The goal of this project is to identify genes that are involved in susceptibility and resistance tohuman vaccinia infection, and, consequently, in some of the adverse effects seen with smallpox vaccination.We (R.B.B.) recently led a multi-center prospective study on the clinical response to vaccinia immunization in680 na'l've individuals. Among the 665 individuals responding to the vaccine, 84 (13%) developed fever,muscle aches and lymphadenopathy giving rise to what we have called Acute Vaccinia Syndrome (AVS) inapproximately 30% of vaccines. The timing of the onset of these symptoms matched the timing of thehighest levels of viral shedding, indicating that fever, and the other components of AVS appear to besecondary to the virus. We hypothesize that individuals developing AVS (and especially fever) havedisease-predisposing alleles that are associated with abnormal innate immune or delayed adaptive immuneresponses to vaccinia. These individuals may be more susceptible to poxviruses in general, and couldconstitute a group at increased risk for mortality if exposed to smallpox. We propose to identify genes thatare expressed in response to vaccinia infection at the site of inoculation and systemically using atranscriptional analysis. We will compare responses between individuals that develop AVS, and thoseindividuals who develop no adverse reactions to immunization. These studies will provide us with atranscriptional profile of the host response to vaccinia infection, identify key molecules in the host response,and, establish parameters for protective immune responses that could be used to test the efficacy of newvaccines. We will also identify alleles associated with adverse effects to vaccinia immunization andabnormal innate immune responses to the virus through the analysis of haplotypes based on singlenucleotide polymorphisms in candidate genes. The identify of these alleles may provide clues to the criticalelements of the host response to poxvirus, and could provide a method to identify individuals at increasedrisk for adverse effects to the vaccine, or more severe disease with poxvirus infection. The design of thestudy, with the inclusion of transcriptional profiling of individuals receiving vaccinia immunization coupledwith a detailed virologic and immunologic profile, ensures that we will obtain valuable information on the hostresponse to vaccinia immunization.
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