Summary The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria.

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The most widespread form of malaria is caused by Plasmodium vivax. To replicate, this parasite must invade immature red blood cells, through a process which requires interaction of the Plasmodium vivax Duffy binding protein, PvDBP with its human receptor, the Duffy antigen receptor for chemokines, DARC. Naturally acquired antibodies that inhibit this interaction associate with clinical immunity, suggesting PvDBP as a leading candidate for inclusion in a vaccine to prevent malaria due to Plasmodium vivax. Here, we isolated a panel of monoclonal antibodies from human volunteers immunised in the first clinical vaccine trial of PvDBP. We screened their ability to prevent PvDBP from binding to DARC, and their capacity to block red blood cell invasion by a transgenic Plasmodium knowlesi parasite genetically modified to express PvDBP and to prevent reticulocyte invasion by multiple clinical isolates of Plasmodium vivax. This identified a broadly neutralising human monoclonal antibody which inhibited invasion of all tested strains of Plasmodium vivax. Finally, we determined the structure of a complex of this antibody bound to PvDBP, revealing the molecular basis for inhibition. These findings will guide future vaccine design strategies and open up possibilities for testing the prophylactic use of such an antibody.