DESIGN AND IMMUNE MECHANISMS OF P FALCIPARUM CS VACCINE

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The design of an effective malaria vaccine capable of inducing an immune response that is primarily antibody or cell mediated, or ideally a combination of both, requires a through knowledge of all the effector mechanisms of protection. Studies on P. falciparum and on rodent malaria parasites have shown that antibody against repeat, as well as non-repeat regions of these circumsporozoite proteins can decrease or abolish parasite infectivity by blocking parasite/host cell interactions. In addition, cell mediated immune responses, mediated by CD4+ and CD8+ cytotoxic T lymphocytes and/or lymphokines, can destroy the subsequent stages of intracellular development of the parasite within the hepatocyte. In order to better understand the molecular basis and unique role of each effector mechanisms of immunity, and to develop optimal immunogens capable of inducing these multiple immune responses, we propose to: 1. Induce a protective cytotoxic T cell response, as well as neutralizing antisporozoite antibodies by immunization with recombinant live vectors containing defined sequences of the CS protein of P. yoelii and P. falciparum. 2. Define the specificity, kinetics and mechanism of action of class II restricted CD4+ cytotoxic and helper T cell, derived from sporozoite- immunized human, primate and murine hosts and assay the immunogenicity and antigenicity of MAPs constructs containing epitopes defined by these CD4+ T cells. 3. Develop monoclonal antibodies specific for conserved non-repeat regions of the CS proteins of P. berghei and P. falciparum which function as ligands in parasite/host cell receptor interactions and determine whether these monoclonals can inhibit sporozoite infectivity.