ENHANCEMENT OF ADENOVIRUS INDUCED ANTIMALARIA PROTECTION

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The major goal of this project is to enhance and prolong the duration of the protective anti-malaria immunity elicited by a recombinant adenovirus expressing the circumsporozoite (CS) protein [Ads (CS)], and clarify the molecular mechanism of this protection. Our earlier studies had shown that the subcutaneous immunization of mice with Ade (CS) elicited a large number of CS specific T cells and a striking inhibition of the intrahepatocytic development of the malaria parasites, as well as sterile immunity in approximately 40 percent of the immunized mice. This protection was mediated primarily by CD8+ T cell, but was not mediated by interferon-gamma. We currently plan to clarify the possible role of certain cytolytic T cell derived molecules in this protection, such as perforin, Fas-Fas ligand, etc. (Specific Aim number 1). We also plan to determine the nature of the cells which take up this virus, process the plasmodial antigen and present it to T cells, by using Ade (CS) co-expressing the fluorescent green protein (Specific Aim number 2). We will determine whether adenovirus expressing only a single, or multiple repeats of the same CD8+ T cell epitopes of the CS protein of P. yoelii, are as effective or more than Ade (CS) in eliciting anti-malaria immunity (Specific Aim number 3). In order to increase the immunogenicity of the recombinant adenovirus expressing the CS protein, and increase the duration of the protective immune response, we plan to co-express certain cytokines or chemokines with the plasmodial protein in the viral vectors (Specific Aim number 4). The selection of a cytokine such as GM-CSF or others, as well as of a chemokine will be based on its known enhancing activity of the response to malaria or other microbial antigens. All the recombinant adenoviruses to be used in the proposed research are being constructed in my laboratory, which is turning out to be more expeditious.