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© Research
Publication : Immunity

A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Immunity - 13 Oct 2020

Lawrence Wang, Lais Pereira, Yevel Flores-Garcia, James O'Connor, Barbara Flynn, Arne Schön, Nicholas Hurlburt, Marlon Dillon, Annie Yang, Amanda Fabra-García, Azza Idris, Bryan Mayer, Monica Gerber, Raphael Gottardo, Rosemarie Mason, Nicole Cavett, Reid Ballard, Neville Kisalu, Alvaro Molina-Cruz, Jorgen Nelson, Rachel Vistein, Carolina Barillas-Mury, Rogerio Amino, David Baker, Neil King, Robert Sauerwein, Marie Pancera, Ian Cockburn, Fidel Zavala, Joseph Francica, Robert Seder

Link to Pubmed [PMID] – 32946741

Link to HAL – pasteur-03265812

Link to DOI – 10.1016/j.immuni.2020.08.014

Immunity, 2020, 53 (4), pp.733-744.e8. ⟨10.1016/j.immuni.2020.08.014⟩

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.