This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Exposure to Yersinia pestis causes severe disease, with the pneumonic form of the disease being the most severe. There are a number of vaccine candidates under development to protect against this disease. It has been shown that a candidate vaccine containing F1 and V (given intramuscularly) was protective in Cynomolgus monkeys (Macaca fascicularis), but was poorly protective in African green monkeys (Chlorocebus aethiops). The basis for this disparity is not known. These findings raise the need to evaluate ways to enhance the response in African green monkeys?especially if the African green monkey is a potentially better predictor of the response in humans. Our prior studies have established that flagellin is a highly efficacious mucosal adjuvant in mice and Cynomolgus monkeys. Animals immunized intra-nasally with flagellin and the F1 and/or V antigens of Yersinia pestis produce very high levels of antigen-specific IgA and IgG. The flagellin and Y. pestis proteins may be separate or in the form of a single fusion protein in which the F1 and V sequences have been inserted into the hypervariable region of flagellin. Immunized mice are fully protective against lethal respiratory challenge with 150 LD50 of Y. pestis CO92. Plasma from Cynomolgus monkeys immunized with flagellin and F1 and V provides full and complete protection against lethal respiratory challenge with Y. pestis in na?ve mice. In view of 1) the extraordinary potency of flagellin as a mucosal adjuvant, 2) the finding that a vaccine containing flagellin and the F1 and V antigens generates much higher titers of anti-F1 and V antibodies than the candidate vaccine, and 3) the ability of a mucosal flagellin-based vaccine, as opposed to a vaccine given i.m., to induce protective IgA, we propose to evaluate the relative efficacy of a mucosal flagellin/F1/V vaccine in Cynomolgus and African green monkeys to induce anti-F1 and V specific IgA and IgG and to provide protection against an aerosol challenge with Y. pestis CO92. To date, the phase of this study that includes the African green monkeys is underway;the animals have been immunized and await aerosol challenge with Y. pestis.
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