Plasmodium falciparum uses multiple strategies to evade the human immune response. While infection is established by a small number of sporozoites that are largely ignored by the immune system, the abundant blood stage parasites use multiple and polymorphic variant surface antigens to avoid clearance and subvert the immune response. From volunteers immunized with irradiated sporozoites, we identified a family of potent neutralizing antibodies that bind to multiple sites of the CSP protein and represent a new tool for prophylaxis and for vaccine design. Using a systematic search for antibodies that bind broadly to infected erythrocytes, we discovered, in 10% of malaria-exposed individuals, a new class of antibodies generated by insertions of genomic DNA encoding human inhibitory receptors (LAIR1 or LILRB1) into antibody genes (at the V-DJ junction or in the switch region). LAIR1- and LILRB1-containing antibodies bind to different families of parasite RIFINs and opsonize infected erythrocytes. These findings demonstrate that the parasite uses multiple RIFINs to target inhibitory receptors as part of its evasion strategy. They also illustrate a new mechanism of diversification based on the insertion of host receptors into immunoglobulin genes, leading to the production of receptor-based antibodies, with implications for antibody and B cell engineering.

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