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A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates

Placental malaria (PM) is a deadly syndrome most frequent and severe in first pregnancies. PM results from accumulation of Plasmodium falciparum-infected erythrocytes (IE) that express the surface antigen VAR2CSA and bind to chondroitin sulfate A (CSA) in the placenta. Women become PM-resistant over...

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Autores principales: Doritchamou, Justin YA, Renn, Jonathan P, Jenkins, Bethany, Mahamar, Almahamoudou, Dicko, Alassane, Fried, Michal, Duffy, Patrick E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959597/
https://www.ncbi.nlm.nih.gov/pubmed/35103596
http://dx.doi.org/10.7554/eLife.76264
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author Doritchamou, Justin YA
Renn, Jonathan P
Jenkins, Bethany
Mahamar, Almahamoudou
Dicko, Alassane
Fried, Michal
Duffy, Patrick E
author_facet Doritchamou, Justin YA
Renn, Jonathan P
Jenkins, Bethany
Mahamar, Almahamoudou
Dicko, Alassane
Fried, Michal
Duffy, Patrick E
author_sort Doritchamou, Justin YA
collection PubMed
description Placental malaria (PM) is a deadly syndrome most frequent and severe in first pregnancies. PM results from accumulation of Plasmodium falciparum-infected erythrocytes (IE) that express the surface antigen VAR2CSA and bind to chondroitin sulfate A (CSA) in the placenta. Women become PM-resistant over successive pregnancies as they develop anti-adhesion and anti-VAR2CSA antibodies, supporting VAR2CSA as the leading PM-vaccine candidate. However, the first VAR2CSA subunit vaccines failed to induce broadly neutralizing antibody and it is known that naturally acquired antibodies target both variant-specific and conserved epitopes. It is crucial to determine whether effective vaccines will require incorporation of many or only a single VAR2CSA variants. Here, IgG from multigravidae was sequentially purified on five full-length VAR2CSA ectodomain variants, thereby depleting IgG reactivity to each. The five VAR2CSA variants purified ~0.7% of total IgG and yielded both strain-transcending and strain-specific reactivity to VAR2CSA and IE-surface antigen. In two independent antibody purification/depletion experiments with permutated order of VAR2CSA variants, IgG purified on the first VAR2CSA antigen displayed broad cross-reactivity to both recombinant and native VAR2CSA variants, and inhibited binding of all isolates to CSA. IgG remaining after depletion on all variants showed significantly reduced binding-inhibition activity compared to initial total IgG. These findings demonstrate that a single VAR2CSA ectodomain variant displays conserved epitopes that are targeted by neutralizing (or binding-inhibitory) antibodies shared by multiple parasite strains, including maternal isolates. This suggests that a broadly effective PM-vaccine can be achieved with a limited number of VAR2CSA variants.
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spelling pubmed-89595972022-03-29 A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates Doritchamou, Justin YA Renn, Jonathan P Jenkins, Bethany Mahamar, Almahamoudou Dicko, Alassane Fried, Michal Duffy, Patrick E eLife Immunology and Inflammation Placental malaria (PM) is a deadly syndrome most frequent and severe in first pregnancies. PM results from accumulation of Plasmodium falciparum-infected erythrocytes (IE) that express the surface antigen VAR2CSA and bind to chondroitin sulfate A (CSA) in the placenta. Women become PM-resistant over successive pregnancies as they develop anti-adhesion and anti-VAR2CSA antibodies, supporting VAR2CSA as the leading PM-vaccine candidate. However, the first VAR2CSA subunit vaccines failed to induce broadly neutralizing antibody and it is known that naturally acquired antibodies target both variant-specific and conserved epitopes. It is crucial to determine whether effective vaccines will require incorporation of many or only a single VAR2CSA variants. Here, IgG from multigravidae was sequentially purified on five full-length VAR2CSA ectodomain variants, thereby depleting IgG reactivity to each. The five VAR2CSA variants purified ~0.7% of total IgG and yielded both strain-transcending and strain-specific reactivity to VAR2CSA and IE-surface antigen. In two independent antibody purification/depletion experiments with permutated order of VAR2CSA variants, IgG purified on the first VAR2CSA antigen displayed broad cross-reactivity to both recombinant and native VAR2CSA variants, and inhibited binding of all isolates to CSA. IgG remaining after depletion on all variants showed significantly reduced binding-inhibition activity compared to initial total IgG. These findings demonstrate that a single VAR2CSA ectodomain variant displays conserved epitopes that are targeted by neutralizing (or binding-inhibitory) antibodies shared by multiple parasite strains, including maternal isolates. This suggests that a broadly effective PM-vaccine can be achieved with a limited number of VAR2CSA variants. eLife Sciences Publications, Ltd 2022-02-01 /pmc/articles/PMC8959597/ /pubmed/35103596 http://dx.doi.org/10.7554/eLife.76264 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (https://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Immunology and Inflammation
Doritchamou, Justin YA
Renn, Jonathan P
Jenkins, Bethany
Mahamar, Almahamoudou
Dicko, Alassane
Fried, Michal
Duffy, Patrick E
A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
title A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
title_full A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
title_fullStr A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
title_full_unstemmed A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
title_short A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
title_sort single full-length var2csa ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959597/
https://www.ncbi.nlm.nih.gov/pubmed/35103596
http://dx.doi.org/10.7554/eLife.76264
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