A strain-transcending anti-AMA1 human monoclonal antibody neutralizes malaria parasites independent of direct RON2L receptor blockade.

Plasmodium falciparum apical membrane antigen 1 (AMA1) binds a loop in rhoptry neck protein 2 (RON2L) during red cell invasion and is a target for vaccines and therapeutic antibodies against malaria. Here, we report a panel of AMA1-specific naturally acquired human monoclonal antibodies (hmAbs) derived from individuals living in malaria-endemic regions. Two neutralizing hmAbs engage AMA1 independent of the RON2L-binding site. The hmAb 75B10 demonstrates potent strain-transcending neutralization that is independent of RON2L blockade, emphasizing that epitopes outside the RON2L-binding site elicit broad protection against variant parasite strains. The combination of these hmAbs synergistically enhances parasite neutralization. Vaccination with a structure-based design (SBD1) that mimics the AMA1-RON2L complex elicited antibodies similar to the two neutralizing hmAbs connecting vaccination to naturally acquired immunity in humans. The structural definition of a strain-transcending epitope on AMA1 targeted by naturally acquired hmAb establishes paradigms for developing AMA1-based vaccines and therapeutic antibodies.