Targeting a site of vulnerability on circumsporozoite protein inhibits Plasmodium vivax malaria infection

Circumsporozoite protein (CSP) is the most abundant Plasmodium sporozoite surface antigen. It is the major component of licensed Plasmodium falciparum vaccines and, hence, is the logical lead candidate for Plasmodium vivax (P. vivax) vaccines. However, our limited knowledge of protective B cell epitopes on P. vivax CSP remains a major roadblock. Here we identified two Plasmodium vivax CSP (PvCSP) B cell epitopes, PvCSP-A and PvCSP-B/NAGG, by screening inhibitory plasma from P. vivax-infected individuals. The epitopes were located in the N- and C-terminal regions of PvCSP, respectively, and were distinct from the canonical central repeat region epitope. We isolated a monoclonal antibody, GRAM-4, that recognized the PvCSP-B/NAGG epitope and mediated potent inhibition of traversal, hepatocyte invasion, and liver-stage development in vitro, confirming PvCSP-B/NAGG as a genuine neutralization target. Structural resolution of the GRAM-4:PvCSP-B/NAGG interaction at 2.65 Å revealed the molecular basis of epitope recognition, providing a blueprint for PvCSP vaccine development.