DESCRIPTION (provided by applicant): We have shown that immunization of rabbits with multiple antigenic peptides (MAPs) displaying sequence from domain 2 of protective antigen (PA) elicit antibodies specific for a linear determinant within the 2?2-2?3 loop of PA, that mediate potent neutralization of lethal toxin (LeTx) in vitro. We have now shown in two separate large studies that antibodies against this site, referred to as the loop neutralizing determinant (LND), can mediate complete protection of rabbits from an aerosolized spore inhalation challenge with a 200 LD50-targeted dose of B. anthracis Ames strain. LND-specific antibody is not present in rabbit PA-antiserum and more importantly, is not present in AVA-vaccinee sera. The LND specificity, therefore, is non-overlapping with the specificities present in PA antisera, and therefore represents a unique and novel specificity for development of a stand-alone or adjunctive vaccine for anthrax. We have now developed an optimized highly immunogenic LND-VLP vaccine using our novel proprietary platform technology which incorporates the vaccine target sequence into highly immunogenic virus like particles. This new LND vaccine, when formulated with human use adjuvants, has the potential to elicit potent and rapid protective immunity against anthrax with only one or two injections. In the current project, we will further optimize the LND-VLP vaccine through insertion of a second linear neutralizing epitope we have identified in lethal factor, to establish additional critical redundancy and increased potency in a new bivalent LND-LF-VLP vaccine, which promises to be a safe and strategic new pre- and post-exposure vaccine for anthrax.

PUBLIC HEALTH RELEVANCE: Inhalation anthrax remains a severe threat to our military and to the general population, yet while all non-immune individuals would be at grave risk in the event of exposure to aerosolized anthrax, protecting all members of the population through universal vaccination is not feasible or desirable. In this project, we will continue our development of a novel vaccine for anthrax that has the potential to very rapidly elicit protective levels of antibody in vaccines after only one or two vaccine doses, and promises to be a uniquely efficacious pre- and post-exposure vaccine for anthrax.