Extensive studies in humans and animal models indicate that acquired immunity to malaria develops. Nevertheless, the goal of reducing malaria morbidity and mortality through active immunization has not been achieved. As such, Plasmodium falciparum malaria remains one of the most significant public health problems in the world today. The long-term goal of our research is to maximize the protective immunity against malaria induced by immunization with defined subunit vaccines. We utilize the Plasmodium yoelii and Plasmodium chabaudi rodent models of malaria to gain in vivo experimental data on protective antigens and immune mechanisms. We apply these data to the investigation of human malaria in parallel in vitro studies of P. falciparum blood-stage parasites.

Primary Interest

The malaria vaccine development field has faced several challenges but 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 work focuses on vaccine targets where antibody-dependent mechanisms of immunity are essential, but where immunogenicity of neutralizing B cell epitopes has not been optimal. In proof-of-concept studies, we overcome obstacles related to both production and suboptimal immunogenicity of recombinant antigen-based vaccines by engineering a well-conserved, highly immunogenic, P. falciparum-specific carrier protein that induces potent CD4+ T cell help for the production of neutralizing antibodies. Genetic fusion of neutralizing B cell epitopes of P. falciparum to a parasite-specific carrier protein will also allow concurrent boosting of vaccine-primed B cells and vaccine-primed CD4+ T cells by natural P. falciparum infection.

In our main project, we are systematically evaluating leading vaccine candidates to define highly efficacious, multi-antigen formulations and link antibody specificity and isotype with functional assays of parasite neutralization. We are targeting merozoite surface protein 2 (PfMSP2), reticulocyte-binding protein homologue 5 (PfRh5), the 25 kDa sexual stage antigen of P. falciparum (Pfs25) and most recently, the pre-erythrocytic stage circumsporozoite protein. Each is being produced as a single recombinant antigen and as a chimeric fusion protein with the rPfMSP8 (ΔAsn/Asp) carrier. We are comparing the immunogenicity of single versus chimeric antigen vaccines formulated with Th1/Th2 biasing adjuvants with respect to antibody titer, epitope specificity, isotype and activity in functional assays of parasite neutralization. In mice and non-human primates, we will test highly immunogenic recombinant vaccines in combined formulations with rPfMSP1/8, a chimeric MSP-based vaccine shown to elicit high titers of growth inhibitory antibodies. For antibodies elicited by PfMSP1, PfMSP2 and PfRh5 vaccines, the neutralization of extracellular, invasive merozoites by antibody in concert with complement and/or Fc receptor bearing phagocytic cells will be key. In contrast, antibodies to PfCSP and Pfs25 and will be tested for their ability to block infection of hepatocytes and reduce transmission of sexual stage parasites back to mosquitoes respectively. Success in these efforts would 1) represent a major step toward the goal of producing a combined pre-erythrocytic-stage/blood-stage/sexual-stage malaria vaccine to concurrently reduce the severity of clinical disease and block transmission and 2) provide a solid foundation for subsequent safety and immunogenicity testing in human subjects.