Genetic predisposition for adverse events after vaccination.

The host response to infection or immunization varies within a population. Historically, we have ascribed variation of response among individuals inoculated with identical vaccines to stochastic processes that could not have been predicted. Now that the human genome has been defined and extensive variation in the ge-nome has been noted in both coding and regulatory regions, we can consider the hypothesis that some features of host response to infection or immunization are influenced by genetic factors. In a study in this issue of the Journal, Stanley et al. [1] show that haplotypes in the interleu-kin-1 gene complex and the IL18 gene are associated with an increased incidence of fever after vaccination of healthy adults with live vaccinia virus, the classic vaccine for protection against smallpox. Recent trials of live smallpox vaccines, sponsored by the National Institutes of Health, have provided an ideal setting in which to explore the mechanisms underlying adverse events after vaccination with a live virus. Variola virus has not circulated for decades, and vaccinia virus immunization also has not been used for decades except in the military and in some laboratory workers. Recent political events led to the retesting of the safety and potency of vaccines that had been stored for many years, in case widespread immunization of the population became a necessity. Therefore , there have been clinical trials of primary infection with vaccinia virus enrolling hundreds of seronegative healthy adults. A significant proportion of the volunteers suffered some type of adverse event (most commonly fever). Severe adverse events have not been attributed to vaccine, which is to be expected given the moderate size of trials conducted to date and the expected rarity of these events. In very large vaccination programs, such as in the military, some severe adverse events have been noted, and the association between vaccinia inoculation and cardiac inflammation is of concern. The relatively high frequency of individuals developing fever after primary inoculation with this vaccine provides a setting in which genomic and proteomic technologies can be brought to bear to explore mechanisms underlying adverse events. In studies recently published in the Journal [2, 3], high-throughput proteomic techniques were used in this setting to define alterations in cytokines and other soluble factors whose patterns were associated with fever, rash, and lymphade-nopathy. The results of such studies are complex, revealing that a single cytokine does not account for the clinical phenotype of adverse events; …