TY - JOUR
T1 - Proteo-Genomic Analysis Identifies Two Major Sites of Vulnerability on Ebolavirus Glycoprotein for Neutralizing Antibodies in Convalescent Human Plasma
AU - Gilchuk, Pavlo
AU - Guthals, Adrian
AU - Bonissone, Stefano R.
AU - Shaw, Jared B.
AU - Ilinykh, Philipp A.
AU - Huang, Kai
AU - Bombardi, Robin G.
AU - Liang, Jenny
AU - Grinyo, Ariadna
AU - Davidson, Edgar
AU - Chen, Elaine C.
AU - Gunn, Bronwyn M.
AU - Alter, Galit
AU - Saphire, Erica Ollmann
AU - Doranz, Benjamin J.
AU - Bukreyev, Alexander
AU - Zeitlin, Larry
AU - Castellana, Natalie
AU - Crowe, James E.
N1 - Publisher Copyright:
© Copyright © 2021 Gilchuk, Guthals, Bonissone, Shaw, Ilinykh, Huang, Bombardi, Liang, Grinyo, Davidson, Chen, Gunn, Alter, Saphire, Doranz, Bukreyev, Zeitlin, Castellana and Crowe.
PY - 2021/7/16
Y1 - 2021/7/16
N2 - Three clinically relevant ebolaviruses – Ebola (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) viruses, are responsible for severe disease and occasional deadly outbreaks in Africa. The largest Ebola virus disease (EVD) epidemic to date in 2013-2016 in West Africa highlighted the urgent need for countermeasures, leading to the development and FDA approval of the Ebola virus vaccine rVSV-ZEBOV (Ervebo®) in 2020 and two monoclonal antibody (mAb)-based therapeutics (Inmazeb® [atoltivimab, maftivimab, and odesivimab-ebgn] and Ebanga® (ansuvimab-zykl) in 2020. The humoral response plays an indispensable role in ebolavirus immunity, based on studies of mAbs isolated from the antibody genes in peripheral blood circulating ebolavirus-specific human memory B cells. However, antibodies in the body are not secreted by circulating memory B cells in the blood but rather principally by plasma cells in the bone marrow. Little is known about the protective polyclonal antibody responses in convalescent plasma. Here we exploited both single-cell antibody gene sequencing and proteomic sequencing approaches to assess the composition of the ebolavirus glycoprotein (GP)-reactive antibody repertoire in the plasma of an EVD survivor. We first identified 1,512 GP-specific mAb variable gene sequences from single cells in the memory B cell compartment. Using mass spectrometric analysis of the corresponding GP-specific plasma IgG, we found that only a portion of the large B cell antibody repertoire was represented in the plasma. Molecular and functional analysis of proteomics-identified mAbs revealed recognition of epitopes in three major antigenic sites - the GP head domain, the glycan cap, and the base region, with a high prevalence of neutralizing and protective mAb specificities that targeted the base and glycan cap regions on the GP. Polyclonal plasma antibodies from the survivor reacted broadly to EBOV, BDBV, and SUDV GP, while reactivity of the potently neutralizing mAbs we identified was limited mostly to the homologous EBOV GP. Together these results reveal a restricted diversity of neutralizing humoral response in which mAbs targeting two antigenic sites on GP – glycan cap and base – play a principal role in plasma-antibody-mediated protective immunity against EVD.
AB - Three clinically relevant ebolaviruses – Ebola (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) viruses, are responsible for severe disease and occasional deadly outbreaks in Africa. The largest Ebola virus disease (EVD) epidemic to date in 2013-2016 in West Africa highlighted the urgent need for countermeasures, leading to the development and FDA approval of the Ebola virus vaccine rVSV-ZEBOV (Ervebo®) in 2020 and two monoclonal antibody (mAb)-based therapeutics (Inmazeb® [atoltivimab, maftivimab, and odesivimab-ebgn] and Ebanga® (ansuvimab-zykl) in 2020. The humoral response plays an indispensable role in ebolavirus immunity, based on studies of mAbs isolated from the antibody genes in peripheral blood circulating ebolavirus-specific human memory B cells. However, antibodies in the body are not secreted by circulating memory B cells in the blood but rather principally by plasma cells in the bone marrow. Little is known about the protective polyclonal antibody responses in convalescent plasma. Here we exploited both single-cell antibody gene sequencing and proteomic sequencing approaches to assess the composition of the ebolavirus glycoprotein (GP)-reactive antibody repertoire in the plasma of an EVD survivor. We first identified 1,512 GP-specific mAb variable gene sequences from single cells in the memory B cell compartment. Using mass spectrometric analysis of the corresponding GP-specific plasma IgG, we found that only a portion of the large B cell antibody repertoire was represented in the plasma. Molecular and functional analysis of proteomics-identified mAbs revealed recognition of epitopes in three major antigenic sites - the GP head domain, the glycan cap, and the base region, with a high prevalence of neutralizing and protective mAb specificities that targeted the base and glycan cap regions on the GP. Polyclonal plasma antibodies from the survivor reacted broadly to EBOV, BDBV, and SUDV GP, while reactivity of the potently neutralizing mAbs we identified was limited mostly to the homologous EBOV GP. Together these results reveal a restricted diversity of neutralizing humoral response in which mAbs targeting two antigenic sites on GP – glycan cap and base – play a principal role in plasma-antibody-mediated protective immunity against EVD.
KW - convalescent plasma
KW - ebolavirus
KW - ebolavirus infection
KW - epitope mapping
KW - glycoprotein
KW - neutralizing antibodies
KW - proteo-genomics
KW - viral antibodies
UR - http://www.scopus.com/inward/record.url?scp=85111582950&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85111582950&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.706757
DO - 10.3389/fimmu.2021.706757
M3 - Article
C2 - 34335620
AN - SCOPUS:85111582950
SN - 1664-3224
VL - 12
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 706757
ER -