A dually active anthrax vaccine that confers protection against both bacilli and toxins

Abstract

Systemic anthrax is caused by unimpeded bacillar replication and toxin secretion. We developed a dually active anthrax vaccine (DAAV) that confers simultaneous protection against both bacilli and toxins. DAAV was constructed by conjugating capsular poly-␥-D-glutamic acid (PGA) to protective antigen (PA), converting the weakly immunogenic PGA to a potent immunogen, and synergistically enhancing the humoral response to PA. PGA-specific antibodies bound to encapsulated bacilli and promoted the killing of bacilli by complement. PA-specific antibodies neutralized toxin activity and protected immunized mice against lethal challenge with anthrax toxin. Thus, DAAV combines both antibacterial and antitoxic components in a single vaccine against anthrax. DAAV introduces a vaccine design that may be widely applicable against infectious diseases and provides additional tools in medicine and biodefense.

mAbs toBacillus anthraciscapsular antigen for immunoprotection in anthrax and detection of antigenemia

“…As shown by others (8,9), preliminary studies found little or no Ab response after immunization with ␥DPGA alone. As a consequence, we attempted immunization of BALB͞c mice with B. licheniformis ␥DPGA in combination with CD40 agonist mAb.…”

“…The extent to which a toxin-based immunity alone can protect against the potential large inoculum that might occur in a bioterrorism attack is not known. One approach to an improved vaccine formulation is a conjugate vaccine that targets both the antiphagocytic capsule and the toxin (8,9). Our results provide strong proof of concept for targeting ␥DPGA in a vaccine formulation and suggest efficacy of passive immunization in individuals who have not been immunized (21).…”

“…anthracis is surrounded by an antiphagocytic capsule composed of poly ␥-D-glutamic acid (␥DPGA). Recent studies highlighted the ␥DPGA capsule as a potential target for vaccine development (8,9). ␥DPGA is poorly immunogenic and shares many properties with T cell-independent polysaccharides, e.g., high molecular weight, repeating epitopes, resistance to degradation in vivo, and enhanced immunogenicity when complexed to protein.…”

“…␥DPGA is poorly immunogenic and shares many properties with T cell-independent polysaccharides, e.g., high molecular weight, repeating epitopes, resistance to degradation in vivo, and enhanced immunogenicity when complexed to protein. Two recent reports demonstrated that protein conjugates of ␥DPGA are immunogenic in mice (8,9). However, the ability of anti-␥DPGA to prevent anthrax in vivo has not been reported.…”

Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

“…Given the important role of the capsule in virulence, several recent studies have used the capsule of B. anthracis as a potential target for vaccine and neutralizing mAb development (14)(15)(16)(17)(18)(19)(20). These studies demonstrated that both active and passive vaccination targeting the B. anthracis capsule protected animals against experimental infection, suggesting that methods to increase the phagocytosis of encapsulated B. anthracis bacilli may be valuable in the treatment of anthrax.…”