Impact of HLA Polymorphism on the Immune Response to Bacillus Anthracis Protective Antigen in Vaccination versus Natural Infection

Abstract

The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination is vital in planning protective strategies against anthrax.

Anthrax Vaccination, Gulf War Illness, and Human Leukocyte Antigen (HLA)

“…In fact, variation in the allele composition of this set from individual to individual is a major determinant for a successful vaccination, namely the production of specific antibodies against the vaccine antigen. In the case of anthrax vaccination, the dependence of production of anti-PA antibodies on HLA has been documented [ 5 , 33 , 38 ]. Therefore, we analyzed the HLA composition of the vaccinated participants and identified 18 Class II HLA alleles which were present only in the group of veterans who did not develop GWI but were absent from the group that developed GWI.…”

Anthrax Vaccines in the 21st Century

“…In fact, effective protection of vaccinated people upon exposure depends critically on the production of suitable antibodies against anthrax toxins and/or spores (see below). The production of such antibodies depends, in turn, on the genetic immune makeup (HLA Class II genes) of the vaccinated subject [ 6 , 48 ] and their general immunocompetence; the actual degree of protection conferred by the vaccine would be the result of both the vaccination and the host immune system, as discussed in more detail below.…”