부산대학교 도서관

Plasmodium falciparum, the pathogen responsible for the deadliest form of malaria, continues to exact an immense human toll, disproportionality shouldered by countries in sub-Saharan Africa. Significant progress has been made this century in reducing global malaria mortality and morbidity, but these gains remain fragile. The development of a malaria vaccine that protects against clinical disease would be an invaluable addition to the malaria control toolkit, but has remained elusive to date. As a result, the search for new, more potent vaccine antigens continues. Emerging from these efforts was the identification of the PfRH5:PfCyRPA:PfRipr complex (RCR), which is essential for merozoite invasion into the host erythrocyte. Here, a new panel of anti-PfCyRPA antibodies are evaluated for their ability to block merozoite invasion, including two new mAbs that are the most potently inhibitory anti-PfCyRPA mAbs described to-date. Structural studies revealed a single critical face of PfCyRPA that elicits neutralizing antibodies, where all four of the newly described inhibitory mAbs bound, opening the door for further studies on synthetic PfCyRPA immunogens that can focus the immune response on this vulnerable region of PfCyRPA. Finally, studies of synergy and antagonism between pairs of anti-PfCyRPA mAbs revealed that non-competing inhibitory anti-PfCyRPA mAbs potently synergize with each other. A novel mechanism of synergy to explain this observation was described, whereby lateral interactions between adjacent antibody Fab arms stabilize and enhance antibody affinity for PfCyRPA. Together, these data can inform the design of the next generation of malaria therapeutics.