Therapeutic Intervention of Pneumonic Plague by Monoclonal Antibodies to LcrV

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Yersinia pestis is the causative agent of pneumonic plague and a category A select agent. There are currently no licensed vaccines for plague, and though the bacterium is sensitive to several antibiotics, recent emergence of mUlti-drug resistant Y. pestis has raised the need to continue research and development of new therapeutics to prevent resurgent plague. In a collaboration funded by the Great Lakes RCE, we have been working on improving LcrV as a single subunit vaccine capable of protecting mice and rats against high challenge doses of Y. pestis in pneumonic plague modeis. In our efforts to identify immune correlates of protection, we defined a critical role for antibodies to LcrV and found these antibodies could aiso protect mice in a passive transfer model. We have identified three LcrV epitopes which can generate protective antibodies and at least five LcrV epitopes that were non-neutralizing. The strength of neutralization of bubonic plague by individual monoclonal antibodies to these epitopes was found to correlate with antigen binding affinity as well as antibody isotype, with IgG1 being the most protective. In this New Opportunities application, we propose to investigate the therapeutic potential of three monoclonal antibodies to LcrV, each binding to a distinct neutralizing epitope, against pneumonic plague in the Brown Norway rat and begin to develop this as a post-exposure treatment option. We will not only characterize efficacy but also antigen binding and bacterial clearance which may lead to future improvements in the development of medical countermeasures to the threat of plague.