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.

恶性疟原虫网织红细胞结合蛋白同源物 5 (RH5) 是最先进的血期疟疾候选疫苗，正在流行地区评估其功效，强调需要研究自然感染期间对 RH5 的潜在抗体反应，这可能会增强或抵消疫苗接种的反应。在这里，我们发现 RH5 反应性 B 细胞很少见，尽管多年来反复感染，但在暴露于疟疾的马里个体中，循环免疫球蛋白 G (IgG) 对 RH5 的反应是短暂的。从 8 名接触过疟疾的个体中分离出的 RH5 特异性单克隆抗体主要针对非中和表位，而与从 5 名接种过 RH5 且未患过疟疾的英国个体中分离出的抗体相比。然而，从两名接触疟疾的马里个体中分离出来的 MAD8-151 和 MAD8-502 是这两个群体的 186 种抗体中最有效的中和剂之一，并且与最有效的疫苗诱导抗体靶向相同的表位。这些结果表明，自然疟疾感染可能会增强 RH5 疫苗诱导的反应，并为下一代 RH5 疫苗的开发提供明确的策略。