A public antibody lineage that potently inhibits malaria infection by dual binding to the circumsporozoite protein

Tan, Joshua; Sack, Brandon K; Oyen, David; Zenklusen, Isabelle; Piccoli, Luca; Barbieri, Sonia; Foglierini, Mathilde; Fregni, Chiara Silacci; Marcandalli, Jessica; Jongo, Said; Abdulla, Salim; Perez, Laurent; Corradin, Giampietro; Varani, Luca; Sallusto, Federica; Sim, B Kim Lee; Hoffman, Stephen L; Kappe, Stefan H I; Daubenberger, Claudia; Wilson, Ian A; Lanzavecchia, Antonio

Immunization with attenuated Plasmodium falciparum sporozoites (PfSPZ) has been shown to be protective, but the features of the antibody response induced by this treatment remain unclear. To investigate this response at high resolution, we isolated IgM and IgG monoclonal antibodies from Tanzanian volunteers who were immunized by repeated injection of irradiated PfSPZ and who were found to be protected from controlled human malaria infection (CHMI) with infectious homologous PfSPZ. All IgG monoclonals isolated bound to P. falciparum circumsporozoite protein (PfCSP) and recognized distinct epitopes in the N-terminus, NANP repeat region, and C-terminus. Strikingly, the most effective antibodies, as assessed in a humanized mouse model, bound not only to the repeat region, but also to a minimal peptide at the PfCSP N-terminal junction that is not in the RTS,S vaccine. These dual-specific antibodies were isolated from different donors and used VH3-30 or VH3-33 alleles carrying tryptophan or arginine at position 52. Using structural and mutational data, we describe the elements required for germline recognition and affinity maturation. Our study provides potent neutralizing antibodies and relevant information for lineage-targeted vaccine design and immunization strategies.