Human Leukocyte Antigen Genotypes in the Genetic Control of Adaptive Immune Responses to Smallpox Vaccine

Background. The role of human leukocyte antigen (HLA) genes in mediating adaptive immune responses to smallpox vaccine remains unknown. Methods. We determined genotypes for a group of individuals (n = 1071) who received a single dose of smallpox vaccine (Dryvax, Wyeth Laboratories) and examined associations between HLA alleles and 15 immune outcomes to smallpox vaccine on a per-locus and a per-allele level. Results. We found significant associations between the HLA-B and HLA - DQB1 loci and vaccinia-induced antibodies (P = .04 for each locus), with the HLA-B(star)1302 (P = .036), B(star)3802 (P = .011), DQB1(star)0302 (P = .015), and DQB1(star)0604 (P = .017) alleles being associated with higher levels. Significant global associations were identified between vaccinia-specific interferon (IFN)-gamma and DQA1 (P = .003), interleukin (IL)-1 beta and HLA-B (P = .004), tumor necrosis factor (TNF)-alpha and HLA-B (P = .006), and IL-6 and HLA-B locus (P = .016) for secreted cytokines, as well as between CD8 alpha(+) IFN-gamma Elispot responses and DQB1 (P = .027). Subjects carrying B(star)3906 (P = .006) and B(star)5701 (P < .001) secreted higher levels of IL-1 beta than did subjects who did not carry these alleles. Subjects carrying the B(star)5301 (P = .047) and B(star)5601 (P = .008) alleles secreted less IL-1 beta, compared with subjects who did not carry these alleles. The B(star)3502 (P = .009), B(star)5601 (P = .004), and B(star)5701 (P < .001) alleles were significantly associated with variations in TNF-alpha secretion. Conclusions. These data suggest that variations in antibody and cellular IFN-gamma, IL-1 beta, TNF-alpha, and IL-6 immune responses after receipt of smallpox vaccine are genetically controlled by HLA genes or genes in close linkage disequilibrium to these alleles.