Tuberculosis Vaccine Strategy Using Salmonella Vectors

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The candidate is applying for a Career Development Award in order to gain additional training in vaccine research. He will work in Dr. Josephine Clark-Curtiss' lab, with Dr. Roy Curtiss serving as a co- mentor. The collaborative research environment of these laboratories should provide an ideal setting for the candidate to extend his previous research experience toward tuberculosis vaccine development. Several investigators in these laboratories are working on mycobacterial genetics and on the development of vaccines for other bacterial pathogens. During the award period the candidate will use a Salmonella live vaccine system to deliver specific mycobacterial polypeptide epitopes to the cytoplasm of antigen presenting cells, in order to stimulate an MHC class I-restricted CD8+ T cell response to these antigens. Growing evidence suggests a role for CD8+ T cells in natural immunity to tuberculosis. This hypothesis suggests that vaccine strategies designed to stimulate a CD8+ T cell response system may yield advances in tuberculosis vaccine technology. In addition, such advances may have implications for vaccines against other intracellular pathogens. The goals of this proposal are to: (1) test the ability of recombinant proteins based on SptP, or other proteins secreted and translocated by Salmonella, to stimulate a CD8+ T cell response to ESAT-6, (Z) test the ability of the elicited ESAT-6- specific T cells to kill intracellular mycobacteria, (3) test the ability of the recombinant SptP/ESAT-6-expressing, attenuated Salmonella typhimurium vaccine strain to protect mice from an aerosol challenge with a virulent Mycohac(erium (ttherculosis strain and (4) screen for additional mycobacterial antigens that could serve as alternative vaccine candidates in this antigen presentation system.