Analyzing the function and antibody-mediated inhibition of the malaria vaccine candidate PF3D7_1136200

Project Summary Malaria remains one of the most significant public health concerns with a substantial proportion of the global population at risk for disease. In malaria-endemic regions, chronic exposure to the malaria parasite Plasmodium falciparum leads to the development of antibody responses that confer protection from symptomatic disease. However, naturally acquired immunity to malaria develops slowly, leaving children susceptible to severe disease and warranting the development of a highly efficacious malaria vaccine. The only malaria vaccine currently approved for broad use in malaria-endemic areas has low efficacy and will be insufficient to decrease the burden of P. falciparum malaria. Because of the challenges in malaria vaccine development, a combination vaccine that targets multiple parasite stages may be a favorable approach to achieve high vaccine efficacy. Among recently discovered vaccine candidates for the blood stage, the symptomatic stage of infection targeted by naturally acquired immunity, the highly conserved and previously uncharacterized P. falciparum protein, PF3D7_1136200 has high potential. Previous studies have shown that antibody responses against PF3D7_1136200 correlate with protection from symptomatic disease. Despite this strong correlation with protection from disease, little is known about how antibodies against PF3D7_1136200 inhibit the parasite or what role this protein plays in normal parasite biology. Our preliminary data suggest that PF3D7_1136200 has low antigenicity during natural infection, similar to the leading P. falciparum blood stage vaccine candidate PfRh5. However, some malaria-experienced individuals develop relatively strong antibody responses against the protein and harbor PF3D7_1136200-specific B cells. Based on previous findings and our preliminary data, we hypothesize that PFD7_1136200 is essential for parasite invasion and that PF3D7_1136200-specific antibodies are cross-strain reactive and inhibit P. falciparum growth in vitro. In Specific Aim 1, we aim to characterize PF3D7_1136200-specific antibodies and determine which regions of the protein are targeted by inhibitory antibodies in an effort to better guide vaccine design. In Specific Aim 2, we aim to utilize PF3D7_1136200-specific antibodies to determine the localization and expression of PF3D7_1136200 during the P. falciparum asexual replication cycle. Additionally, we aim to determine the importance of PF3D7_1136200 through the generation of a drug-inducible PF3D7_1136200 knockdown parasite line and subsequent growth and survival analysis. The data generated from these studies will elucidate the importance of PF3D7_1136200 in normal P. falciparum biology and identify the domains on PF3D7_1136200 best suited for targeting via vaccine strategies.