Host immunity to Bacillus anthracis lethal factor and other immunogens: implications for vaccine design

Abstract

Infections of humans with Bacillus anthracis are an issue with respect to the biothreat both to civilians and military personnel, infections of individuals by infected livestock in endemic regions and, recently, infections of intravenous drug users injecting anthrax-contaminated heroin. Existing vaccination regimens are reliant on protective antigen neutralization induced by repeated boosts with the AVA or AVP vaccines. However, there is ongoing interest in updated approaches in light of the intensive booster regime and extent of reactogenicity inherent in the current protocols. Several other immunogens from the B. anthracis proteome have been characterized in recent years, including lethal factor. Lethal factor induces strong CD4 T-cell immunity and encompasses immunodominant epitopes of relevance across diverse HLA polymorphisms. Taken together, recent studies emphasize the potential benefits of vaccines able to confer synergistic immunity to protective antigen and to other immunogens, targeting both B-cell and T-cell repertoires.

Keywords:

• anthrax
• Bacillus anthracis
• HLA
• lethal factor
• T-cell epitopes
• T-cell immunity

Financial & competing interests disclosure

Anthrax immunity studies in the Altmann lab have been funded by US NIH-NIAID under Contract HHSN266200400084C. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Anthrax infection remains of concern with respect to spread from livestock to humans in endemic countries, exposures in some intravenous drug users and potential biothreat.

• Current vaccination protocols reliant on the anthrax vaccine adsorbed and AVP vaccines are likely effective enough, but cumbersome, with poor long-term protection in the absence of annual boosters. The protocols have been exhaustively studied in efforts to understand and decrease reactogenicity and maximize immunological memory.

• There is increasing understanding of the B. anthracis immunome beyond protective antigen: the message from these studies is that protective antigen will likely continue to be at the center of any protective strategy, but other immunogens including lethal factor may offer synergistic protection. Furthermore, the notion of being able to also target spore antigens expressed prior to synthesis of toxins is particularly appealing.

• Any future vaccine strategies would do well to consider targeting both the B-cell and T-cell repertoire.

• There is a potentially important niche for human monoclonal antibodies in the acute medicine response to anthrax.