Anthrax vaccine design: strategies to achieve comprehensive protection against spore, bacillus, and toxin

Abstract

The successful use of Bacillus anthracis as a lethal biological weapon has prompted renewed research interest in the development of more effective vaccines against anthrax. The disease consists of three critical components: spore, bacillus, and toxin, elimination of any of which confers at least partial protection against anthrax. Current remedies rely on postexposure antibiotics to eliminate bacilli and pre- and postexposure vaccination to target primarily toxins. Vaccines effective against toxin have been licensed for human use, but need improvement. Vaccines against bacilli have recently been developed by us and others. Whether effective vaccines will be developed against spores is still an open question. An ideal vaccine would confer simultaneous protection against spores, bacilli, and toxins. One step towards this goal is our dually active vaccine, designed to destroy both bacilli and toxin. Existing and potential strategies towards potent and effective anthrax vaccines are discussed in this review.

Figure 1

Models illustrating the different cellular fates of PA and DNI. Top: Upon binding cellular receptors (step 1), PA is cleaved (step 2). The small fragments diffuse away, and the cell-bound fraction self-assembles into heptameric cores termed (PA₆₃)₇ (step 3). The heptamers then undergo receptor-mediated endocytosis (step 4). Once inside the acidic endosomal compartment, the PA heptamers change conformation and insert into the endosomal membrane (step 5). Bottom: DNI, similar to PA, enters the endosome (steps 1–4). However, DNI heptamers do not undergo the necessary conformational changes for insertion into the membrane and therefore remain trapped inside the endosome.