Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes

Abstract Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt hu...

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Autores principales:	Roos M. de Jong, Lisette Meerstein-Kessel, Dari F. Da, Sandrine Nsango, Joseph D. Challenger, Marga van de Vegte-Bolmer, Geert-Jan van Gemert, Elias Duarte, Noam Teyssier, Robert W. Sauerwein, Thomas S. Churcher, Roch K. Dabire, Isabelle Morlais, Emily Locke, Martijn A. Huynen, Teun Bousema, Matthijs M. Jore
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/852c3163e8664f10865e9f61f43db532
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spelling	oai:doaj.org-article:852c3163e8664f10865e9f61f43db5322021-12-02T18:50:54ZMonoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes10.1038/s41541-021-00366-92059-0105https://doaj.org/article/852c3163e8664f10865e9f61f43db5322021-08-01T00:00:00Zhttps://doi.org/10.1038/s41541-021-00366-9https://doaj.org/toc/2059-0105Abstract Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt human-to-mosquito transmission and may form important tools for malaria elimination. Although most epitopes of these antigens are considered highly conserved, little is known about the impact of natural genetic diversity on the functional activity of transmission-blocking antibodies. Here we measured the efficacy of three mAbs against leading TBV candidates (Pfs48/45, Pfs25 and Pfs230) in transmission assays with parasites from naturally infected donors compared to their efficacy against the strain they were raised against (NF54). Transmission-reducing activity (TRA) was measured as reduction in mean oocyst intensity. mAb 45.1 (α-Pfs48/45) and mAb 4B7 (α-Pfs25) reduced transmission of field parasites from almost all donors with IC80 values similar to NF54. Sequencing of oocysts that survived high mAb concentrations did not suggest enrichment of escape genotypes. mAb 2A2 (α-Pfs230) only reduced transmission of parasites from a minority of the donors, suggesting that it targets a non-conserved epitope. Using six laboratory-adapted strains, we revealed that mutations in one Pfs230 domain correlate with mAb gamete surface binding and functional TRA. Our findings demonstrate that, despite the conserved nature of sexual stage antigens, minor sequence variation can significantly impact the efficacy of transmission-blocking mAbs. Since mAb 45.1 shows high potency against genetically diverse strains, our findings support its further clinical development and may inform Pfs48/45 vaccine design.Roos M. de JongLisette Meerstein-KesselDari F. DaSandrine NsangoJoseph D. ChallengerMarga van de Vegte-BolmerGeert-Jan van GemertElias DuarteNoam TeyssierRobert W. SauerweinThomas S. ChurcherRoch K. DabireIsabelle MorlaisEmily LockeMartijn A. HuynenTeun BousemaMatthijs M. JoreNature PortfolioarticleImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Vaccines, Vol 6, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Roos M. de Jong Lisette Meerstein-Kessel Dari F. Da Sandrine Nsango Joseph D. Challenger Marga van de Vegte-Bolmer Geert-Jan van Gemert Elias Duarte Noam Teyssier Robert W. Sauerwein Thomas S. Churcher Roch K. Dabire Isabelle Morlais Emily Locke Martijn A. Huynen Teun Bousema Matthijs M. Jore Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes
description	Abstract Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt human-to-mosquito transmission and may form important tools for malaria elimination. Although most epitopes of these antigens are considered highly conserved, little is known about the impact of natural genetic diversity on the functional activity of transmission-blocking antibodies. Here we measured the efficacy of three mAbs against leading TBV candidates (Pfs48/45, Pfs25 and Pfs230) in transmission assays with parasites from naturally infected donors compared to their efficacy against the strain they were raised against (NF54). Transmission-reducing activity (TRA) was measured as reduction in mean oocyst intensity. mAb 45.1 (α-Pfs48/45) and mAb 4B7 (α-Pfs25) reduced transmission of field parasites from almost all donors with IC80 values similar to NF54. Sequencing of oocysts that survived high mAb concentrations did not suggest enrichment of escape genotypes. mAb 2A2 (α-Pfs230) only reduced transmission of parasites from a minority of the donors, suggesting that it targets a non-conserved epitope. Using six laboratory-adapted strains, we revealed that mutations in one Pfs230 domain correlate with mAb gamete surface binding and functional TRA. Our findings demonstrate that, despite the conserved nature of sexual stage antigens, minor sequence variation can significantly impact the efficacy of transmission-blocking mAbs. Since mAb 45.1 shows high potency against genetically diverse strains, our findings support its further clinical development and may inform Pfs48/45 vaccine design.
format	article
author	Roos M. de Jong Lisette Meerstein-Kessel Dari F. Da Sandrine Nsango Joseph D. Challenger Marga van de Vegte-Bolmer Geert-Jan van Gemert Elias Duarte Noam Teyssier Robert W. Sauerwein Thomas S. Churcher Roch K. Dabire Isabelle Morlais Emily Locke Martijn A. Huynen Teun Bousema Matthijs M. Jore
author_facet	Roos M. de Jong Lisette Meerstein-Kessel Dari F. Da Sandrine Nsango Joseph D. Challenger Marga van de Vegte-Bolmer Geert-Jan van Gemert Elias Duarte Noam Teyssier Robert W. Sauerwein Thomas S. Churcher Roch K. Dabire Isabelle Morlais Emily Locke Martijn A. Huynen Teun Bousema Matthijs M. Jore
author_sort	Roos M. de Jong
title	Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes
title_short	Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes
title_full	Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes
title_fullStr	Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes
title_full_unstemmed	Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes
title_sort	monoclonal antibodies block transmission of genetically diverse plasmodium falciparum strains to mosquitoes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/852c3163e8664f10865e9f61f43db532
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Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes

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