| Literature DB >> 32946741 |
Lawrence T Wang1, Lais S Pereira1, Yevel Flores-Garcia2, James O'Connor3, Barbara J Flynn1, Arne Schön4, Nicholas K Hurlburt5, Marlon Dillon1, Annie S P Yang6, Amanda Fabra-García6, Azza H Idris1, Bryan T Mayer5, Monica W Gerber5, Raphael Gottardo7, Rosemarie D Mason1, Nicole Cavett1, Reid B Ballard1, Neville K Kisalu1, Alvaro Molina-Cruz8, Jorgen Nelson9, Rachel Vistein1, Carolina Barillas-Mury8, Rogerio Amino10, David Baker9, Neil P King9, Robert W Sauerwein6, Marie Pancera5, Ian A Cockburn11, Fidel Zavala2, Joseph R Francica1, Robert A Seder12.
Abstract
Discovering 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.Entities:
Keywords: Monoclonal antibodies; NVDP minor repeats; Plasmodium falciparum; circumsporozoite protein; malaria vaccines; passive transfer; sporozoites
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Year: 2020 PMID： 32946741 PMCID： PMC7572793 DOI： 10.1016/j.immuni.2020.08.014
Source DB: PubMed Journal: Immunity ISSN： 1074-7613 Impact factor: 31.745