| Francisella tularensis is listed as a Category A bioterrorism agent because of the ease of dissemination via aerosolization, and because of the extremely low number of organisms needed to establish a lethal infection in humans. To date, there is no safe method of prophylaxis against a possible exposure to this bacterium. The goal of these studies was to develop a safe and efficacious vaccine against Francisella tularensis using replication-restricted vesicular stomatitis virus as an in vivo delivery vector for cytokine-assisted immunization.; Since it has been well established that CD4+ and CD8 + T cells play an important role in clearance of FT, and that antibodies may or may not play a role, three separate vaccination strategies were employed to elicit both types of immune responses. The first approach involved the use of replication restricted VSV as an in vivo delivery vector for the known T cell target TUL4, and the cytokine adjuvant IL-12 (as IL12F). Although this strategy did produce TUL4-specific T and B cell responses, it was not effective for eliciting protective immunity to FT.; A second vaccination approach evaluated was to use a mixture of exogenous forms of the five known T cell targets of FT, namely DnaK, Cpn60, Cpn10, 23kDa and TUL4, in combination with virally-expressed IL-12F (vIL-12F) to elicit primarily a CD4+ T cell response, as well as the production of antibodies. Immunization of mice with the FT protein mix elicited protein-specific T and B cell responses that were augmented by co-administration of vIL-12F. Immunization of mice with the FT protein mix and vIL-12F elicited partial protection against a high dose challenge with FT.; Immunization with a heat killed preparation of FT (HKFT), either alone or in combination with a replication restricted VSV expressing IL-12F (VSVDeltaG-IL12F), was a third approach evaluated in these studies. Immunization with HKFT or HKFT in combination with VSVDeltaG-IL12F elicited protective immunity against a challenge with FT that appears to be antibody-mediated. Transfer of antibodies produced using these vaccine formulations was found to protect naive mice from a high dose challenge with FT, suggesting a previously underappreciated role for FT-specific antibodies in protection from this intracellular pathogen. |
