COCCIDIOIDES IMMITIS ANTIGENS AS VACCINES

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The overall goal of this program is to define C. immitis antigens which are effective vaccines in experimental coccidioidomycosis, and presumably, hman coccidioidomycosis. Since T- cell mediated immunity is critical in coccidioidomycosis, we propose to test antigens which elicit vigorous T- cell responses. The role of this project is essentially twofold: to perform the immunologic testing in mice, selecting candidate antigens for immunoprotection experiments; and to test those antigens as vaccines in mice. We will use a two-pronged approach to find T-cell reactive C. immitis antigens. We have already identified and cloned one protein which stimulated a C. immitis-specific murine T-cell line, as well as the C. immitis homologs of two heat-shock proteins, hsp 60 and dnaJ. These will be tested for ability to stimulate T-cell proliferation in lymph node T- cells from immune mice and several spherule-specific T-cell lines. These will also be tested for their ability to immunize mice for a proliferative response to C. immitis spherules. In collaboration with Project 3, we will determine what type of T-cells are activated by these antigens and what lymphokines they produce. A second, complementary approach will be to test cDNA libraries derived from spherules for T-cell reactivity. The clones expressing C. immitis proteins will be expressed in "naked vectors" and the mice "infected" with the DNA. The T-cell proliferative responses of the mice will be determined, and those that elicit T-cell responses will be expressed as recombinant proteins and tested as outlined above. The magnitude of the T-cell responses, the ability to elicit good responses against intact spherules, and the lymphokines produced will be factors in deciding which antigens will be tested for immunoprotection. Immunoprotection assays will be done in two strains of genetically susceptible mice. Single proteins will be tested first and then combinations. We anticipate that these studies will provide information critical to the development of a human vaccine.