ANTIMALARIA VACCINE BASED ON AN INFLUENZA VIRUS VECTOR

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We have shown that live influenza viruses expressing foreign epitopes can induce an efficient antibody and cytotoxic T cell (CTL) response. Specifically, we generated recombinant influenza viruses expressing CTL and B cell epitopes of the circumsporozoite (CS) protein of P. yoelii. Immunization of mice with these recombinant influenza viruses, alone or followed by a recombinant vaccinia virus expressing the entire CS protein, induced protective immunity against this murine malaria. We now propose to expand this approach and extend it to human malaria caused by P. falciparum. This work should generate data necessary for defining the optimal design of recombinant viruses for their future use as vaccines against malaria and possibly also against other infectious diseases. For this purpose we plan to: 1. Construct recombinant influenza viruses, expressing B and T cell epitopes of the CS protein of the human malaria parasite, P. falciparum. 2. Determine the degree of attenuation of these constructs in mice, and characterize the influenza-specific immune responses of animals exposed to the viral vectors. 3. Characterize the humoral and T cell mediated anti-malaria immune responses of mice immunized with recombinant influenza-CS viruses. 4. Construct additional influenza viruses expressing selected sequences of a second P. falciparum antigen, the Trombospondin Related Anonymous Protein (TRAP), and assess their immunogenicity in mice. Also define the immune response to influenza viruses expressing both CS and TRAP epitopes. 5. Attempt to potentiate these immune responses by priming and boosting with transfectants of two subtypes of influenza viruses, or two entirely different viral vectors, both expressing the same foreign epitopes.