MOLECULAR STRATEGIES TOWARDS A COCCIDIOIDOMYCOSIS VACCIN

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OVERALL DESCRIPTION (Adapted from application): Coccidioidomycosis is an important infection in the Southwestern United States responsible for considerable morbidity and mortality. Based on skin test conversions, it is estimated that 25,000 to 100,000 new infections occur each year. The incidence of disseminated (extra-pulmonary) infection is high in pregnancy, the immunosuppressed, and some ethnic groups. Second infections are extraordinarily rare, indicating that natural immunity works. The investigators have found two proteins that confer protective immunity in a mouse model of infection. One is a cytoplasmic enzyme; immunization with this protein results in a 10 to 50-fold reduction in the number of organisms per lung. These results provide proof of concept that an effective vaccine for Coccidioides immitis is a realistic goal. The program consists of five projects. Project I focuses on antigen identification, expression, and preliminary testing. Project II will evaluate PRA as a protective antigen in detail. The goal is to define T-cell epitopes within PRA that might be more effective vaccines than PRA. Project III will investigate the critical types of lymphocytes and cytokines required for vaccination, using knock-out mice with targeted immune defects. Project IV will evaluate the genetic diversity of C. immitis. The goal of this project is to determine how polymorphic potential vaccine candidates are in the DNA sequence and level of expression. Project V will test antigens, adjutants, and delivery systems that provide protective immunity in the mouse model. Within Project V (and Project I) Dr. Neil Ampel plans to test antigens for their ability to elicit T-cell responses in skin test positive people. The two cores are designed to provide Protein and DNA to the projects (Core A) and administrative support (Core B). This program is a highly interactive, coordinated, and focused effort to design a vaccine to protect mice from experimental coccidioidomycosis. A great deal of emphasis is placed on finding adjuvants and immunization schemes that can be transferred to human beings. The investigators are also interested in defining the critical immune responses and in vitro tests of immunity that correlate with resistance to infection. This information is important to test the immune response to vaccination in people, which would be a crucial step in the evaluation process of a human vaccine for coccidioidomycosis.