usually provide considerably more detail about alternative etiologic candidates, the timing of the onset of the adverse event following vaccine administration, and clinical and pathologic descriptions of the adverse event.

Uncontrolled epidemiologic studies do not yield direct estimates of the effect of vaccine exposure on the risk of developing the adverse event. Sometimes, however, the existence of reliable data on the risk in unexposed subjects can form the basis of an external (to the study) control group and, hence, an indirect estimate of the vaccine effect.

Controlled Observational Studies

Controlled observational studies permit a direct estimate of the effect of vaccine exposure on the occurrence of the adverse event. Most are based on either a cohort or a case-control design. In controlled cohort studies, a defined group of individuals exposed to a given vaccine are followed longitudinally for the occurrence of one or more adverse events of interest, and the rate of such occurrence is compared with the rate in an otherwise similar group of nonexposed individuals by using either the ratio of rates (relative risk) or their difference (risk difference). In many populations, however, exposure to vaccines is virtually universal; exposure can then be defined within a rather narrow time window; that is, the rate of occurrence of an adverse event within 2 weeks of vaccine administration can be compared with the rate of occurrence of an adverse event several weeks or months thereafter. In case-control studies, rates of prior exposure to the suspected vaccine between individuals with (the cases) and without (the controls) the adverse event are compared. No direct calculation of relative risk or risk difference can be made from a case-control study, but the exposure odds ratio (the odds of exposure among the cases divided by the odds of exposure among the controls) can be shown to be a very good estimate of the true relative risk when the adverse event is rare. In fact, the case-control design is often the only feasible epidemiologic research design for rare events (e.g., GBS, transverse myelitis, optic neuritis, and Stevens-Johnson syndrome). As with cohort studies, the time window of exposure (prior to the occurrence of the adverse event) should be defined narrowly to reflect the biologic latent period corresponding to the pathogenesis of the suspected adverse event.

Other types of controlled epidemiologic studies can also provide useful information. In ecologic studies, for example, the rates of a given adverse event are compared among otherwise similar regions or countries with different policies for administering a suspected vaccine. Such studies assess the vaccine-adverse event association at the population level, and therefore provide only indirect evidence of the association among individuals.



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