Wang, Lawrence T.Pereira, LaisFlores-Garcia, YevelO Connor, JamesFlynn, Barbara JSchon, ArneHurlburt, NicholasDillon, MarlonYang, AnnieFabra-Garcia, AmandaIdris, AzzaCockburn, Ian2023-11-071074-7613http://hdl.handle.net/1885/305628Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.This work was supported by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute (HHSN261200800001E to A.S.), the Dutch Research Council (NWO) talent program veni (VI.Veni.192.171 to A.S.P.Y.), the Bill & Melinda Gates Foundation for N.K.H and M.P. (OPP1156262) and Y.F.-G. and F.Z., who also thank the Bloomberg Philanthropies for continued support.application/pdfen-AU© 2020 The authorsMonoclonal antibodiesPlasmodium falciparumcircumsporozoite proteinNVDP minor repeatssporozoitesmalaria vaccinespassive transfer202010.1016/j.immuni.2020.08.0142022-09-11