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The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
Authors:Yevel Flores-Garcia  Lawrence T Wang  Minah Park  Beejan Asady  Azza H Idris  Neville K Kisalu  Christian Muoz  Lais S Pereira  Joseph R Francica  Robert A Seder  Fidel Zavala
Institution:1. Johns Hopkins Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Malaria Research Institute, Baltimore, Maryland, United States of America;2. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;3. Medical Technology Department, Faculty of Health Science, University of Antofagasta, Antofagasta, Chile; Francis Crick Institute, UNITED KINGDOM
Abstract:Rare and potent monoclonal antibodies (mAbs) against the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) on infective sporozoites (SPZ) preferentially bind the PfCSP junctional tetrapeptide NPDP or NVDP minor repeats while cross-reacting with NANP central repeats in vitro. The extent to which each of these epitopes is required for protection in vivo is unknown. Here, we assessed whether junction-, minor repeat- and central repeat-preferring human mAbs (CIS43, L9 and 317 respectively) bound and protected against in vivo challenge with transgenic P. berghei (Pb) SPZ expressing either PfCSP with the junction and minor repeats knocked out (KO), or PbCSP with the junction and minor repeats knocked in (KI). In vivo protection studies showed that the junction and minor repeats are necessary and sufficient for CIS43 and L9 to neutralize KO and KI SPZ, respectively. In contrast, 317 required major repeats for in vivo protection. These data establish that human mAbs can prevent malaria infection by targeting three different protective epitopes (NPDP, NVDP, NANP) in the PfCSP repeat region. This report will inform vaccine development and the use of mAbs to passively prevent malaria.
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