Immunopathogenesis of Pulmonary Tularemia and Plague

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Francisella tularensis (F. tularensis) has many characteristics that warrant its classification as a category A pathogen and potential bioweapon. It is easy to grow and as an aerosol, it has a high rate of infection in exposed populations. The tularemia vaccine history is remarkable in that the Live Vaccine Strain (LVS) demonstrated protection in nonhuman primates and humans but FDA approval was problematic because the basis and stability of its attenuation has not been identified. Identification of vaccine candidates encoded by the F. tularensis genome that induce protection could lead to a subunit vaccine. We have developed a murine model for primary pulmonary infection with Biovar A virulent F. tularensis for which LVS induces a protective response against a respiratory challenge with virulent F. tularensis. We intend to study the lung-pathogen interaction during the acquired responses for F. tularensis in mice and primates. We have partnered with MacroGenics, a vaccine candidate discovery company, and Lovelace Respiratory Research Institute (LRRI). Using expression library immunization, we will identify protective epitopes encoded by the virulent F. tularensis genome that will lead to a vaccine. Finally, the vaccine candidates will be tested in a nonhuman primate model of aerosolized F. tularensis. Aim 1. Determine the role for specific immune cells and inflammatory mediators in the lung during the acquired pulmonary immune response to Biovar A F. tularensis. Aim 2. Identify new subunit vaccine candidates against F. tularensis using expression library immunization Aim 3. Determine the clinical phenotype and characterize the host response to pneumonic tularemia in the non-human primate model, providing critical background data to permit efficient testing of vaccine candidates in the model.