A human antibody epitope map of Pfs230D1 derived from analysis of individuals vaccinated with a malaria transmission-blocking vaccine

Pfs230 domain 1 (Pfs230D1) is an advanced malaria transmission-blocking vaccine antigen demonstrating high functional activity in clinical trials. However, the structural and functional correlates of transmission-blocking activity are not defined. Here, we characterized a panel of human monoclonal antibodies (hmAbs) elicited in vaccinees immunized with Pfs230D1. These hmAbs exhibited diverse transmission-reducing activity, yet all bound to Pfs230D1 with nanomolar affinity. We compiled epitope-binning data for seventeen hmAbs and structures of nine hmAbs complexes to construct a high-resolution epitope map and revealed that potent transmission-reducing hmAbs bound to one face of Pfs230D1, while non-potent hmAbs bound to the opposing side. The structure of Pfs230D1D2 revealed that non-potent transmission-reducing epitopes were occluded by the second domain. The hmAb epitope map delineated binary hmAb combinations that synergized for extremely high-potency, transmission-reducing activity. This work provides a high-resolution guide for structure-based design of enhanced immunogens and informs diagnostics that measure the transmission-reducing response. [Display omitted] •Derived a human antibody epitope map of Pfs230D1 by analyzing vaccinated individuals•Potent and non-potent transmission-reducing hmAbs bind opposing faces of Pfs230D1•Protective hmAbs display synergistic enhancement of transmission-reducing activity•Pfs230D2 overlaps with non-potent transmission-reducing hmAb epitopes of Pfs230D1 There is a limited understanding of the epitopes targeted by antibodies upon vaccination with malaria transmission-blocking vaccines in humans. Tang and Coelho et al. characterized a panel of monoclonal antibodies elicited in vaccinees and generated a human monoclonal antibody epitope map that defines the area of functional transmission-reducing activity on the surface of the leading malaria transmission-blocking vaccine antigen Pfs230D1.