The Plasmodium falciparum major merozoite surface precursor protein, gp 195 is a candidate human malaria vaccine. However, increasing evidence indicates that vaccines against infectious diseases such as malaria may depend on the development of a safe and potent adjuvant capable of stimulating both humoral and cell-mediated immunity. Synthetic immunomodulators are potent adjuvant systems with low toxicity and therefore are prime candidates for a vaccine adjuvant for human use. Preliminary studies with some of these compounds showed that they are equally efficient as Freund's complete adjuvant in stimulating and anti- gp195 antibody response. Some of these formulations also induced parasite growth inhibitory antibodies. These studies also provide evidence for a significant influence of immunomodulators on the specificity of the anti-gp195 response. Our long-term objectives are (A) to develop an adjuvant formulation based on these immunomodulators for a human gp195- based vaccine, (B) to identify B and T cell epitopes that correlate with gp195-induced immunity, and (C) to study the nature and extent of influence of these immunomodulators on the immune responses to protein antigens using gp195 as a model. To this end, our specific aims are: 1) To evaluate in mice the ability of different adjuvants to induce anti- gp195 antibodies that inhibit parasites growth in an in vitro assay. 2) To evaluate in mice the ability of adjuvants to induce cell-mediated responses as measured by T cell proliferation and cytokine production. 3) To evaluate the efficacy of several adjuvant formulations, based on their ability to induce inhibitory antibodies and/or cell-mediated response to gp195, to induce gp195-specific protective immunity to P. falciparum in vaccination studies in the Aotus monkey model, and to correlate in vitro parasite growth inhibition by Aotus anti-gp195 antibodies with in vivo protection. 4) To characterize in monkeys and mice the gp195-specific antibody response induced by different adjuvants, described in (3), in order to correlate in vivo protection and in vitro inhibition with antibody titer, kinetics, immunological memory, antibody avidity, immunoglobulin isotypes, and specificity of B cell epitope recognition. 5) To characterize in monkeys and mice the cell-mediated response induced by different adjuvants, described in (3), in order to correlate protection with T cell proliferation, cytokine production, and the recognition of T cell epitopes.
