event Reporting System (see Chapter 10 for a discussion of this passive surveillance system and Figure B-1 for a copy of the reporting form); the creation of a National Vaccine Program Office to coordinate federal vaccine initiatives and to help meet immunization coverage goals; the establishment of advisory groups to the National Vaccine Program and the National Vaccine Injury Compensation Program; and better communication of the potential risks of vaccines through public information pamphlets that are distributed at the time of vaccination (under the direction of the Centers for Disease Control and Prevention) and changes in vaccine package inserts (under the direction of the U.S. Food and Drug Administration). The NCVIA also mandated that the Secretary of the U.S. Department of Health and Human Services enlist the help of the Institute of Medicine (IOM) of the National Academy of Sciences to study the adverse effects of childhood vaccines. The NCVIA called for two specific studies. The first,

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality mandated under Section 312 of P.L. 99-660, was to address the serious adverse effects of pertussis and rubella vaccines. The Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines published its findings in 1991 (Institute of Medicine, 1991). Appendix A contains the Executive Summary of that report. The second study, mandated under Section 313 of P.L. 99-660, was to review adverse events associated with other vaccines commonly administered during childhood. The Vaccine Safety Committee, which was charged with performing the second study, was convened early in 1992. The results of that inquiry are provided in this report. THE CHARGE TO THE COMMITTEE The members of the interdisciplinary, 14-member Vaccine Safety Committee have expertise in such areas as immunology, pediatrics, internal medicine, infectious diseases, neurology, virology, microbiology, epidemiology, and public health. The committee was charged with (1) reviewing the relevant scientific and medical literature on specific risks to children associated with the vaccines or vaccine components directed against tetanus, diphtheria, measles, mumps, polio, Haemophilus influenzae type b, and hepatitis B currently licensed for use in the United States and (2) reviewing the available data on specific risk-modifying factors, that is, circumstances under which administration of these vaccines increases the risk of an adverse event, characteristics of groups known to be at increased risk of an adverse event, and timing of vaccination that increases the risk of an adverse event. Risk-benefit comparisons or recommendations about immunization schedules were not within the charge to the Vaccine Safety Committee. Despite the name of the committee, many aspects of vaccine safety, such as purity standards or production techniques, also were beyond the committee's charge. Both IOM studies mandated in P.L. 99-660 entailed the evaluation of the weight of scientific and medical evidence bearing on the question of whether a causal relation exists between certain vaccines and specific serious adverse events. Like the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines, the Vaccine Safety Committee approached its task from a position of neutrality, presuming neither the presence nor the absence of a causal relation between the vaccines and the adverse events under consideration. THE STUDY PROCESS Over the course of 18 months, the committee met six times, reviewed more than 7,000 abstracts of scientific and medical studies, read more than 2,000 published books and articles (including many sources in the non-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality English literature), analyzed information from U.S. Public Health Service-administered reporting systems for adverse reactions to vaccines, and considered material submitted by interested parties. The committee solicited input from scientists who were invited to participate in two open scientific meetings and from other interested parties at two open public meetings. Details regarding how the committee gathered information are given in Appendix B. All salient information from those reviews is contained in this report. P.L. 99-660 stated that the review was to include those vaccines covered by the National Vaccine Injury Compensation Program. Haemophilus influenzae type b (Hib) and hepatitis B vaccines were added for consideration because of the increasing use of these vaccines and the supposition that in the near future they could be mandatory vaccines covered by the National Vaccine Injury Compensation Program. The list of adverse events investigated for this report derived primarily from negotiations with representatives of the U.S. Public Health Service. However, preliminary investigations into additional adverse events were prompted by queries from interested parties or committee members. After considering the information from these preliminary investigations, the committee added several vaccine-adverse event relations to the original list. Table B-1 in Appendix B contains a complete listing of the specific vaccine-adverse event relations under study. The report begins with background information. Chapter 2 contains an in-depth discussion of the approach used by the committee to weight the evidence and assess causality. Information on the neurologic disorders and immunologic reactions discussed in much of the report is contained in Chapters 3 and 4. Chapters 5 through 9 include the vaccine-specific evidence and conclusions. All information (evidence, causality argument, and conclusions) regarding death as an adverse event associated with vaccination is contained in Chapter 10. Adverse Effects of Pertussis and Rubella Vaccines (Institute of Medicine, 1991), the report of the predecessor IOM committee, provides an in-depth review of the literature concerning the adverse events associated with diphtheria and tetanus toxoids and pertussis vaccine (DPT), as well as pertussis vaccine, and should be referred to for conclusions regarding DPT. Appendix A contains the Executive Summary of that report. The charge to the Vaccine Safety Committee was to examine adverse events associated with tetanus toxoid as well as tetanus and diphtheria toxoid combination preparations. The committee reviewed data concerning DPT if the data also concerned diphtheria and tetanus toxoids for pediatric use (DT); however, it was beyond the committee's scope to make conclusions about pertussis vaccine or DPT. The IOM Committee to Review the Adverse Consequences of Pertussis

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality and Rubella Vaccines made determinations of causality only for rubella vaccine and the rubella vaccine component of multivalent vaccines, but not for measles-mumps-rubella vaccine (MMR). Thus, the Vaccine Safety Committee reviewed data regarding immunization with MMR as well as data on monovalent measles and mumps preparations. The committee has made separate determinations of causality for the measles and mumps vaccine components for the adverse events for which data were available, particularly if measles or mumps vaccine-strain virus was isolated from the patient. In circumstances in which a causality assessment specific to monovalent measles or mumps vaccine was not possible, this is stated in the conclusion regarding that specific adverse event. In circumstances in which the committee determined that a component of a multivalent preparation was causally related to a specific adverse event, but there is no direct experience of such an adverse event being caused by the multivalent preparation, the committee states this, but judges that the combined preparation also is causally related to that adverse event. Many case reports described an adverse event(s) in a patient who received more than one vaccine. A common combination, as a result of the immunization schedules recommended in the United States, is DPT, oral polio vaccine, and Hib vaccine. Assessment of causality in those reports was more difficult than if the patient had received only one vaccine or vaccine component, but the committee considered that the reports could be theoretically supportive of causality for the combination but not in themselves sufficient to allow a firm judgment regarding causality. CAUSALITY AND WEIGHT OF EVIDENCE As discussed in detail in Chapter 2, the committee considered four types of evidence: biologic plausibility; case reports, case series, and uncontrolled observational studies; controlled observational studies; and controlled clinical trials. The committee used qualitative and quantitative approaches to weigh each type of evidence. Table 1-1 contains a summary of the different types of evidence for every vaccine-adverse event relation studied. The committee believes that although it is plausible that there is a causal relation between any of the vaccine-adverse event associations under review, plausibility has been demonstrated only for certain ones of these. Therefore, information on the plausibility of a causal relation was classified in Table 1-1 as either theoretical only or as demonstrated. The other types of evidence were classified in Table 1-1 as nonexistent, indeterminate, or as weighing, on the whole, for or against a determination of a causal relation. The consideration of all four types of evidence as a whole led to a conclusion of the final weight of evidence regarding causality. Table 1-2 contains these conclusions.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality TABLE 1-1 Summary of the Evidence For or Against a Determination of a Causal Relationa Vaccine and Adverse Event Biologic Plausibilityb Case Reports, Case Series, and Uncontrolled Observational Studies Controlled Observational Studies and Controlled Clinical Trials Diphtheria and Tetanus Toxoidsc       Encephalopathy Demonstrated Indeterminate Against (DT) No data (Td, T) Infantile spasmsd (DT only) Theoretical only No data Against Residual seizure disorders other than infantile spasms Theoretical only Indeterminate (DT, T) No data (Td) No data Demyelinating diseases of the central nervous system Demonstrated For No data Guillain-Barré syndrome Demonstrated For (T) Indeterminate (DT, Td) No data Mononeuropathy Theoretical only Indeterminate (T, Td)No data (DT) No data Brachial neuritis Theoretical only For (T) Indeterminate (Td) No data (DT) No data

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Vaccine and Adverse Event Biologic Plausibilityb Case Reports, Case Series, and Uncontrolled Observational Studies Controlled Observational Studies and Controlled Clinical Trials Arthritis Theoretical only Indeterminate No data Erythema multiforme Theoretical only Indeterminate (DT, Td) NO data (T) No data Anaphylaxis Demonstrated For (T) Indeterminate (DT, Td) No data Death from SIDS (DT only)e Theoretical only Indeterminate Against Measles Vaccinef       Encephalopathy Demonstrated Indeterminate Indeterminate Subacute sclerosing panencephalitis Demonstrated Indeterminate Indeterminate Residual seizure disorder Demonstrated Indeterminate No data Sensorineural deafness Theoretical only Indeterminate (MMR) No data Optic neuritis Demonstrated Indeterminate No data Transverse myelitis Demonstrated Indeterminate No data Guillain-Barré syndrome Demonstrated Indeterminate No data Thrombocytopenia Demonstrated Indeterminate (measles) For (MMR) Indeterminate (measles) No data (MMR) Insulin-dependent diabetes mellitus Theoretical only Indeterminate Indeterminate

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Vaccine and Adverse Event Biologic Plausibilityb Case Reports, Case Series, and Uncontrolled Observational Studies Controlled Observational Studies and Controlled Clinical Trials Anaphylaxis Theoretical only For No data Death from vaccine-strain vital infectione Demonstrated For No data Mumps Vaccinef       Encephalopathy Demonstrated Indeterminate No data Aseptic meningitis Demonstrated Indeterminate No data Residual seizure disorder Theoretical only No data No data Neuropathy Theoretical only No data No data Sensorineural deafness Demonstrated Indeterminate (MMR) No data Insulin-dependent diabetes mellitus Demonstrated Indeterminate Indeterminate Sterility Demonstrated No data No data Thrombocytopenia Demonstrated Indeterminate No data Anaphylaxis Theoretical only Indeterminate (MMR) No data

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Vaccine and Adverse Event Biologic Plausibilityb Case Reports, Case Series, and Uncontrolled Observational Studies Controlled Observational Studies and Controlled Clinical Trials Polio Vaccine (OPV and IPV)g       Guillain-Barré syndrome Demonstrated (OPV) Theoretical only (IPV) For (OPV) Indeterminate (IPV) For (OPV) No data (IPV) Transverse myelitis Demonstrated (OPV) Theoretical only (IPV) Indeterminate (OPV) No data (IPV) No data Poliomyelitis (OPV only) Demonstrate For No data Thrombocytopenia (IPV) Theoretical only No data No data Anaphylaxis (IPV) Theoretical only No data No data Death from SIDSe Theoretical only Indeterminate Indeterminate Death from vaccine-strain vital infection, including from paralytic polio myelitis (OPV only)e Demonstrated For No data Hepatitis B Vaccine       Guillain-Barré syndrome Demonstrated Indeterminate No data Demyelinating diseases of the central nervous system Demonstrated Indeterminate No data Arthritis Demonstrated Indeterminate No data Anaphylaxis Theoretical only For No data Death from SIDSe Theoretical only Indeterminate No data

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Vaccine and Adverse Event Biologic Plausibilityb Case Reports, Case Series, and Uncontrolled Observational Studies Controlled Observational Studies and Controlled Clinical Trials Haemophilus influenzae type b Vaccine       Guillain-Barré syndrome Theoretical only Indeterminate No data Transverse myelitis Theoretical only Indeterminate No data Thrombocytopenia Theoretical only Indeterminate Indeterminate Susceptibility to early Hib diseaseh Demonstrated Indeterminate For (PRP) Against (conjugated) Anaphylaxis Theoretical only Indeterminate No data Death from SIDSe Theoretical only Indeterminate No dam a Indeterminate indicates that there is evidence in this category, but the committee did not consider that, on the whole, it weighed either for or against a causal relation. No data indicates that the committee did not find data of tiffs type directly bearing on a causal relation between the vaccine and the adverse event. b The committee considered all adverse events to be theoretically plausible and, therefore, classified plausibility in support of causality as either theoretical only or demonstrated. Demonstrated biologic plausibility refers to information on the known effects of the natural disease against which the vaccine is given and the results of animal experiments and in vitro studies. c Unless noted otherwise, the classification for tetanus toxoid (T), diphtheria-tetanus toxoid for pediatric use (DT), and tetanus-diphtheria toxoid for adult use (Td) is the same. The committee was not charged with assessing monovalent diphtheria toxoid or the combined diphtheria and tetanus toxoids and pertussis vaccine (DPT). In Appendix A, see the Executive Summary of Adverse Effects of Pertussis and Rubella Vaccines for conclusions about DPT.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality d Infantile spasms occur only in the age group that receives DT but not Td or T. A possible causal relation between infantile spasms and Td and T was not examined. e In this table, the committee summarizes the data regarding the causal relation between the vaccine and only those deaths that are classified as sudden infant death syndrome (SIDS) or that are a consequence of vaccine-strain viral infection. SIDS occurs primarily in infants too young to receive tetanus and diphtheria toxoids for adult use, measles vaccine, mumps vaccine, or usually, tetanus toxoid. Therefore, a relation between these vaccines and SIDS was not assessed. If the evidence favors the acceptance of (or establishes) a causal relation between a vaccine and an adverse event, and if that adverse. event can be fatal, then in the committee's judgment the evidence favors the acceptance of (or establishes) a causal relation between the vaccine and death from the adverse event. Direct evidence regarding death in association with a potentially fatal adverse event that itself is causally related to the vaccine is limited to tetanus-diphtheria toxoid for adult use and Guillain-Barré syndrome, tetanus toxoid and anaphylaxis, and oral polio vaccine (OPV) and poliomyelitis. Direct evidence regarding death in association with a potentially fatal adverse event that itself is causally related to the vaccine is lacking for measles vaccine and anaphylaxis, MMR and anaphylaxis, OPV and Guillain-Barré syndrome, hepatitis B vaccine and anaphylaxis, and Haemophilus influenzae type b unconjugated PRP vaccine and early-onset Haemophilus influenzae type b disease in children age 18 months or older who receive their first Hib immunization with unconjugated PRP vaccine. See Chapter 10 for details, The data are indeterminate regarding the causal relation between the vaccine and causes of death other than those discussed above. Data regarding death as an adverse consequence of the vaccines under review are discussed in Chapter 10 rather than in the vaccine-specific chapters. f The committee was charged with assessing the causal relation between several adverse events and measles vaccine or mumps vaccine. The committee was not charged with assessing monovalent rubella vaccine. In Appendix A, see the Executive Summary of Adverse Effects of Pertussis and Rubella Vaccines for conclusions regarding rubella vaccine. (MMR) indicates that the data derive exclusively from the multivalent preparation. g OPV is oral polio vaccine; IPV is inactivated polio vaccine. h The committee assessed data regarding the increased susceptibility to Haemophilus influenzae type b disease within 7 days of immunization with Haemophilus influenzae type b vaccine. For this adverse event only, the committee was able to separate the data regarding the unconjugated (PRP) vaccine from the data regarding the conjugated vaccines.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality TABLE 1-2 Conclusions Based on the Evidence Bearing on Causality DT/Td/T Measlesa Mumpsa OPV/IPVb Hepatitis B H. influenzae typeb Category, 1: No Evidence Bearing on a Causal Relation     Neuropathy Transverse myelitis (IPV)         Residual seizure disorder Thrombocytopenia (IPV)           Anaphylaxis (IPV)     Category, 2: The Evidence Is Inadequate to Accept or Reject a Causal Relation Residual seizure disorder other than infantile spasms Encephalopathy Encephalopathy Transverse myelitis (OPV) Guillain-Barré syndrome Guillain-Barré syndrome   Subacute sclerosing panencephalitis Aseptic meningitis             Guillain-Barré syndrome (IPV) Demyelinating diseases of the central nervous system Transverse myelitis Demyelinating discases of the central nervous system Residual seizure Sensorineural deafness (MMR) Death from SIDSe   Thrombocytopenia     Insulin-dependent diabetes mellitus     Anaphylaxis Mononeuropathy Sensorineural deafness (MMR)     Arthritis             Death from SIDSc Arthritis   Sterility   Death from SIDSc     Optic neuritis        

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality DT/Td/T Measlesa Mumpsa OPV/IPVb Hepatitis B H. influenzae typeb Erythema multiforme Transverse myelitis Thrombocytopenia         Guillain-Barré syndrome Anaphylaxisd         Thrombocytopenia           Insulin-dependent diabetes mellitus         Category 3: The Evidence Favors Rejection of a Causal Relation Encephalopathye         Early onset H. influenzaeb disease (conjugate vaccines) Infantile spasms (DT only)f           Death from SIDS (DT only)f,g           Category 4: The Evidence Favors Acceptance of a Causal Relation Guillain-Barré syndromeh Anaphylaxisd   Guillain-Barré syndrome (OPV)   Early-onset H. influenzaeb disease in children age 18 months or older who receive their first Hib immunization with unconjugated PRP vaccine Brachial neuritish          

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality DT/Td/T Measlesa Mumpsa OPV/IPVb Hepatitis B H. influenzae typeb Category 5: The Evidence Establishes a Causal Relation Anaphylaxish Thrombocytopenia (MMR)   Poliomyelitis in recipient or contact (OPV) Anaphylaxis     Anaphylaxis (MMR)d           Death from measles vaccine-strain viral infectionc,i   Death from polio vaccine-strain viral infectionc,i     a If the data derive from a monovalent preparation, then in the committee's judgment the causal relation extends to multivalent preparations. If the data derive exclusively from MMR, that is so indicated by (MMR). In the absence of any data on the monovalent preparation, in the committee's judgment the causal relation determined for the multivalent preparations does not extend to the monovalent components. b For some adverse events, the committee was charged with assessing the causal relation between the adverse event and only oral polio vaccine (OPV) (paralytic and nonparalytic poliomyelitis) or only inactivated polio vaccine (IPV) (anaphylaxis and thrombocytopenia). If the conclusions are different for OPV than for IPV for the other adverse events, that is so noted. c This table lists weight-of-evidence determinations only for deaths that are classified as SIDS and deaths that are a consequence of vaccine-strain adverse event can be fatal, then in the committee's judgment the evidence favors the acceptance of (or establishes) a causal relation between the vaccine and death from the adverse event. Direct evidence regarding death in association with a vaccine-associated adverse event is limited to tetanus-diphtheria toxoid for adult use (Td) and Guillain-Barré syndrome, tetanus toxoid and anaphylaxis, and OPV and poliomyelitis. Direct evidence regarding death in association with a potentially fatal adverse event that itself is causally related to the vaccine is lacking for measles vaccine and anaphylaxis, MMR and anaphylaxis, OPV and Guillain-Barré syndrome, hepatitis B vaccine and anaphylaxis, and H. influenzae type b unconjugated PRP vaccine and early-onset H. influenzae type b disease in children age 18 months or older who receive their first Hib immunization with unconjugated PRP vaccine. See Chapter 10 for details.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality d The evidence that establishes a causal relation for anaphylaxis derives from MMR. The evidence regarding monovalent measles vaccine favors acceptance of a causal relation, but are less convincing, mostly because of incomplete documentation of symptoms or the possible attenuation of symptoms by medical intervention. e The evidence derives from studies of diphtheria-tetanus toxoid for pediatric use (DT). If the evidence favors rejection of a causal relation between DT and encephalopathy, then in the committee's judgment the evidence favors rejection of a causal relation between Td and tetanus toxoid and encephalopathy. f Infantile spasms and SIDS occur only in an age group that receives DT but not Td or tetanus toxoid. g The evidence derives mostly from DPT. Because there are supportive data favoring rejection of a causal relation between DT and SIDS as well, if the evidence favors rejection of a causal relation between DPT and SIDS, then in the committee's judgment the evidence favors rejection of a causal relation between DT and SIDS. h The evidence derives from tetanus toxoid. If the evidence favors acceptance of (or establishes) a causal relation between tetanus toxoid and an adverse event, then in the committee's judgment the evidence favors acceptance of (or establishes) a causal relation between DT and Td and the adverse event as well. i The data come primarily from individuals proven to be immunocompromised.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality The committee organized these conclusions into five categories. Because some confusion has arisen over the meaning of the category descriptions used by the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines, despite extensive explanations in both the footnotes and the text, the Vaccine Safety Committee adopted some minor modifications in wording intended to help in the interpretation of the present report. To facilitate reading by those familiar with the report of the previous committee, the present committee maintained both the number of categories (five) and the order of those categories but modified the wording in an attempt to clarify its meaning. However, the Vaccine Safety Committee (which has some overlap in committee membership and staff with the earlier committee) believes that the categories represent the same concepts intended by the predecessor committee. The categories are: No evidence bearing on a causal relation. The evidence is inadequate to accept or reject a causal relation. The evidence favors rejection of a causal relation. The evidence favors acceptance of a causal relation. The evidence establishes a causal relation. Chapter 2 contains a discussion of the criteria used by the committee for each determination of the final weight of evidence. The evidence favors rejection of, favors acceptance of, or establishes a causal relation between a vaccine and an adverse event in approximately one-third of the relations studied. For the other relations the evidence was inadequate to accept or reject a causal relation or there was no evidence bearing on the relation. It is important to note that the use of the term inadequate does not necessarily imply that the data were scarce. In some cases the committee identified an abundance of data. However, as a whole, it did not favor either acceptance or rejection of a causal relation. In the lists below, the superscript letters refer to the appropriate notes in Table 1-2. The notes in Tables 1-1 and 1-2 are integral to interpretation of the findings. The committee reached the following conclusions regarding causality. The evidence favors rejection of a causal relation between: diphtheria and tetanus toxoids and encephalopathy,e infantile spasms,f and death from sudden infant death syndrome (SIDS),f,g and conjugate Hib vaccines and early-onset Hib disease. The evidence favors acceptance of a causal relation between: diphtheria and tetanus toxoids and Guillain-Barré syndromeh and brachial neuritis,h measles vaccine and anaphylaxis,d

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality oral polio vaccine and Guillain-Barré syndrome, and unconjugated (PRP) Hib vaccine and early-onset Hib disease in children age 18 months or older who receive their first Hib immunization with unconjugated (PRP) vaccine. The evidence establishes a causal relation between: diphtheria and tetanus toxoids and anaphylaxis,h measles vaccine and death from measles vaccine-strain vital infection, c,i measles-mumps-rubella vaccine and thrombocytopenia and anaphylaxis, oral polio vaccine and poliomyelitis and death from polio-vaccine-strain viral infection,c,i and hepatitis B vaccine and anaphylaxis. For the vast majority of vaccine-adverse event relations studied, the data came predominantly from uncontrolled studies and case reports. Most of the pathologic conditions studied are rare in the general population. The risk of developing these conditions because of vaccination would seem to be low. Without age-specific incidence rates and relative risk estimates, however, it is not possible to calculate the proportion of individuals whose condition is causally related to a vaccine. When the data permitted, such calculations (i.e., the risk difference or excess risk) were made and can be found in the conclusions in Chapters 5 through 9. Because age-specific incidence rates were not available for many of the pathologic conditions studied and because controlled epidemiologic studies of these relations are lacking, few such estimates could be made. NEED FOR RESEARCH AND SURVEILLANCE During its attempt to find evidence regarding causality, the committee identified needs for research and surveillance of adverse events. Work in these areas will help to ensure that all vaccines used are as free from the risk of causing adverse events as possible. Some of the needs identified are for increased surveillance of reports of demyelinating disease and arthritis following hepatitis B vaccination, better follow-up of reports of death and other serious adverse events following vaccination, increased use of large databases (currently used only on a small scale) to supplement passive surveillance reporting systems, and disease registries for the rare pathologic conditions studied by the committee. REFERENCES Coulter HL. Vaccination, Social Violence, and Criminality: The Medical Assault on the American Brain. Berkeley. CA: North Atlantic Books: 1990.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Coulter HL, Fisher BL. DPT: A Shot in the Dark. San Diego: Harcourt Brace Jovanovich; 1985. Iglehart JK. Compensating children with vaccine-related injuries. New England Journal of Medicine 1987;316:1282-1288. Institute of Medicine. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: National Academy Press; 1991. Institute of Medicine. Vaccine Supply and Innovation. Washington, DC: National Academy Press; 1985. Mariner WK. The National Vaccine Injury Compensation Program: update. Health Affairs 1992(Spring):255-265. Miller NZ. Vaccines: Are They Really Safe and Effective? A Parent's Guide to Childhood Shots. Santa Fe, NM: New Atlantean Press, 1992. Office of Technology Assessment. Compensation for Vaccine-Related Injuries: A Technical Memorandum. Washington, DC: U.S. Government Printing Office; 1980. Wilson GS. The Hazards of Immunization. London: The Athlone Press; 1967. WRC-TV. DPT: Vaccine Roulette. Washington, DC: WRC-TV; 1982.