for other information from the clinical and biological (human, animal, or in vitro studies) literature that would provide evidence of a pathophysiological process or mechanism that is reasonably likely to cause the adverse event or to occur in response to a specific immunization. Chapter 3 contains a discussion of the major mechanisms the committee invokes as possible explanations of how a given adverse event can occur after vaccination.

The committee identified many case reports in the literature describing adverse events following vaccination. For the purposes of this report, case report refers to a description of an individual patient; one publication could describe multiple case reports. The committee evaluated each case report using a well-established set of criteria called attribution elements for case evaluation (Miller et al., 2000). At a minimum, for a case to factor into the weight-of-evidence assessment, it had to include specific mention of the vaccine administered, evidence of a clinician-diagnosed health outcome, and a specified and reasonable time interval (i.e., temporality or latency) between vaccination and symptoms. Case descriptions that did not have the three basic elements described above were not considered in the mechanistic weight-of-evidence assessments. These three criteria were only necessary but not sufficient to affect the weight of mechanistic evidence. After identifying cases with the three basic elements, the committee looked for evidence in the case descriptions and in other clinical or biological literature of a possible operative mechanism(s) that would support a judgment that the vaccination was related to the adverse event. See Chapter 3 for a description of possible mechanisms identified by the committee.

An important attribute in the evaluation of the clinical evidence from case reports is rechallenge, an adverse event that occurred after more than one administration of a particular vaccine in the same individual. Each challenge in a patient, however, must meet the same attributes of reasonable latency, documentation of vaccination receipt, and clinician diagnosis of the health outcome. The value of any case report is much greater if the clinical workup eliminated well-accepted alternative explanations for the condition, thus increasing the possibility that the vaccine could be associated with the adverse event. A particularly strong piece of evidence in the case description is laboratory-confirmed isolation of a vaccine strain virus in the patient.

The committee follows the convention of previous IOM committees in considering the effects of the natural infection as one type, albeit minor, of clinical or biological evidence in support of mechanisms.6 Other evidence,

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6 The committee relied on standard textbooks of infectious disease or internal medicine for this evaluation; the committee did not review original research to come to this determination. This is consistent with previous IOM committees tasked with reviewing evidence of causality for vaccine safety. Evidence consisting only of parallels with the natural infections is never sufficient to merit a conclusion other than the evidence is inadequate to accept or reject a causal relationship.