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 IgG 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, 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 3 or 4 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 significantlylower 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.

Human Leukocyte Antigens and Cellular Immune Responses to Anthrax Vaccine Adsorbed

“…A relationship between specific DRB1-DQA1-DQB1 haplotypes and a significantly lower AbPA humoral response to AVA has been previously demonstrated (14). In particular, that study found an association between the DRB1*01:02-DQA1*01:01-DQB1*05:01 haplotype and significantly lower AbPA levels following AVA (14).…”

“…A relationship between specific DRB1-DQA1-DQB1 haplotypes and a significantly lower AbPA humoral response to AVA has been previously demonstrated (14). In particular, that study found an association between the DRB1*01:02-DQA1*01:01-DQB1*05:01 haplotype and significantly lower AbPA levels following AVA (14). Our study found that A, DQA1, and DQB1 homozygosity (at four-digit molecular resolution) and A, B, DRB1, and DQA1 homozygosity (at two-digit molecular resolution) are significantly associated with diminished PA-specific lymphoproliferation.…”

“…HLA class II alleles are encoded by DR, DQ, and DP polymorphic genes, and many class II alleles have been found to be important immunogenetic markers for both vaccine-induced viral and bacterial immune responses (14,27). A relationship between specific DRB1-DQA1-DQB1 haplotypes and a significantly lower AbPA humoral response to AVA has been previously demonstrated (14).…”

“…Details of AVA000 have been published elsewhere (9,14). In brief, 1,564 healthy subjects between 18 and 61 years of age were enrolled at five sites, including the Mayo Clinic (Rochester, MN); Walter Reed Army Institute of Research (Silver Spring, MD); Baylor College of Medicine (Houston, TX); Emory University School of Medicine (Atlanta, GA); and the University of Alabama at Birmingham (Birmingham, AL).…”

“…Among the most likely candidate genes are the highly polymorphic human leukocyte antigen (HLA) loci on chromosome 6 with alleles that are known to bind a repertoire of naturally processed peptides presented to T cells (13). On the basis of the AVA000 data, Pajewski et al (14) examined HLA haplotype associations with various antibody responses to AVA, finding significant associations between several DRB1-DQA1-DQB1 haplotypes (*15:01-*01:02-*06:02, *01:01-*01:01-*05:01, and *01:02-*01:01-*05:01) and lower production of AbPA (14). The objective of the present study was to further examine HLA polymorphisms within the specific context of PA-induced cellular immunity.…”