Structural basis for neutralization of Plasmodium vivax by naturally acquired human antibodies that target DBP.

Abstract

The Plasmodium vivax Duffy binding protein (DBP) is a prime target of the protective immune response and a promising vaccine candidate for P. vivax malaria. Naturally acquired immunity (NAI) protects against malaria in adults residing in infection-endemic regions, and the passive transfer of malarial immunity confers protection. A vaccine that replicates NAI will effectively prevent disease. Here, we report the structures of DBP region II in complex with human-derived, neutralizing monoclonal antibodies obtained from an individual in a malaria-endemic area with naturally acquired immunity. We identified protective epitopes by X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, mutational mapping, and P. vivax invasion studies. These approaches reveal that naturally-acquired human antibodies neutralize P. vivax by targeting the DARC–binding site and dimer interface of P. vivax DBP. Antibody binding is unaffected by polymorphisms in the vicinity of epitopes, suggesting the antibodies have evolved to engage multiple polymorphic variants of DBP. The human antibody epitopes are broadly conserved and are distinct from previously defined epitopes for broadly conserved murine mAbs. A library of globally conserved epitopes of neutralizing human antibodies opens new horizons for rational design of strain-transcending DBP-based vaccines and therapeutics against P. vivax.