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 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Yevel Flores-Garcia [verfasserIn] Lawrence T. Wang [verfasserIn] Minah Park [verfasserIn] Beejan Asady [verfasserIn] Azza H. Idris [verfasserIn] Neville K. Kisalu [verfasserIn] Christian Muñoz [verfasserIn] Lais S. Pereira [verfasserIn] Joseph R. Francica [verfasserIn] Robert A. Seder [verfasserIn] Fidel Zavala [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Übergeordnetes Werk:	In: PLoS Pathogens - Public Library of Science (PLoS), 2005, 17(2021), 11
Übergeordnetes Werk:	volume:17 ; year:2021 ; number:11

Links:	Link aufrufen Link aufrufen Journal toc Journal toc

Katalog-ID:	DOAJ06318575X

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245	1	4	\|a The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
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520			\|a 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.
653		0	\|a Immunologic diseases. Allergy
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700	0		\|a Minah Park \|e verfasserin \|4 aut
700	0		\|a Beejan Asady \|e verfasserin \|4 aut
700	0		\|a Azza H. Idris \|e verfasserin \|4 aut
700	0		\|a Neville K. Kisalu \|e verfasserin \|4 aut
700	0		\|a Christian Muñoz \|e verfasserin \|4 aut
700	0		\|a Lais S. Pereira \|e verfasserin \|4 aut
700	0		\|a Joseph R. Francica \|e verfasserin \|4 aut
700	0		\|a Robert A. Seder \|e verfasserin \|4 aut
700	0		\|a Fidel Zavala \|e verfasserin \|4 aut
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author_variant	y f g yfg l t w ltw m p mp b a ba a h i ahi n k k nkk c m cm l s p lsp j r f jrf r a s ras f z fz
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allfields	(DE-627)DOAJ06318575X (DE-599)DOAJ111b6dad7a6b41a189095f7767ef2b17 DE-627 ger DE-627 rakwb eng RC581-607 QH301-705.5 Yevel Flores-Garcia verfasserin aut The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Immunologic diseases. Allergy Biology (General) Lawrence T. Wang verfasserin aut Minah Park verfasserin aut Beejan Asady verfasserin aut Azza H. Idris verfasserin aut Neville K. Kisalu verfasserin aut Christian Muñoz verfasserin aut Lais S. Pereira verfasserin aut Joseph R. Francica verfasserin aut Robert A. Seder verfasserin aut Fidel Zavala verfasserin aut In PLoS Pathogens Public Library of Science (PLoS), 2005 17(2021), 11 (DE-627)501074422 (DE-600)2205412-1 15537374 nnns volume:17 year:2021 number:11 https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b17 kostenfrei https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601602/?tool=EBI kostenfrei https://doaj.org/toc/1553-7366 Journal toc kostenfrei https://doaj.org/toc/1553-7374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2021 11
spelling	(DE-627)DOAJ06318575X (DE-599)DOAJ111b6dad7a6b41a189095f7767ef2b17 DE-627 ger DE-627 rakwb eng RC581-607 QH301-705.5 Yevel Flores-Garcia verfasserin aut The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Immunologic diseases. Allergy Biology (General) Lawrence T. Wang verfasserin aut Minah Park verfasserin aut Beejan Asady verfasserin aut Azza H. Idris verfasserin aut Neville K. Kisalu verfasserin aut Christian Muñoz verfasserin aut Lais S. Pereira verfasserin aut Joseph R. Francica verfasserin aut Robert A. Seder verfasserin aut Fidel Zavala verfasserin aut In PLoS Pathogens Public Library of Science (PLoS), 2005 17(2021), 11 (DE-627)501074422 (DE-600)2205412-1 15537374 nnns volume:17 year:2021 number:11 https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b17 kostenfrei https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601602/?tool=EBI kostenfrei https://doaj.org/toc/1553-7366 Journal toc kostenfrei https://doaj.org/toc/1553-7374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2021 11
allfields_unstemmed	(DE-627)DOAJ06318575X (DE-599)DOAJ111b6dad7a6b41a189095f7767ef2b17 DE-627 ger DE-627 rakwb eng RC581-607 QH301-705.5 Yevel Flores-Garcia verfasserin aut The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Immunologic diseases. Allergy Biology (General) Lawrence T. Wang verfasserin aut Minah Park verfasserin aut Beejan Asady verfasserin aut Azza H. Idris verfasserin aut Neville K. Kisalu verfasserin aut Christian Muñoz verfasserin aut Lais S. Pereira verfasserin aut Joseph R. Francica verfasserin aut Robert A. Seder verfasserin aut Fidel Zavala verfasserin aut In PLoS Pathogens Public Library of Science (PLoS), 2005 17(2021), 11 (DE-627)501074422 (DE-600)2205412-1 15537374 nnns volume:17 year:2021 number:11 https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b17 kostenfrei https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601602/?tool=EBI kostenfrei https://doaj.org/toc/1553-7366 Journal toc kostenfrei https://doaj.org/toc/1553-7374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2021 11
allfieldsGer	(DE-627)DOAJ06318575X (DE-599)DOAJ111b6dad7a6b41a189095f7767ef2b17 DE-627 ger DE-627 rakwb eng RC581-607 QH301-705.5 Yevel Flores-Garcia verfasserin aut The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Immunologic diseases. Allergy Biology (General) Lawrence T. Wang verfasserin aut Minah Park verfasserin aut Beejan Asady verfasserin aut Azza H. Idris verfasserin aut Neville K. Kisalu verfasserin aut Christian Muñoz verfasserin aut Lais S. Pereira verfasserin aut Joseph R. Francica verfasserin aut Robert A. Seder verfasserin aut Fidel Zavala verfasserin aut In PLoS Pathogens Public Library of Science (PLoS), 2005 17(2021), 11 (DE-627)501074422 (DE-600)2205412-1 15537374 nnns volume:17 year:2021 number:11 https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b17 kostenfrei https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601602/?tool=EBI kostenfrei https://doaj.org/toc/1553-7366 Journal toc kostenfrei https://doaj.org/toc/1553-7374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2021 11
allfieldsSound	(DE-627)DOAJ06318575X (DE-599)DOAJ111b6dad7a6b41a189095f7767ef2b17 DE-627 ger DE-627 rakwb eng RC581-607 QH301-705.5 Yevel Flores-Garcia verfasserin aut The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Immunologic diseases. Allergy Biology (General) Lawrence T. Wang verfasserin aut Minah Park verfasserin aut Beejan Asady verfasserin aut Azza H. Idris verfasserin aut Neville K. Kisalu verfasserin aut Christian Muñoz verfasserin aut Lais S. Pereira verfasserin aut Joseph R. Francica verfasserin aut Robert A. Seder verfasserin aut Fidel Zavala verfasserin aut In PLoS Pathogens Public Library of Science (PLoS), 2005 17(2021), 11 (DE-627)501074422 (DE-600)2205412-1 15537374 nnns volume:17 year:2021 number:11 https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b17 kostenfrei https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601602/?tool=EBI kostenfrei https://doaj.org/toc/1553-7366 Journal toc kostenfrei https://doaj.org/toc/1553-7374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 17 2021 11
language	English
source	In PLoS Pathogens 17(2021), 11 volume:17 year:2021 number:11
sourceStr	In PLoS Pathogens 17(2021), 11 volume:17 year:2021 number:11
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Immunologic diseases. Allergy Biology (General)
isfreeaccess_bool	true
container_title	PLoS Pathogens
authorswithroles_txt_mv	Yevel Flores-Garcia @@aut@@ Lawrence T. Wang @@aut@@ Minah Park @@aut@@ Beejan Asady @@aut@@ Azza H. Idris @@aut@@ Neville K. Kisalu @@aut@@ Christian Muñoz @@aut@@ Lais S. Pereira @@aut@@ Joseph R. Francica @@aut@@ Robert A. Seder @@aut@@ Fidel Zavala @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	501074422
id	DOAJ06318575X
language_de	englisch
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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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callnumber-first	R - Medicine
author	Yevel Flores-Garcia
spellingShingle	Yevel Flores-Garcia misc RC581-607 misc QH301-705.5 misc Immunologic diseases. Allergy misc Biology (General) The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
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topic_title	RC581-607 QH301-705.5 The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
topic	misc RC581-607 misc QH301-705.5 misc Immunologic diseases. Allergy misc Biology (General)
topic_unstemmed	misc RC581-607 misc QH301-705.5 misc Immunologic diseases. Allergy misc Biology (General)
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title	The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
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title_full	The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
author_sort	Yevel Flores-Garcia
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author_browse	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
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title_sort	p. falciparum csp repeat region contains three distinct epitopes required for protection by antibodies in vivo
callnumber	RC581-607
title_auth	The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
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. 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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo
url	https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b17 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601602/?tool=EBI https://doaj.org/toc/1553-7366 https://doaj.org/toc/1553-7374
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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.</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Immunologic diseases. 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Kisalu</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Christian Muñoz</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Lais S. Pereira</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Joseph R. Francica</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Robert A. Seder</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Fidel Zavala</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">PLoS Pathogens</subfield><subfield code="d">Public Library of Science (PLoS), 2005</subfield><subfield code="g">17(2021), 11</subfield><subfield code="w">(DE-627)501074422</subfield><subfield code="w">(DE-600)2205412-1</subfield><subfield code="x">15537374</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:17</subfield><subfield code="g">year:2021</subfield><subfield code="g">number:11</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/111b6dad7a6b41a189095f7767ef2b17</subfield><subfield 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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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