Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and is being evaluated for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection, which could augment or counteract responses to vaccination. Here, we found that RH5-reactive B cells were rare, and circulating immunoglobulin G (IgG) responses to RH5 were short-lived in malaria-exposed Malian individuals, despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from eight malaria-exposed individuals mostly targeted non-neutralizing epitopes, in contrast to antibodies isolated from five RH5-vaccinated, malaria-naive UK individuals. However, MAD8–151 and MAD8–502, isolated from two malaria-exposed Malian individuals, were among the most potent neutralizers out of 186 antibodies from both cohorts and targeted the same epitopes as the most potent vaccine-induced antibodies. These results suggest that natural malaria infection may boost RH5-vaccine-induced responses and provide a clear strategy for the development of next-generation RH5 vaccines. [Display omitted] •Malaria-exposed individuals have rare but detectable RH5-specific B cells•Potency of RH5 mAbs from infection and vaccination is tightly linked to their epitope•Infection can elicit very potent mAbs that target sites of vulnerability on RH5•Malaria infection may boost protective RH5-vaccine-induced antibody responses An in-depth analysis of the naturally acquired antibody response to the malaria vaccine candidate RH5 reveals that infection can induce rare but potently neutralizing antibodies that target the same sites on the protein as potent vaccine-induced antibodies.