The committee attempted to establish objective criteria for the expected timing of onset for each type of adverse event under consideration. For example, data on experimental acute demyelinating encephalomyelitis and postinfectious GBS were used to establish a time window of 5 days to 6 weeks for the likely occurrence of a vaccine-caused case of GBS, with those cases occurring 7 to 21 days postvaccination judged as being especially likely to be caused by the vaccine. In the absence of reliable age- and sex-specific background (i.e., in the absence of vaccine exposure) incidence rates for GBS, however, the mere occurrence of a case of GBS 2 weeks after receipt of a vaccine becomes interpretable only when compared with the background number of cases that would be expected to occur in individuals of that age and sex in the absence of vaccination. Because of the rather diffuse time window and the lack of reliable descriptive epidemiologic information, therefore, appropriate timing of onset, in and of itself, is insufficient to infer causality for an individual case. A useful contrast is provided by anaphylaxis, which is caused by exposure to a foreign antigen or drug. Given the occurrence of a clinically and pathologically typical case of anaphylaxis within minutes of receipt of a vaccine, it is very difficult to blame anything else.

The characteristics of the adverse event can also be helpful. Thus, the committee tried to ensure that cases of GBS or anaphylaxis met established clinical and laboratory criteria for those conditions. But mere confirmation that a case is "true GBS," although necessary, is insufficient to infer vaccine causation, because such cases do not differ from background cases that occur after a viral infection or spontaneously. On the other hand, clinical and pathologic findings consistent with the diagnosis of anaphylaxis are helpful in distinguishing sudden collapse or death caused by anaphylaxis from sudden collapse or death caused by myocardial infarction, stroke, or some other sudden catastrophic event.

Dechallenge, that is, discontinuing the suspected vaccine or reducing its dose, rarely contributes useful information. Unlike drugs, vaccines are administered at a single point in time, and their immunologic effects tend to persist well after the vaccine antigen(s) has been eliminated. Thus, the evolution of the adverse event is often not helpful in assessing vaccine causation.

Rechallenge is unusual, because physicians are unlikely to readminister a vaccine previously associated with an adverse event. When rechallenge does occur, however, the recurrence or nonrecurrence of the adverse event will often have a major impact on the causality assessment.

Will It?

The Will It? causality question refers to how frequently a vaccine causes a specific adverse event and can relate to either individuals or populations.



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