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Research Strategies for Assessing Adverse Events Associated withVaccines:: A Workshop Summary
vaccine with respect to the onset of the event, (5) characteristicsof the adverse event, both clinical and pathologic, (6) dechallenge(removing or ceasing the exposure; this element is less relevantto evaluation of vaccines because vaccine exposure occurs at a singlepoint exposure, rather than regularly for a period of time as a drugmight be), and (7) rechallenge (again, this occurs less commonlywith vaccines, but this element can sometimes be helpful in the evaluationif a vaccine is readministered). The features of case reports thatare most useful in helping investigators reach conclusions aboutthe relation between a vaccine and an adverse event include the absenceof a good alternative etiologic candidate (this feature is necessarybut not sufficient for inferring causality), timing of receipt ofthe vaccine with respect to the onset of the adverse event (particularlyfor well-defined events such as anaphylaxis), characteristics ofthe adverse event (for specific clinical and/or pathologic features[e.g., anaphylaxis or vaccine strain-disseminated viral infection])and rechallenge.
Passive surveillance systems refer to systems that collect and analyzeindividual case reports of adverse reactions that are sent to thesystem voluntarily by physicians and patients. Pharmaceutical companiesas well as government agencies maintain passive surveillance systems.
The Vaccine Adverse Event Reporting System (VAERS) of the PHS isa fairly new passive surveillance system. Under the aegis of theCenters for Disease Control and Prevention (CDC) and the U.S. Foodand Drug Administration (FDA), VAERS was established by Public Law99-660. Anyone who knows of a possible adverse reaction—the patient,a parent, or even a non relative who witnessed or merely heard ofa reaction—can submit a report to VAERS. Letters are sent to about240,000 health care providers every 6 to 9 months explaining whatthey are required to report and emphasizing that a temporal relationto vaccination is the criterion for reporting an adverse event. Thereare plans to increase educational efforts aimed at physicians. ThePHS closely examines the reports to determine whether a particularpattern is emerging; weekly reports are reviewed to discover whatnew serious events or fatalities have been reported. Events relatedto newly-marketed vaccines are especially carefully scrutinized.
Passive surveillance systems can identify a problem, serving as analerting system. Once there is an alert, other surveillance methodsthat are more sensitive and specific for determining causation canbe used. For example, in the United Kingdom, reports to a passivesurveillance system indicated a problem with meningitis after theadministration of the Urabe strain mumps vaccine. (This strain isNOT used in the United States.) Stimulated reporting, that is, activesurveillance (letters were sent to every pediatrician), was thenemployed. A rate of one case of meningitis (diagnosis confirmed byvaccine-strain virus isolated from the cerebrospinal fluid) per 250,000doses of vaccine distributed was found by that method. By using LLDBsto link records of lumbar punctures with immunization histories,the rate of meningitis after administration of that vaccine was foundto be 1 in 10,000 immunized children.