Integrating a pre-erythrocytic component into a multistage malaria vaccine

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Malaria control continues to attract international attention. While current integrated control efforts are being maintained, new tools need to be added if further reduction in the global malaria burden is to be realized. The development and introduction of an efficacious vaccine has great potential to be one such tool. However, successes in the malaria vaccine effort to date have been limited. While there are several challenges that must be addressed, two key issues have repeatedly emerged. First, the immunogenicity of subunit vaccines must be improved. Second, there is no indication that immunity to these complex, multi-stage plasmodial parasites is directed toward a single protective antigen. Vaccine candidate antigens will need to be formulated in combination, without any reduction in the immunogenicity of individual components. Our prior efforts have focused on both blood-stage and sexual stage vaccine targets where antibody-dependent mechanisms of immunity are essential, but where immunogenicity of neutralizing B cell epitopes has not been optimal. In our approach, we engineered a well-conserved, highly immunogenic, P. falciparum specific carrier protein based on merozoite surface protein 8 that facilitates vaccine production and induces potent CD4+ T cell help for the production of neutralizing antibodies. We demonstrated its utility as a carrier for P. falciparum blood-stage vaccine candidates including merozoite surface protein 1, merozoite surface protein 2, reticulocyte-binding protein homologue 5 and the 25 kDa sexual stage antigen. Of importance, neutralizing antibody responses to targeted domains were maintained within the context of a multi-antigen, multi-stage formulation. A pre- erythrocytic stage vaccine component is currently lacking from our formulation. In this project, we will test the hypothesis that PfMSP8 is an effective carrier protein for a recombinant P. falciparum circumsporozoite surface protein-based vaccine to elicit potent, durable antibody responses to multiple protective B cell epitopes (repeat and non-repeat domains) that neutralize sporozoites. In aim 1, we will express and purify four recombinant PfCSP-based vaccines designed to increase the breadth of immune responses to relevant epitopes, some of which are lacking in the current PfCSP-based RTS,S vaccine. In aim 2, we will determine the magnitude and epitope specificity of T and B cell responses elicited by each rPfCSP-based vaccine formulated with GLA-SE as adjuvant. Following down-selection, we will evaluate the functionality and durability of vaccine-induced, PfCSP-specific IgG in a rodent challenge model with transgenic Plasmodium berghei parasite expressing P. falciparum CSP. Success in this effort will provide the foundation for subsequent preclinical testing in non- human primates to determine if a rPfCSP* vaccine can be formulated in combination with existing rPfMSP1/8, rPfMSP2/8, rPfRh5/8 and rPfs25/8 vaccines without compromising responses to individual components.