The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo

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 wh...

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Autores principales:	Yevel Flores-Garcia, Lawrence T. Wang, Minah Park, Beejan Asady, Azza H. Idris, Neville K. Kisalu, Christian Muñoz, Lais S. Pereira, Joseph R. Francica, Robert A. Seder, Fidel Zavala
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b17
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spelling	oai:doaj.org-article:111b6dad7a6b41a189095f7767ef2b172021-11-25T05:47:33ZThe P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo1553-73661553-7374https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b172021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601602/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Rare 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. Author summary Human monoclonal antibodies are a promising approach for preventing malaria. Highly potent human antibodies show preferential binding to the junction or minor repeat regions of the circumsporozoite protein (CSP) of P. falciparum and cross-react to repetitive (NANP) repeats. The requirement for these binding sites for mediating protection in vivo remains unknown. Here, using transgenic P. berghei parasites expressing PfCSP containing deletions of these junctional or minor epitopes, or PbCSP containing additions of these PfCSP epitopes, we demonstrate these epitopes are necessary and sufficient to mediate protection and don’t require cross-reactivity to the NANP repeats. Our findings establish a mechanism of antibody mediated protection in vivo to prevent malaria and provide the rationale for multi-epitope vaccines to increase the breadth of the antibody responses.Yevel Flores-GarciaLawrence T. WangMinah ParkBeejan AsadyAzza H. IdrisNeville K. KisaluChristian MuñozLais S. PereiraJoseph R. FrancicaRobert A. SederFidel ZavalaPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Yevel Flores-Garcia Lawrence T. Wang Minah Park Beejan Asady Azza H. Idris Neville K. Kisalu Christian Muñoz Lais S. Pereira Joseph R. Francica Robert A. Seder Fidel Zavala The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
description	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. Author summary Human monoclonal antibodies are a promising approach for preventing malaria. Highly potent human antibodies show preferential binding to the junction or minor repeat regions of the circumsporozoite protein (CSP) of P. falciparum and cross-react to repetitive (NANP) repeats. The requirement for these binding sites for mediating protection in vivo remains unknown. Here, using transgenic P. berghei parasites expressing PfCSP containing deletions of these junctional or minor epitopes, or PbCSP containing additions of these PfCSP epitopes, we demonstrate these epitopes are necessary and sufficient to mediate protection and don’t require cross-reactivity to the NANP repeats. Our findings establish a mechanism of antibody mediated protection in vivo to prevent malaria and provide the rationale for multi-epitope vaccines to increase the breadth of the antibody responses.
format	article
author	Yevel Flores-Garcia Lawrence T. Wang Minah Park Beejan Asady Azza H. Idris Neville K. Kisalu Christian Muñoz Lais S. Pereira Joseph R. Francica Robert A. Seder Fidel Zavala
author_facet	Yevel Flores-Garcia Lawrence T. Wang Minah Park Beejan Asady Azza H. Idris Neville K. Kisalu Christian Muñoz Lais S. Pereira Joseph R. Francica Robert A. Seder Fidel Zavala
author_sort	Yevel Flores-Garcia
title	The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
title_short	The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
title_full	The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
title_fullStr	The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
title_full_unstemmed	The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
title_sort	p. falciparum csp repeat region contains three distinct epitopes required for protection by antibodies in vivo
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b17
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The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo

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