Genetic basis for adverse events after smallpox vaccination

Abstract

Identifying genetic factors associated with the development of adverse events might allow screening before vaccinia virus administration. Two independent clinical trials of the smallpox vaccine (Aventis Pasteur) were conducted in healthy, vaccinia virus-naive adult volunteers. Volunteers were assessed repeatedly for local and systemic adverse events (AEs) associated with the receipt of vaccine and underwent genotyping for 1,442 singlenucleotide polymorphisms (SNPs). In the first study, 36 SNPs in 26 genes were associated with systemic AEs (P <or= .05); these 26 genes were tested in the second study. In the final analysis, 3 SNPs were consistently associated with AEs in both studies. The presence of a nonsynonymous SNP in the methylenetetrahydrofolate reductase (MTHFR)gene was associated with the risk ofAEin both trials (odds ratio [OR], 2.3 [95% confidence interval {CI}, 1.1-5.2] [P = .04] and OR, 4.1 [95% CI, 1.4 -11.4] [P<.01]). Two SNPs in the interferon regulatory factor-1 (IRF1) gene were associated with the risk of AE in both sample sets (OR, 3.2 [95% CI, 1.1-9.8] [P = .03] andOR, 3.0 [95% CI, 1.1- 8.3] [P = .03]). Genetic polymorphisms in genes expressing an enzyme previously associated with adverse reactions to a variety of pharmacologic agents (MTHFR) and an immunological transcription factor (IRF1) were associated with AEs after smallpox vaccination in 2 independent study samples.

Figure 1. Haploview plot of SNPs at chromosome 5q31.1

Panel A =first study; panel B =second study. Squares are shaded to indicate strength of evidence for LD between the pairwise markers. Dark = strong evidence (r² > 0.90), light gray = weak evidence (r² < 0.10), white = no evidence (r² < 0.0). The same two LD blocks are apparent in both studies, encompassing SNPs in IRF1 (rs839 and rs9282763) or IL4 (rs2070874, rs2243268, and rs2243290).