biostudies-literatureIvanochko DEuropean Research CouncilNIAID NIH HHSNIH HHS420-432.e7https://www.ebi.ac.uk/biostudies/studies/S-EPMC9942874biostudies-literatureUnknown56(2)Pfs230 is essential for Plasmodium falciparum transmission to mosquitoes and is the protein targeted by the most advanced malaria-transmission-blocking vaccine candidate. Prior understanding of functional epitopes on Pfs230 is based on two monoclonal antibodies (mAbs) with moderate transmission-reducing activity (TRA), elicited from subunit immunization. Here, we screened the B cell repertoire of two naturally exposed individuals possessing serum TRA and identified five potent mAbs from sixteen Pfs230 domain-1-specific mAbs. Structures of three potent and three low-activity antibodies bound to Pfs230 domain 1 revealed four distinct epitopes. Highly potent mAbs from natural infection recognized a common conformational epitope that is highly conserved across P. falciparum field isolates, while antibodies with negligible TRA derived from natural infection or immunization recognized three distinct sites. Our study provides molecular blueprints describing P. falciparum TRA, informed by contrasting potent and non-functional epitopes elicited by natural exposure and vaccination.ImmunityPotent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230.PMC9942874K24 AI113002864180U19 AI089674R01 AI093615K24 AI144048S10 OD012289Jore MMde Bruijni MIvanochko DGreenhouse BMacGill RSDuncan SSzabat MRichter King CSemesi AFabra-Garcia ALee SMFeeney MENewton JJagannathan Pvan de Vegte-Bolmer MKamya MRBolscher JSauerwein RWVogt SJulien JPKraft Lvan Gemert GJBousema TTeelen KRamjith JfalsePotent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230.Pfs230 is essential for Plasmodium falciparum transmission to mosquitoes and is the protein targeted by the most advanced malaria-transmission-blocking vaccine candidate. Prior understanding of functional epitopes on Pfs230 is based on two monoclonal antibodies (mAbs) with moderate transmission-reducing activity (TRA), elicited from subunit immunization. Here, we screened the B cell repertoire of two naturally exposed individuals possessing serum TRA and identified five potent mAbs from sixteen Pfs230 domain-1-specific mAbs. Structures of three potent and three low-activity antibodies bound to Pfs230 domain 1 revealed four distinct epitopes. Highly potent mAbs from natural infection recognized a common conformational epitope that is highly conserved across P. falciparum field isolates, while antibodies with negligible TRA derived from natural infection or immunization recognized three distinct sites. Our study provides molecular blueprints describing P. falciparum TRA, informed by contrasting potent and non-functional epitopes elicited by natural exposure and vaccination.2023-01-01T00:00:00Z2023 Feb2026-05-28T20:10:58.186Z2025-02-19T04:45:53.947ZS-EPMC99428743679257510.1016/j.immuni.2023.01.013