Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD

Yaozong Chen; Jérémie Prévost; Irfan Ullah; Hugo Romero; Veronique Lisi; William D Tolbert; Jonathan R Grover; Shilei Ding; Shang Yu Gong; Guillaume Beaudoin-Bussières; Romain Gasser; Mehdi Benlarbi; Dani Vézina; Sai Priya Anand; Debashree Chatterjee; Guillaume Goyette; Michael W Grunst; Ziwei Yang; Yuxia Bo; Fei Zhou; Kathie Béland; Xiaoyun Bai; Allison R Zeher; Rick K Huang; Dung N Nguyen; Rebekah Sherburn; Di Wu; Grzegorz Piszczek; Bastien Paré; Doreen Matthies; Di Xia; Jonathan Richard; Priti Kumar; Walther Mothes; Marceline Côté; Pradeep D Uchil; Vincent-Philippe Lavallée; Martin A Smith; Marzena Pazgier; Elie Haddad; Andrés Finzi

doi:10.1016/j.isci.2022.105783

Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD

Yaozong Chen, Jérémie Prévost, Irfan Ullah, Hugo Romero, Veronique Lisi, William D Tolbert, Jonathan R Grover, Shilei Ding, Shang Yu Gong, Guillaume Beaudoin-Bussières, Romain Gasser, Mehdi Benlarbi, Dani Vézina, Sai Priya Anand, Debashree Chatterjee, Guillaume Goyette, Michael W Grunst, Ziwei Yang, Yuxia Bo, Fei ZhouKathie Béland, Xiaoyun Bai, Allison R Zeher, Rick K Huang, Dung N Nguyen, Rebekah Sherburn, Di Wu, Grzegorz Piszczek, Bastien Paré, Doreen Matthies, Di Xia, Jonathan Richard, Priti Kumar, Walther Mothes, Marceline Côté, Pradeep D Uchil, Vincent-Philippe Lavallée, Martin A Smith, Marzena Pazgier, Elie Haddad, Andrés Finzi

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

Abstract

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

Original language	English
Pages (from-to)	105783
Journal	iScience
Volume	26
Issue number	1
DOIs	https://doi.org/10.1016/j.isci.2022.105783
State	Published - 20 Jan 2023
Externally published	Yes

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Chen, Y., Prévost, J., Ullah, I., Romero, H., Lisi, V., Tolbert, W. D., Grover, J. R., Ding, S., Gong, S. Y., Beaudoin-Bussières, G., Gasser, R., Benlarbi, M., Vézina, D., Anand, S. P., Chatterjee, D., Goyette, G., Grunst, M. W., Yang, Z., Bo, Y., ... Finzi, A. (2023). Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD. iScience, 26(1), 105783. https://doi.org/10.1016/j.isci.2022.105783

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title = "Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD",

abstract = "Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.",

author = "Yaozong Chen and J{\'e}r{\'e}mie Pr{\'e}vost and Irfan Ullah and Hugo Romero and Veronique Lisi and Tolbert, {William D} and Grover, {Jonathan R} and Shilei Ding and Gong, {Shang Yu} and Guillaume Beaudoin-Bussi{\`e}res and Romain Gasser and Mehdi Benlarbi and Dani V{\'e}zina and Anand, {Sai Priya} and Debashree Chatterjee and Guillaume Goyette and Grunst, {Michael W} and Ziwei Yang and Yuxia Bo and Fei Zhou and Kathie B{\'e}land and Xiaoyun Bai and Zeher, {Allison R} and Huang, {Rick K} and Nguyen, {Dung N} and Rebekah Sherburn and Di Wu and Grzegorz Piszczek and Bastien Par{\'e} and Doreen Matthies and Di Xia and Jonathan Richard and Priti Kumar and Walther Mothes and Marceline C{\^o}t{\'e} and Uchil, {Pradeep D} and Vincent-Philippe Lavall{\'e}e and Smith, {Martin A} and Marzena Pazgier and Elie Haddad and Andr{\'e}s Finzi",

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doi = "10.1016/j.isci.2022.105783",

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Chen, Y, Prévost, J, Ullah, I, Romero, H, Lisi, V, Tolbert, WD, Grover, JR, Ding, S, Gong, SY, Beaudoin-Bussières, G, Gasser, R, Benlarbi, M, Vézina, D, Anand, SP, Chatterjee, D, Goyette, G, Grunst, MW, Yang, Z, Bo, Y, Zhou, F, Béland, K, Bai, X, Zeher, AR, Huang, RK, Nguyen, DN, Sherburn, R, Wu, D, Piszczek, G, Paré, B, Matthies, D, Xia, D, Richard, J, Kumar, P, Mothes, W, Côté, M, Uchil, PD, Lavallée, V-P, Smith, MA, Pazgier, M, Haddad, E & Finzi, A 2023, 'Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD', iScience, vol. 26, no. 1, pp. 105783. https://doi.org/10.1016/j.isci.2022.105783

TY - JOUR

T1 - Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD

AU - Chen, Yaozong

AU - Prévost, Jérémie

AU - Ullah, Irfan

AU - Romero, Hugo

AU - Lisi, Veronique

AU - Tolbert, William D

AU - Grover, Jonathan R

AU - Ding, Shilei

AU - Gong, Shang Yu

AU - Beaudoin-Bussières, Guillaume

AU - Gasser, Romain

AU - Benlarbi, Mehdi

AU - Vézina, Dani

AU - Anand, Sai Priya

AU - Chatterjee, Debashree

AU - Goyette, Guillaume

AU - Grunst, Michael W

AU - Yang, Ziwei

AU - Bo, Yuxia

AU - Zhou, Fei

AU - Béland, Kathie

AU - Bai, Xiaoyun

AU - Zeher, Allison R

AU - Huang, Rick K

AU - Nguyen, Dung N

AU - Sherburn, Rebekah

AU - Wu, Di

AU - Piszczek, Grzegorz

AU - Paré, Bastien

AU - Matthies, Doreen

AU - Xia, Di

AU - Richard, Jonathan

AU - Kumar, Priti

AU - Mothes, Walther

AU - Côté, Marceline

AU - Uchil, Pradeep D

AU - Lavallée, Vincent-Philippe

AU - Smith, Martin A

AU - Pazgier, Marzena

AU - Haddad, Elie

AU - Finzi, Andrés

PY - 2023/1/20

Y1 - 2023/1/20

N2 - Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

AB - Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

U2 - 10.1016/j.isci.2022.105783

DO - 10.1016/j.isci.2022.105783

M3 - Article

C2 - 36514310

SN - 2589-0042

VL - 26

SP - 105783

JO - iScience

JF - iScience

IS - 1

ER -

Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD

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