During the course of the previous grant the PI characterized the humoral and cellular anti-malaria immune responses induced by recombinant influenza and vaccinia viruses expressing selected sequences or the entire CS protein or malaria parasites. She characterized the immune responses of mice resulting from their successive vaccination with these two recombinant viruses, expressing the CS protein of rodent (P. yoelii) and human (P. falciparum) malaria parasites. These studies demonstrated that in the case of Py, the combined immunization with these two viruses induces protecting, mediated by malaria-specific antibodies and T cells which confer extensive resistance to challenge with viable parasites. In the case of Pf, the presence of in vivo activated circulating, protective CS-specific T cells was shown indirectly by the increased resistance of immunized mice to the intracerebral replication of recombinant vaccinia virus expressing the same CS-specific epitope. Considering the possibility of applying this approach to the development of a human malaria vaccine, we currently propose to pursue the following aims: Determine the optimal conditions for the engineering of highly immunogenic recombinant influenza viruses expressing a) a unique B cell epitope which has been shown to induce effective antibody responses against the native parasite protein, and b) a universal CD4+ T cell epitope which can be recognized by individuals bearing different class II MHC molecules. With the purpose of developing safe and effective malaria vaccines, she will generate highly attenuated recombinant viruses expressing an optimal set of CS epitopes. She will use cold adapted influenza viruses and the MVA strain of vaccinia viruses, both of which have been used to immunize large numbers of humans, without severe side effects. These attenuated vectors will be evaluated with regard to their safety and immunogenicity to induce antibodies and CD4+ and CD8+ T cell responses against malaria epitopes/antigens.
