Summary

Congress passed the National Childhood Vaccine Injury Act (P.L. 99-660) in 1986. The legislation was intended to bolster vaccine research and develop ment through federal coordination of vaccine efforts in government by providing relief to vaccine manufacturers who reported at the time that financial burdens from awards in the tort system threatened their financial viability. The legislation was also intended to address concerns about the safety of vaccines through a multipronged approach involving instituting a compensation program financed by an excise tax on covered vaccines, setting up a passive surveillance system for vaccine adverse events, and providing information to consumers.

Sections 312 and 313 of the legislation required the secretary of the U.S. Department of Health and Human Services to consult with the Institute of Medicine (IOM) to conduct a review of the scientific literature related to a set of serious adverse events1 following immunizations recommended for use in children. Two reports were issued (IOM, 1991, 1994). These reports contain a framework for causality assessment of adverse events following vaccination. The reports embraced all vaccines covered by the National Vaccine Injury Compensation Program (VICP) up to that point: diphtheria- and tetanus-toxoids and whole cell pertussis (DTwP) vaccine2 and other tetanus toxoid–containing vaccines; measles, mumps, and rubella

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1 Adverse events are distinguished from adverse effects in that an event is something that occurs but may not be causally associated, whereas an adverse effect implies causation. All adverse effects are adverse events, but not all adverse events are adverse effects.

2 Acellular pertussis vaccine (aP) has replaced whole cell pertussis vaccine in the United States.



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Summary Congress passed the National Childhood Vaccine Injury Act (P.L. 99-660) in 1986. The legislation was intended to bolster vaccine research and devel- opment through federal coordination of vaccine efforts in government by providing relief to vaccine manufacturers who reported at the time that financial burdens from awards in the tort system threatened their financial viability. The legislation was also intended to address concerns about the safety of vaccines through a multipronged approach involving instituting a compensation program financed by an excise tax on covered vaccines, setting up a passive surveillance system for vaccine adverse events, and providing information to consumers. Sections 312 and 313 of the legislation required the secretary of the U.S. Department of Health and Human Services to consult with the Institute of Medicine (IOM) to conduct a review of the scientific literature related to a set of serious adverse events1 following immunizations recommended for use in children. Two reports were issued (IOM, 1991, 1994). These reports contain a framework for causality assessment of adverse events following vaccination. The reports embraced all vaccines covered by the National Vaccine Injury Compensation Program (VICP) up to that point: diphtheria- and tetanus-toxoids and whole cell pertussis (DTwP) vaccine2 and other tetanus toxoid–containing vaccines; measles, mumps, and rubella 1 Adverse events are distinguished from adverse effects in that an event is something that occurs but may not be causally associated, whereas an adverse effect implies causation. All adverse effects are adverse events, but not all adverse events are adverse effects. 2 Acellular pertussis vaccine (aP) has replaced whole cell pertussis vaccine in the United States. 1

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2 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY (MMR) vaccines; Haemophilus influenzae type B vaccine; hepatitis B vac- cine; and both inactivated and oral polio vaccines.3 The reports informed the secretary’s review of the Vaccine Injury Table. The reports have also been referenced extensively as a source of definitive scientific understanding of the evidence by Special Masters in decisions regarding injuries not listed on the Vaccine Injury Table. The IOM was subsequently asked to review specific vaccine safety concerns in a series of reports requested by the Centers for Disease Control and Prevention (CDC). These reports (IOM, 2001a,b, 2002a,b, 2003a,b, 2004a,b) included causality assessments similar to the previous IOM re- ports, but included other conclusions and recommendations regarding re- search, communications, and policy review. CHARGE TO THE COMMITTEE In 2009 the IOM entered into a contract with the Health Resources and Services Administration (HRSA)4 to convene a committee of experts to review the epidemiologic, clinical, and biological evidence regarding ad- verse health events associated with specific vaccines covered by the VICP. The committee was composed of individuals with expertise in pediatrics, internal medicine, neurology, immunology, immunotoxicology, neurobiol- ogy, rheumatology, epidemiology, biostatistics, and law. The vaccines to be reviewed included varicella zoster vaccine; influ- enza vaccines;5 hepatitis B vaccine; human papillomavirus vaccine (HPV); tetanus toxoid–containing vaccines other than those containing the whole cell pertussis component; measles, mumps, and rubella vaccines; hepatitis A vaccine; and meningococcal vaccines. It is expected that the report will provide the scientific basis for review and adjudication of claims of vaccine injury by the VICP. HRSA presented a list of specific adverse events for the committee to review (see Table S-1). The selection criteria was described at the first committee meeting (Johann-Liang, 2009) as including the vast majority of adverse events in the claims for compensation. The committee added ad- verse events to the list if it identified epidemiologic studies or case reports for an adverse event not originally assigned by HRSA. These additions were all-cause mortality and seizures following influenza vaccine; optic neuritis 3 Vaccines are included in the VICP if they are recommended by the CDC for routine ad- ministration in children and are subject to an excise tax. Adults who experience an adverse reaction to one of these “childhood” vaccines are also covered by the program. 4 The CDC and the National Vaccine Program Office also provided funds for the project via the contract with HRSA. 5 The 2009 H1N1 influenza vaccine is covered by the Countermeasures Injury Compensation Program, and evidence about its safety is not covered in this report.

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TABLE S-1 Adverse Events and Causality Conclusions Included in the Vaccine Chapters DT–, TT–, and aP– Injection- MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Disseminated Oka VZV CS without Other Organ Involvement Disseminated Oka VZV CSa with Subsequent Infection Resulting in Pneumonia, Meningitis, or Hepatitis Vaccine Strain Viral CS Reactivation without Other Organ Involvement Vaccine Strain Viral CS Reactivation with Subsequent Infection Resulting in Meningitis or Encephalitis Measles Inclusion Body CSa,b Encephalitis Encephalitis I I I I I Encephalopathy I I I I I I Infantile Spasms I 3 continued

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4 TABLE S-1 Continued DT–, TT–, and aP– Injection- MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Febrile Seizures CS Afebrile Seizures I Seizures I Ic I I Meningitis Ic Cerebellar Ataxia I Ataxia I I Autism FR I Acute Disseminated I I I I I I I I Encephalomyelitis Transverse Myelitis I I I I I I I I Optic Neuritis Ic Ic Ic Ic Neuromyelitis Optica Ic I I I Multiple Sclerosis Onset in I I I I Adults Multiple Sclerosis Onset in I I Children Multiple Sclerosis Relapse I I I in Adults

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Multiple Sclerosis Relapse I I in Children Multiple Sclerosis I I I First Demyelinating Event I in Adults First Demyelinating Event I in Children Guillain-Barré Syndrome I I I I I I I I Chronic Inflammatory I I I I I I I Disseminated Polyneuropathy Opsoclonus Myoclonus I I Syndrome Bell’s Palsy FR I I Brachial Neuritis I I I I Amyotrophic Lateral I Sclerosis Small Fiber Neuropathy Ic I Anaphylaxis CS CS CS I CSd FA CSe CS Chronic Urticaria I Serum Sickness I 5 continued

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6 TABLE S-1 Continued DT–, TT–, and aP– Injection- MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Inactivated Influenza FR Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Children and Adults Live Attenuated Influenza I Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Children Younger Than 5 Years of Age Live Attenuated Influenza I Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Persons 5 Years of Age or Older Erythema Nodosum Ic Systemic Lupus I I Erythematosus Vasculitis I I Polyarteritis Nodosa I I

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Psoriatic Arthritis I Reactive Arthritis I Rheumatoid Arthritis I Juvenile Idiopathic I Arthritis Transient Arthralgia in FAf Women Transient Arthralgia in FA Children Transient Arthralgia I Chronic Arthralgia in I Women Chronic Arthritis in I Women Chronic Arthropathy in I Children Arthropathy in Men I Arthropathy I I I Type 1 Diabetes FR I FR Autoimmune Hepatitis I Myocarditis I Pancreatitis I 7 continued

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8 TABLE S-1 Continued DT–, TT–, and aP– Injection- MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Hepatitis I Thromboembolic Events I Stroke Ic I Hypercoagulable States I Myocardial Infarction I Chronic Fatigue Syndrome I Chronic Headache I Fibromyalgia I I I I Sudden Infant Death I Syndrome Hearing Loss I All Cause Mortality Ic Oculorespiratory Syndrome FAg Thrombocytopenia I Immune Thrombocytopenic I Purpura Complex Regional Pain I Syndrome

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Deltoid Bursitis CS Syncope CS NOTE: CS = convincingly supports a causal relationship; FA = favors acceptance of a causal relationship; FR = favors rejection of a causal relation- ship; I = inadequate to accept or reject a causal relationship. a The committee attributes causation to individuals with demonstrated immunodeficiencies. b The committee attributes causation to the measles component of the vaccine. c Although not originally charged to the committee by the sponsor, the committee considered this adverse event in its review of the literature. d The committee attributes causation to yeast-sensitive individuals. e The committee attributes causation to the tetanus toxoid vaccine. The evidence is inadequate to accept or reject a causal relationship between anaphylaxis and diphtheria toxoid or acellular pertussis vaccine. f The committee attributes causation to the rubella component of the vaccine. g The committee attributes causation to two particular vaccines used in three particular years in Canada. 9

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10 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY following MMR, influenza, hepatitis B, and DTaP vaccines; neuromyelitis optica and meningitis following MMR vaccine; erythema nodosum follow- ing hepatitis B vaccine; and stroke and small fiber neuropathy following varicella vaccine. It is important to note that the committee was not tasked with assess- ing the benefits (effectiveness) of vaccines or any policy issues related to vaccination. The committee’s task is focused only on an assessment of the risk of vaccines. ASSESSING THE WEIGHT OF EVIDENCE Two streams of evidence support the committee’s causality conclusions: epidemiologic evidence derived from studies of populations (most often based on observational designs but randomized trials when available), and mechanistic evidence derived primarily from biological and clinical studies in animals and individual humans (see Figure S-1). Some studies provide evidence capable of addressing both epidemiologic and mechanistic ques- tions. Drawing from both sources of evidence to support causal inference is well established in the literature. The committee made three assessments for each relationship reviewed. The first assessment applies to the weight of evidence from the epide- miologic literature; the second applies to the weight of evidence from the mechanistic literature. Each individual article (or findings within an article if more than one outcome or vaccine was studied) was evaluated for its strengths and weaknesses. The committee then synthesized the body of evi- dence of each type (epidemiologic or mechanistic) and assigned a “weight- of-evidence” for each. These weights-of-evidence represent the committee’s assessment of the quality and quantity of evidence. The two weight-of- evidence assessments contributed to the third assessment, a conclusion about the causal relationship. Weight of Epidemiologic Evidence Each peer-reviewed epidemiologic study was evaluated for its methodo- logic limitations (e.g., flawed measurement of either vaccine administration or adverse event, or failure to adequately control confounding variables) and for the precision of the reported results (e.g., the width of the 95% confidence interval around an effect estimate, reflecting the statistical power to detect a significantly increased risk of an adverse event). A specific study involving multiple outcomes or vaccines could have fewer limitations for the analysis of some vaccines or some outcomes than for others. Small clini- cal studies can be well conducted but the low number of subjects may limit the ability to detect most adverse events. Although most efficacy studies

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ORIGINAL RESEARCH IN HUMANS OTHER LITERATURE Controlled Uncontrolled Reviews of Animal and Observational Studies and Clinical Studies and Case Reports Consequences of the In Vitro Studies Randomized Trials Surveillance Studies Natural Infection Included studies Excluded reports Included reports Excluded studies Excluded studies with case descriptions that did not meet with case descriptions with very serious with very serious that met minimum minimum attribution that met minimum limitations from limitations from attribution elements elements for attribution elements the Epidemiologic the Epidemiologic in the Mechanistic Mechanistic in the Mechanistic Evidence Evidence Evidence Evidence Evidence Studies Included in the Studies Included in the Weight of Epidemiologic Evidence Weight of Mechanistic Evidence High Moderate Strong Intermediate Weak Lacking Limited (increased or (increased or null/decreased) null/decreased) CAUSALITY CONCLUSION 11 FIGURE S-1 Epidemiologic and mechanistic evidence reviewed by the committee.

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16 EPIDEMIOLOGIC ASSESSMENT MECHANISTIC ASSESSMENT CAUSALITY CONCLUSION Inadequate Low- High Moderate Favors Favors Convincingly Inter- to Accept Inter- (decreased risk (decreased risk High Moderate (increased risk) (increased risk) Limited Strong Rejection Acceptance Supports mediate Weak Lacking or Reject mediate High (increased risk) Convincingly Supports Strong Moderate (increased risk) Favors Acceptance Inter- mediate High Favors (decreased risk Rejection * Moderate , Inadequate to Accept or Reject Low-Intermediate, Weak, or Lacking*** * Causality conclusion is favors rejection only if mechanistic assessment is not strong or intermediate. ** Causality conclusion is inadequate to accept or reject only if mechanistic assessment is not strong or intermediate. *** Causality conclusion is inadequate to accept or reject only if epidemiologic assessment is not FIGURE S-2 Strength of evidence that determined the causality conclusions.

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17 SUMMARY health. The focus of this particular committee is only on the question of what particular vaccines can cause particular adverse effects. The framework also had to accommodate known strengths and limi- tations of both types of evidence. Mechanistic evidence can only support causation, but epidemiologic evidence can support a causal association or can support the absence of (“rejection of”) a causal association in the general population. Mechanistic evidence, particularly that emerging from case reports, occasionally provides compelling evidence of an association between exposure to a vaccine and an adverse event in the individual be- ing studied, but it provides no meaningful information about the risk to the population. Epidemiologic analyses are usually unable to detect an in- creased or decreased risk that is small, unless the study population is very large or the between-group (e.g., vaccinated vs. unvaccinated) difference in risk is very high (e.g., smoking increases the risk of lung cancer by at least 10-fold). Epidemiologic analyses also cannot identify with certainty which individual in a population at risk will develop the condition. The committee does not consider a single epidemiologic study—regard- less of how well it is designed, the size of the estimated effect, or the nar- rowness of the confidence interval—sufficient to merit a weight of “high” or, in the absence of strong or intermediate mechanistic evidence, sufficient evidence to support a causality conclusion other than “inadequate to ac- cept or reject a causal relationship.” This requirement might seem overly rigorous to some readers. However, the Agency for Healthcare Research and Quality advises the Evidence-based Practice Centers that it has funded to produce evidence reports on important issues in health care to view an evidence base of a single study with caution (Owens et al., 2010). It does so due to the inability to judge consistency of results, an important contribu- tor to a strength of evidence, because one cannot “be certain that a single trial, no matter how large or well designed, presents the definitive picture of any particular clinical benefit or harm for a given treatment” (Owens et al., 2010). It is acknowledged by the committee and others (Owens et al., 2010) that policy makers must often make decisions based on only one study. However, the committee is not recommending policy, rather evaluating the evidence using a transparent and justifiable framework. CAUSALITY CONCLUSIONS Convincingly Supports The framework allows for a causality conclusion of “convincingly sup- ports” based on an epidemiologic weight-of-evidence assessment of high in the direction of increased risk (which requires at least two well-conducted epidemiologic studies). Strong mechanistic evidence, which requires at least

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18 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY one case report in which compelling evidence exists that the vaccine indeed did cause the adverse event, always carries sufficient weight for the com- mittee to conclude the evidence convincingly supports a causal relationship. The committee considered the detection of laboratory-confirmed, vaccine- strain virus compelling evidence to attribute the disease to the vaccine-strain virus and not other etiologies. This conclusion can be reached even if the epidemiologic evidence is rated high in the direction of no increased risk or even decreased risk. The simplest explanation in this circumstance is that the adverse effect is real but also very rare. Stating this another way, if the vaccine did cause the adverse effect in one person, then it can cause the adverse effect in someone else; however, the isolated report of one convincing case provides no information about the risk of the adverse effect in the total population of vaccinated individuals compared with unvaccinated individuals. The committee concluded the evidence convincingly supports 14 spe- cific vaccine–adverse event relationships. In all but one of these relation- ships, the conclusion was based on strong mechanistic evidence with the epidemiologic evidence rated as either limited confidence or insufficient. The convincing evidence regarding varicella vaccine and disseminated Oka varicella zoster virus (VZV) and Oka VZV viral reactivation depended on identification of vaccine-strain virus as documented by polymerase chain reaction, as was the evidence regarding MMR vaccine and measles inclu- sion body encephalitis. Epidemiologic evidence, as well as mechanistic evidence, convincingly supported the causal relationship between MMR vaccine and febrile seizures. Clinical evidence from case reports and a well- identified mechanism of hypersensitivity reactions convincingly supported the conclusions regarding anaphylaxis and six vaccines (MMR, varicella, influenza, hepatitis B, meningococcal, and tetanus toxoid vaccine). Mecha- nistic evidence provided the convincing support for the conclusion that injection of vaccine, independent of the antigen involved, can lead to two adverse events: syncope and deltoid bursitis (see Table S-2). Favors Acceptance A conclusion of “favors acceptance of a causal relationship” must be supported by either epidemiologic evidence of moderate certainty of an increased risk or by mechanistic evidence of intermediate weight. The com- mittee concluded the evidence favors acceptance of four specific vaccine– adverse event relationships. These include HPV vaccine and anaphylaxis, MMR vaccine and transient arthralgia in female adults, MMR vaccine and transient arthralgia in children, and certain trivalent influenza vaccines used in Canada and a mild and temporary oculorespiratory syndrome. The con- clusion regarding anaphylaxis was supported by only mechanistic evidence.

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TABLE S-2 Summary of Causality Conclusionsa Studies Cases Contributing Contributing to the to the Epidemiologic Epidemiologic Mechanistic Mechanistic Causality Chapter Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion b 5 Varicella Disseminated Oka Insufficient None Strong – Convincingly VZV without Other Supports Organ Involvement 5 Varicella Disseminated Oka Limited (subsequent 1 Strong 9 Convincingly VZV with Subsequent infection resulting in (in individuals Supportsc Infection Resulting pneumonia) with demonstrated in Pneumonia, immuno- Insufficient (subsequent None Meningitis, or deficiencies) infection resulting in Hepatitis meningitis or hepatitis) b 5 Varicella Vaccine Strain Insufficient None Strong – Convincingly Viral Reactivation Supports without Other Organ Involvement 5 Varicella Vaccine Strain Viral Limited (subsequent 1 Strong 6 Convincingly Reactivation with infection resulting in Supports Subsequent Infection encephalitis) Resulting in Meningitis Insufficient (subsequent None or Encephalitis infection resulting in meningitis) 19 continued

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TABLE S-2 Continued 20 Studies Cases Contributing Contributing to the to the Epidemiologic Epidemiologic Mechanistic Mechanistic Causality Chapter Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion 4 MMR Measles Inclusion Insufficient None Strong 1 Convincingly Body Encephalitis (measles; in Supportsc,d individuals with demonstrated immunodeficiencies) Lacking None (mumps or rubella) 4 MMR Febrile Seizures High (increase) 7 Intermediate 12 Convincingly Supports 4 MMR Anaphylaxis Insufficient None Strong 43e Convincingly Supports 5 Varicella Anaphylaxis Limited 1 Strong 76f Convincingly Supports 6 Influenza Anaphylaxis Limited 1 Strong 22 Convincingly Supports 8 Hepatitis B Anaphylaxis Insufficient None Strong 10 Convincingly (in yeast-sensitive Supportsg individuals) 10 Tetanus Anaphylaxis Insufficient None Strong 6 Convincingly Toxoid Supports 11 Meningococcal Anaphylaxis Insufficient None Strong 1 Convincingly Supports

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12 Injection- Deltoid Bursitis Limited 1 Strong 16 Convincingly Related Event Supports 12 Injection- Syncope Insufficient None Strong 35h Convincingly Related Event Supports 9 HPV Anaphylaxis Insufficient None Intermediate 36 Favors Acceptance 4 MMR Transient Arthralgia in Moderate (increase) 4 Intermediate 13 Favors Women (rubella) (rubella) Acceptancei Insufficient None Lacking None (measles or mumps) (measles or mumps) 4 MMR Transient Arthralgia in Moderate (increase) 7 Weak None Favors Children (rubella) Acceptance Lacking None (measles or mumps) j 6 Influenza Oculorespiratory Moderate (increase) 3 Intermediate – Favors Syndrome Acceptancek 4 MMR Autism High (null) 4 Lacking None Favors Rejection 6 Influenza Inactivated Influenza High (null) 2 Lacking None Favors Vaccine and Bell’s Rejection palsy 21 continued

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TABLE S-2 Continued 22 Studies Cases Contributing Contributing to the to the Epidemiologic Epidemiologic Mechanistic Mechanistic Causality Chapter Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion 6 Influenza Inactivated Influenza High (null) 9 Weak 6 Favors Vaccine and Asthma Rejection Exacerbation or Reactive Airway Disease Episodes in Children and Adults 4 MMR Type 1 Diabetes High (null) 5 Lacking None Favors Rejection 10 DT, TT, or aP Type 1 Diabetes High (null) 5 Lacking None Favors containing Rejection a All other causality conclusions are the evidence is inadequate to accept or reject a causal relationship. b Due to the use of the same surveillance systems in some publications it is likely that some of the cases were presented more than once; thus, it is difficult to determine the number of unique cases. c The committee attributes causation to individuals with demonstrated immunodeficiencies. d The committee attributes causation to the measles component of the vaccine. e Some cases were from passive surveillance systems; however, it is not possible to know how many represent unique cases or were reported elsewhere. f In addition, at least 30 cases were reported to passive surveillance systems; however, it is not possible to know how many represent unique cases or were reported elsewhere. g The committee attributes causation to yeast-sensitive individuals. h In addition, hundreds of cases have been reported to passive surveillance systems; however, it is not possible to known how many represent unique cases or were reported elsewhere. i The committee attributes causation to the rubella component of the vaccine. j Due to the use of the same sample population in some studies it is likely that some of the cases were presented in more than one publication; thus, it is difficult to determine the number of unique cases. kThe committee attributes causation to two particular vaccines used in three particular years in Canada.

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23 SUMMARY The other conclusions were supported by both epidemiologic evidence and by mechanistic evidence (see Table S-2). Favors Rejection The framework allows the committee to “favor rejection” of a causal relationship only in the face of epidemiologic evidence rated as high or moderate in the direction of no effect (the null) or of decreased risk and in the absence of strong or intermediate mechanistic evidence in support of a causal relationship. The committee concluded the evidence favors rejection of five vaccine–adverse event relationships. These include MMR vaccine and type 1 diabetes, diphtheria, tetanus, and pertussis (DTaP) vac- cine and type 1 diabetes, MMR vaccine and autism, inactivated influenza vaccine and asthma exacerbation or reactive airway disease episodes, and inactivated influenza vaccine and Bell’s palsy. The evidence base for these conclusions consisted of epidemiologic studies reporting no increased risk; this evidence was not countered by mechanistic evidence (see Table S-2). Inadequate to Accept or Reject The committee identified two main pathways by which it concludes that the evidence is “inadequate to accept or reject” a causal relationship. The most common pathway to this conclusion occurs when the epidemio- logic evidence was of limited certainty or insufficient and the mechanistic evidence was weak or lacking. Another pathway occurs when the epidemio- logic evidence is of moderate certainty of no effect but the mechanistic evi- dence is intermediate in support of an association. The committee analyzed these sets of apparently contradictory evidence and ultimately depended upon their expert judgment in deciding if a conclusion to favor acceptance based on the intermediate mechanistic data was warranted, or if the con- clusion remained as “inadequate to accept or reject” a causal relationship. The vast majority of causality conclusions in the report are that the evidence was inadequate to accept or reject a causal relationship. Some might interpret that to mean either of the following statements: • Because the committee did not find convincing evidence that the vaccine does cause the adverse event, the vaccine is safe. • Because the committee did not find convincing evidence that the vaccine does not cause the adverse event, the vaccine is unsafe. Neither of these interpretations is correct. “Inadequate to accept or reject” means just that—inadequate. If there is evidence in either direction that is suggestive but not sufficiently strong about the causal relationship, it

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24 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY will be reflected in the weight-of-evidence assessments of the epidemiologic or the mechanistic data. However suggestive those assessments might be, in the end the committee concluded that the evidence was inadequate to accept or reject a causal association. A list of all conclusions, including the weights of evidence for both the epidemiologic evidence and the mechanistic evidence, can be found in Appendix D. SUSCEPTIBILITY The literature supporting several of the causality conclusions discussed in the previous section indicates that individuals with certain characteristics are more likely to suffer adverse effects from particular immunizations. Individuals with an acquired or genetic immunodeficiency are clearly recog- nized as at increased risk for specific adverse reactions to live viral vaccines such as MMR and varicella vaccine. Age is also a risk factor; seizures after immunization, for example, are more likely to occur in young children. Thus, the committee was able at times to reach more limited conclusions that did not generalize to the entire population. CONCLUDING COMMENT Committee members spent an enormous amount of time reading thou- sands of articles. The committee makes 158 causality conclusions in this report. It tried to apply consistent standards when reviewing individual articles and when assessing the bodies of evidence. Some of the conclusions were easy to reach; the evidence was clear and consistent or, in the extreme, completely absent. Some conclusions required substantial discussion and debate. Inevitably, there are elements of expert clinical and scientific judg- ment involved. The committee used the best evidence available at the time. The com- mittee hopes that the report is sufficiently transparent such that when new information emerges from either the clinic or the laboratory, others will be able to assess the importance of that new information within the approach and set of conclusions presented in this report. REFERENCES IOM (Institute of Medicine). 1991. Adverse effects of pertussis and rubella vaccines: A report of the committee to review the adverse consequences of pertussis and rubella vaccines. Washington, DC: National Academy Press. IOM. 1994. Adverse events associated with childhood vaccines: Evidence bearing on causality. Washington, DC: National Academy Press.

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25 SUMMARY IOM. 2001a. Immunization safety review: Measles-mumps-rubella vaccine and autism. Washington, DC: National Academy Press. IOM. 2001b. Immunization safety review: Thimerosal-containing vaccines and neuro- developmental disorders. Washington, DC: National Academy Press. IOM. 2002a. Immunization safety review: Hepatitis B vaccine and demyelinating neurological disorders. Washington, DC: The National Academies Press. IOM. 2002b. Immunization safety review: Multiple immunizations and immune dysfunction. Washington, DC: National Academy Press. IOM. 2003a. Immunization safety review: SV40 contamination of polio vaccine and cancer. Washington, DC: The National Academies Press. IOM. 2003b. Immunization safety review: Vaccinations and sudden unexpected death in infancy. Washington, DC: The National Academies Press. IOM. 2004a. Immunization safety review: Influenza vaccines and neurological complications. Washington, DC: The National Academies Press. IOM. 2004b. Immunization safety review: Vaccines and autism. Washington, DC: The National Academies Press. Johann-Liang, R. 2009. Charge to the Institute of Medicine committee to review adverse effects of vaccines. Paper read at the Meeting of the Institute of Medicine Committee to Review Adverse Effects of Vaccines, Washington, DC. Miller, F. W., E. V. Hess, D. J. Clauw, P. A. Hertzman, T. Pincus, R. M. Silver, M. D. Mayes, J. Varga, T. A. Medsger, Jr., and L. A. Love. 2000. Approaches for identifying and defining environmentally associated rheumatic disorders. Arthritis & Rheumatism 43(2):243-249. Owens, D. K., K. N. Lohr, D. Atkins, J. R. Treadwell, J. T. Reston, E. B. Bass, S. Chang, and M. Helfand. 2010. AHRQ series paper 5: Grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health Care Program. Journal of Clinical Epidemiology 63(5):513-523. Schunemann, H. J., S. Hill, G. H. Guyatt, E. A. Akl, and F. Ahmed. 2011. The GRADE approach and Bradford Hill’s criteria for causation. Journal of Epidemiology and Com- munity Health 65(5):392-395.

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