| Summary: | Malaria remains a disease of great global healthcare burden, with over 600 thousand deaths annually. With an increase of multi-drug resistant malaria, achieving current mortality reduction targets hinges on the development of an efficacious malaria vaccine. Leading malaria vaccine RTS,S contains the major repeat epitope and C-terminal domain, but not the N-terminal domain of the Plasmodium falciparum circumsporozoite protein, which has been under investigated. Herein, the structural basis binding of six novel human and mouse antibodies with their N-terminal CSP peptide epitopes reveal the capacity for an antibody response towards multiple novel epitopes. The MAL071 RTS,S trial has provided renewed interest in antibodies targeting the C-terminal domain of CSP as correlates for protection. The structural basis for engagement of the C-terminal domain of CSP by ten monoclonal antibodies from the MAL071 trials demonstrates the broad antigenic landscape of this domain, including six new antibodies targeting the highly conserved β-epitope. The newfound immunological breadth of the β-epitope is then used to inform second-generation immunogen design combining key protective B-cell epitopes, successfully protecting mice from sporozoite challenge. Plasmodium vivax is responsible for most of the remaining malaria-associated mortality. Region II of the P. vivax Duffy-binding protein is a key antigen for a blood-stage vaccine. Here, the complete structural basis of PvDBP-RII engagement with the DARC ectodomain is revealed in complex with inhibitory human vaccination-induced monoclonal antibody DB1. This study significantly improves our understanding of receptor engagement by providing structural basis for previously described binding determinants and antibody-mediated inhibition of erythrocyte invasion by P. vivax merozoites.
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