In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)

Abstract Plasmodium falciparum malaria contributes to a significant global disease burden. Circumsporozoite protein (CSP), the most abundant sporozoite stage antigen, is a prime vaccine candidate. Inhibitory monoclonal antibodies (mAbs) against CSP map to either a short junctional sequence or the ce...

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Autores principales:	Merricka C. Livingstone, Alexis A. Bitzer, Alish Giri, Kun Luo, Rajeshwer S. Sankhala, Misook Choe, Xiaoyan Zou, S. Moses Dennison, Yuanzhang Li, William Washington, Viseth Ngauy, Georgia D. Tomaras, M. Gordon Joyce, Adrian H. Batchelor, Sheetij Dutta
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f735407d93c347bfbd54ca0405a5bab5
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spelling	oai:doaj.org-article:f735407d93c347bfbd54ca0405a5bab52021-12-02T13:20:11ZIn vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)10.1038/s41598-021-84622-x2045-2322https://doaj.org/article/f735407d93c347bfbd54ca0405a5bab52021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84622-xhttps://doaj.org/toc/2045-2322Abstract Plasmodium falciparum malaria contributes to a significant global disease burden. Circumsporozoite protein (CSP), the most abundant sporozoite stage antigen, is a prime vaccine candidate. Inhibitory monoclonal antibodies (mAbs) against CSP map to either a short junctional sequence or the central (NPNA)n repeat region. We compared in vitro and in vivo activities of six CSP-specific mAbs derived from human recipients of a recombinant CSP vaccine RTS,S/AS01 (mAbs 317 and 311); an irradiated whole sporozoite vaccine PfSPZ (mAbs CIS43 and MGG4); or individuals exposed to malaria (mAbs 580 and 663). RTS,S mAb 317 that specifically binds the (NPNA)n epitope, had the highest affinity and it elicited the best sterile protection in mice. The most potent inhibitor of sporozoite invasion in vitro was mAb CIS43 which shows dual-specific binding to the junctional sequence and (NPNA)n. In vivo mouse protection was associated with the mAb reactivity to the NANPx6 peptide, the in vitro inhibition of sporozoite invasion activity, and kinetic parameters measured using intact mAbs or their Fab fragments. Buried surface area between mAb and its target epitope was also associated with in vivo protection. Association and disconnects between in vitro and in vivo readouts has important implications for the design and down-selection of the next generation of CSP based interventions.Merricka C. LivingstoneAlexis A. BitzerAlish GiriKun LuoRajeshwer S. SankhalaMisook ChoeXiaoyan ZouS. Moses DennisonYuanzhang LiWilliam WashingtonViseth NgauyGeorgia D. TomarasM. Gordon JoyceAdrian H. BatchelorSheetij DuttaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Merricka C. Livingstone Alexis A. Bitzer Alish Giri Kun Luo Rajeshwer S. Sankhala Misook Choe Xiaoyan Zou S. Moses Dennison Yuanzhang Li William Washington Viseth Ngauy Georgia D. Tomaras M. Gordon Joyce Adrian H. Batchelor Sheetij Dutta In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)
description	Abstract Plasmodium falciparum malaria contributes to a significant global disease burden. Circumsporozoite protein (CSP), the most abundant sporozoite stage antigen, is a prime vaccine candidate. Inhibitory monoclonal antibodies (mAbs) against CSP map to either a short junctional sequence or the central (NPNA)n repeat region. We compared in vitro and in vivo activities of six CSP-specific mAbs derived from human recipients of a recombinant CSP vaccine RTS,S/AS01 (mAbs 317 and 311); an irradiated whole sporozoite vaccine PfSPZ (mAbs CIS43 and MGG4); or individuals exposed to malaria (mAbs 580 and 663). RTS,S mAb 317 that specifically binds the (NPNA)n epitope, had the highest affinity and it elicited the best sterile protection in mice. The most potent inhibitor of sporozoite invasion in vitro was mAb CIS43 which shows dual-specific binding to the junctional sequence and (NPNA)n. In vivo mouse protection was associated with the mAb reactivity to the NANPx6 peptide, the in vitro inhibition of sporozoite invasion activity, and kinetic parameters measured using intact mAbs or their Fab fragments. Buried surface area between mAb and its target epitope was also associated with in vivo protection. Association and disconnects between in vitro and in vivo readouts has important implications for the design and down-selection of the next generation of CSP based interventions.
format	article
author	Merricka C. Livingstone Alexis A. Bitzer Alish Giri Kun Luo Rajeshwer S. Sankhala Misook Choe Xiaoyan Zou S. Moses Dennison Yuanzhang Li William Washington Viseth Ngauy Georgia D. Tomaras M. Gordon Joyce Adrian H. Batchelor Sheetij Dutta
author_facet	Merricka C. Livingstone Alexis A. Bitzer Alish Giri Kun Luo Rajeshwer S. Sankhala Misook Choe Xiaoyan Zou S. Moses Dennison Yuanzhang Li William Washington Viseth Ngauy Georgia D. Tomaras M. Gordon Joyce Adrian H. Batchelor Sheetij Dutta
author_sort	Merricka C. Livingstone
title	In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)
title_short	In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)
title_full	In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)
title_fullStr	In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)
title_full_unstemmed	In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)
title_sort	in vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against plasmodium falciparum circumsporozoite protein (csp)
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f735407d93c347bfbd54ca0405a5bab5
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In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)

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