Anthrax toxin fusions as experimental vaccines

Christine Shaw

In several of our ongoing projects we have identified microbial antigens that traffic to the cytoplasm of host cells and stimulate CD8+ T-cells. One of the challenges faced in designing vaccines is how to introduce these microbial antigens into the cytoplasm of host cells in vivo in the absence of infection. We have developed a strategy for CD8+ T-cell immunization using anthrax toxin.

During infection with Bacillus anthracis most of the symptoms (including death) result from the effects of a group of proteins known collectively as anthrax toxin. Anthrax toxin (and many other toxins, e.g. diphtheria, tetanus, botulinum, pertussis) circulates in the bloodstream and has evolved the ability to bind cells and translocate into the cytoplasm. Once in the cytoplasm, the toxin has enzymatic activities that disrupt cellular functions. The domains of the toxin responsible for binding and translocation are separate from the domains responsible for the toxic catalytic activity. We have designed recombinant toxins where the toxic activity has been replaced with CD8+ T-cell epitopes from a variety of bacterial and viral pathogens (Listeria monocytogenes, lymphocytic choriomeningitis virus-LCMV, and HIV). When these experimental vaccines are injected into mice, the toxin fusions stimulate CD8+ T-cells specific for the microbial antigen that was fused to the toxin. We have also immunized groups of mice with fusions containing epitopes from Listeria and LCMV and can demonstrate protection from an infectious challenge.

This project has been an ongoing collaboration with the laboratory of R. John Collier