Genetic Basis for Adverse Events Following Smallpox Vaccination

Background—Although vaccinia immunization is highly effective in preventing smallpox, postvaccination reactions are common. Identifying genetic factors associated with AEs might allow screening before vaccinia administration and provide a rational basis for the development of improved vaccine candidates. Methods—Two independent clinical trials in healthy, vaccinia-naïve adult volunteers were conducted with the Aventis Pasteur smallpox vaccine (APSV). Volunteers were assessed repeatedly for local and systemic AEs to vaccine and were genotyped using the same panel of 1442 singlenucleotide polymorphisms (SNPs). CORRESPONDING AUTHOR: James E. Crowe, Jr., M.D., T2220 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2905, Tel 615-343-8064; Fax 615-343-4456; Email: james.crowe@vanderbilt.edu. CURRENT AUTHOR AFFILIATIONS: David M. Reif, Ph.D. { reif.david@epa.gov}, National Center for Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 Alison A. Motsinger, Ph.D. { motsinger@stat.ncsu. edu}, Bioinformatics Research Center, Department of Statistics, North Carolina State, University, Raleigh, NC 27695 CONFLICT OF INTEREST STATEMENT: Financial Disclosures: Dr. Crowe reported being the recipient of research funding from Sanofi-Aventis, Vaxgen, and a joint STTR award with Mapp Pharmaceuticals. He has consulted for MedImmune, Vaxin, Evogenix, Symphogen, and Syngenta. Dr. Edwards reported being the recipient of research funding from Sanofi-Aventis, MedImmune, Vaxgen, Merck, and Wyeth. She has consulted for MedImmune and Wyeth. No other authors reported disclosures. Role of the Sponsor: The funding organizations played no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. NIH Public Access Author Manuscript J Infect Dis. Author manuscript; available in PMC 2009 September 17. Published in final edited form as: J Infect Dis. 2008 July 1; 198(1): 16–22. doi:10.1086/588670. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript Results—In the first study, thirty-six SNPs in 26 genes were associated with systemic AEs (p-value ≤ 0.05). In the second study, only those SNPs associated with AEs in the first sample were tested. In the final analysis, three SNPs were associated consistently with AEs in both studies. A nonsynonymous SNP in methylenetetrahydrofolate reductase (MTHFR) was associated with AE risk in both trials (odds ratio [OR]; 95% confidence interval [CI]); p-value [p]): (OR=2.3; CI=1.1–5.2; p=0.04) and (OR=4.1; CI=1.4–11.4; p<0.01). Two SNPs in the interferon regulatory factor 1 (IRF1) gene were associated with AE risk in both sample sets: (OR=3.2; CI=1.1–9.8; p=0.03) and (OR=3.0; CI=1.1–8.3; p=0.03). Conclusions—Genetic polymorphisms in 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 two independent study samples. These findings highlight common genetic variants with promising clinical significance that merit further investigation.