The role of HLA-DR-DQ haplotypes in variable antibody responses to anthrax vaccine adsorbed

Abstract

Host genetic variation, particularly within the human leukocyte antigen (HLA) loci, reportedly mediates heterogeneity in immune response to certain vaccines; however, no large study of genetic determinants of anthrax vaccine response has been described. We searched for associations between the immunoglobulin G antibody to protective antigen (AbPA) response to Anthrax Vaccine Adsorbed (AVA) in humans, and polymorphisms at HLA class I (HLA-A, -B, and -C) and class II (HLA-DRB1, -DQA1, -DQB1, -DPB1) loci. The study included 794 European-Americans and 200 African-Americans participating in a 43-month, double-blind and placebo-controlled clinical trial of AVA (clinicaltrials.gov identifier NCT00119067). Among European-Americans, genes from tightly linked HLA-DRB1, -DQA1, -DQB1 haplotypes displayed significant overall associations with longitudinal variation in AbPA levels at 4, 8, 26 and 30 weeks from baseline in response to vaccination with three or four doses of AVA (global P=6.53 × 10(-4)). In particular, carriage of the DRB1-DQA1-DQB1 haplotypes (*)1501-(*)0102-(*)0602 (P=1.17 × 10(-5)), (*)0101-(*)0101-(*)0501 (P=0.009) and (*)0102-(*)0101-(*)0501 (P=0.006) was associated with significantly lower AbPA levels. In carriers of two copies of these haplotypes, lower AbPA levels persisted following subsequent vaccinations. No significant associations were observed amongst African-Americans or for any HLA class I allele/haplotype. Further studies will be required to replicate these findings and to explore the role of host genetic variation outside of the HLA region.

Figures

Figure 1

Distribution of IgG antibody to protective antigen (AbPA) response for European-Americans according to number of HLA-DR-DQ risk haplotypes (3-IM) Intramuscular injection at 0, 4, and 26 weeks (wks). (4-IM) Intramuscular injection at 0, 2, 4, and 26 weeks. (4-SQ) Subcutaneous injection at 0, 2, 4, and 26 weeks. Bold black lines denote sample median of unadjusted log10[AbPA] concentration (along with the inter-quartile range) computed by substituting 1/2 the empirical reactivity threshold (3.7 μ g / mL) of the ELISA assay (gray line) for observations below the limit. Numbers below data points denote the proportion of individuals below the reactivity threshold at a particular measurement time point. HLA-DR-DQ risk haplotypes were defined as the number of copies of the following haplotypes: HLA-DRB1-DQA1-DQB1 *0101-*0101-*0501, *0102-*0101-*0501, or *1501-*0102-*0602

Figure 2

Reverse cumulative distribution plots of IgG antibody to protective antigen (AbPA) for European-Americans prior to and following the 42 month vaccination, stratified according to number of HLA-DR-DQ risk haplotypes Panel A displays the distribution of log10(AbPA) pre-vaccination at 42 months stratified according to the number of HLA DR-DQ risk haplotypes. Panel B displays the log10(AbPA) distribution measured approximately 1 month post-vaccination. HLA-DR-DQ risk haplotypes were defined as the number of copies of the following haplotypes: HLA-DRB1-DQA1-DQB1 *0101-*0101-*0501, *0102-*0101-*0501, or *1501-*0102-*0602. The solid black line denotes the empirical reactivity threshold of the ELISA assay (3.7 μg/dL). Dashed lines correspond to the sample median for each HLA defined subgroup. Displayed p-values compare the AbPA distribution for individuals with two risk haplotypes versus zero/one haplotypes.