Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern

Wenwei Li; Yaozong Chen; Jérémie Prévost; Irfan Ullah; Maolin Lu; Shang Yu Gong; Alexandra Tauzin; Romain Gasser; Dani Vézina; Sai Priya Anand; Guillaume Goyette; Debashree Chaterjee; Shilei Ding; William D. Tolbert; Michael W. Grunst; Yuxia Bo; Shijian Zhang; Jonathan Richard; Fei Zhou; Rick K. Huang; Lothar Esser; Allison Zeher; Marceline Côté; Priti Kumar; Joseph Sodroski; Di Xia; Pradeep D. Uchil; Marzena Pazgier; Andrés Finzi; Walther Mothes

doi:10.1016/j.celrep.2021.110210

Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern

Wenwei Li, Yaozong Chen, Jérémie Prévost, Irfan Ullah, Maolin Lu, Shang Yu Gong, Alexandra Tauzin, Romain Gasser, Dani Vézina, Sai Priya Anand, Guillaume Goyette, Debashree Chaterjee, Shilei Ding, William D. Tolbert, Michael W. Grunst, Yuxia Bo, Shijian Zhang, Jonathan Richard, Fei Zhou, Rick K. HuangLothar Esser, Allison Zeher, Marceline Côté, Priti Kumar, Joseph Sodroski, Di Xia, Pradeep D. Uchil, Marzena Pazgier^*, Andrés Finzi^*, Walther Mothes^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

70 Scopus citations

Abstract

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the “RBD-up” position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among β-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

Original language	English
Article number	110210
Journal	Cell Reports
Volume	38
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2021.110210
State	Published - 11 Jan 2022
Externally published	Yes

Keywords

COVID-19
SARS-CoV-2
emerging variants of concern
epitopes
neutralizing antibodies
receptor-binding domain
β-coronaviruses

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10.1016/j.celrep.2021.110210

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Li, W., Chen, Y., Prévost, J., Ullah, I., Lu, M., Gong, S. Y., Tauzin, A., Gasser, R., Vézina, D., Anand, S. P., Goyette, G., Chaterjee, D., Ding, S., Tolbert, W. D., Grunst, M. W., Bo, Y., Zhang, S., Richard, J., Zhou, F., ... Mothes, W. (2022). Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern. Cell Reports, 38(2), Article 110210. https://doi.org/10.1016/j.celrep.2021.110210

@article{2f1b73df0ebe44b8b8dbd91e9f76052c,

title = "Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern",

abstract = "Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the “RBD-up” position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among β-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.",

keywords = "COVID-19, SARS-CoV-2, emerging variants of concern, epitopes, neutralizing antibodies, receptor-binding domain, β-coronaviruses",

author = "Wenwei Li and Yaozong Chen and J{\'e}r{\'e}mie Pr{\'e}vost and Irfan Ullah and Maolin Lu and Gong, {Shang Yu} and Alexandra Tauzin and Romain Gasser and Dani V{\'e}zina and Anand, {Sai Priya} and Guillaume Goyette and Debashree Chaterjee and Shilei Ding and Tolbert, {William D.} and Grunst, {Michael W.} and Yuxia Bo and Shijian Zhang and Jonathan Richard and Fei Zhou and Huang, {Rick K.} and Lothar Esser and Allison Zeher and Marceline C{\^o}t{\'e} and Priti Kumar and Joseph Sodroski and Di Xia and Uchil, {Pradeep D.} and Marzena Pazgier and Andr{\'e}s Finzi and Walther Mothes",

note = "Publisher Copyright: {\textcopyright} 2021",

year = "2022",

month = jan,

day = "11",

doi = "10.1016/j.celrep.2021.110210",

language = "English",

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Li, W, Chen, Y, Prévost, J, Ullah, I, Lu, M, Gong, SY, Tauzin, A, Gasser, R, Vézina, D, Anand, SP, Goyette, G, Chaterjee, D, Ding, S, Tolbert, WD, Grunst, MW, Bo, Y, Zhang, S, Richard, J, Zhou, F, Huang, RK, Esser, L, Zeher, A, Côté, M, Kumar, P, Sodroski, J, Xia, D, Uchil, PD, Pazgier, M, Finzi, A & Mothes, W 2022, 'Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern', Cell Reports, vol. 38, no. 2, 110210. https://doi.org/10.1016/j.celrep.2021.110210

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T1 - Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern

AU - Li, Wenwei

AU - Chen, Yaozong

AU - Prévost, Jérémie

AU - Ullah, Irfan

AU - Lu, Maolin

AU - Gong, Shang Yu

AU - Tauzin, Alexandra

AU - Gasser, Romain

AU - Vézina, Dani

AU - Anand, Sai Priya

AU - Goyette, Guillaume

AU - Chaterjee, Debashree

AU - Ding, Shilei

AU - Tolbert, William D.

AU - Grunst, Michael W.

AU - Bo, Yuxia

AU - Zhang, Shijian

AU - Richard, Jonathan

AU - Zhou, Fei

AU - Huang, Rick K.

AU - Esser, Lothar

AU - Zeher, Allison

AU - Côté, Marceline

AU - Kumar, Priti

AU - Sodroski, Joseph

AU - Xia, Di

AU - Uchil, Pradeep D.

AU - Pazgier, Marzena

AU - Finzi, Andrés

AU - Mothes, Walther

PY - 2022/1/11

Y1 - 2022/1/11

N2 - Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the “RBD-up” position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among β-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

AB - Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the “RBD-up” position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among β-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

KW - COVID-19

KW - SARS-CoV-2

KW - emerging variants of concern

KW - epitopes

KW - neutralizing antibodies

KW - receptor-binding domain

KW - β-coronaviruses

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DO - 10.1016/j.celrep.2021.110210

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AN - SCOPUS:85122020680

SN - 2211-1247

VL - 38

JO - Cell Reports

JF - Cell Reports

IS - 2

M1 - 110210

ER -

Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern

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Keywords

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