B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV

Johannes F. Scheid; Christopher O. Barnes; Basak Eraslan; Andrew Hudak; Jennifer R. Keeffe; Lisa A. Cosimi; Eric M. Brown; Frauke Muecksch; Yiska Weisblum; Shuting Zhang; Toni Delorey; Ann E. Woolley; Fadi Ghantous; Sung Moo Park; Devan Phillips; Betsabeh Tusi; Kathryn E. Huey-Tubman; Alexander A. Cohen; Priyanthi N.P. Gnanapragasam; Kara Rzasa; Theodora Hatziioanno; Michael A. Durney; Xiebin Gu; Takuya Tada; Nathaniel R. Landau; Anthony P. West; Orit Rozenblatt-Rosen; Michael S. Seaman; Lindsey R. Baden; Daniel B. Graham; Jacques Deguine; Paul D. Bieniasz; Aviv Regev; Deborah Hung; Pamela J. Bjorkman; Ramnik J. Xavier

doi:10.1016/j.cell.2021.04.032

B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV

Johannes F. Scheid, Christopher O. Barnes, Basak Eraslan, Andrew Hudak, Jennifer R. Keeffe, Lisa A. Cosimi, Eric M. Brown, Frauke Muecksch, Yiska Weisblum, Shuting Zhang, Toni Delorey, Ann E. Woolley, Fadi Ghantous, Sung Moo Park, Devan Phillips, Betsabeh Tusi, Kathryn E. Huey-Tubman, Alexander A. Cohen, Priyanthi N.P. Gnanapragasam, Kara RzasaTheodora Hatziioanno, Michael A. Durney, Xiebin Gu, Takuya Tada, Nathaniel R. Landau, Anthony P. West, Orit Rozenblatt-Rosen, Michael S. Seaman, Lindsey R. Baden, Daniel B. Graham, Jacques Deguine, Paul D. Bieniasz, Aviv Regev, Deborah Hung, Pamela J. Bjorkman^*, Ramnik J. Xavier^*

^*Corresponding author for this work

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

63 Scopus citations

Abstract

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.

Original language	English
Pages (from-to)	3205-3221.e24
Journal	Cell
Volume	184
Issue number	12
DOIs	https://doi.org/10.1016/j.cell.2021.04.032
State	Published - 10 Jun 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

COVID-19
cryo-electron microscopy
disordered CDRH3
memory B cells
monoclonal antibodies
SARS-CoV cross-neutralization
single B cell genomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2021.04.032

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Scheid, J. F., Barnes, C. O., Eraslan, B., Hudak, A., Keeffe, J. R., Cosimi, L. A., Brown, E. M., Muecksch, F., Weisblum, Y., Zhang, S., Delorey, T., Woolley, A. E., Ghantous, F., Park, S. M., Phillips, D., Tusi, B., Huey-Tubman, K. E., Cohen, A. A., Gnanapragasam, P. N. P., ... Xavier, R. J. (2021). B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV. Cell, 184(12), 3205-3221.e24. https://doi.org/10.1016/j.cell.2021.04.032

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title = "B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV",

abstract = "Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.",

keywords = "COVID-19, cryo-electron microscopy, disordered CDRH3, memory B cells, monoclonal antibodies, SARS-CoV cross-neutralization, single B cell genomics",

author = "Scheid, {Johannes F.} and Barnes, {Christopher O.} and Basak Eraslan and Andrew Hudak and Keeffe, {Jennifer R.} and Cosimi, {Lisa A.} and Brown, {Eric M.} and Frauke Muecksch and Yiska Weisblum and Shuting Zhang and Toni Delorey and Woolley, {Ann E.} and Fadi Ghantous and Park, {Sung Moo} and Devan Phillips and Betsabeh Tusi and Huey-Tubman, {Kathryn E.} and Cohen, {Alexander A.} and Gnanapragasam, {Priyanthi N.P.} and Kara Rzasa and Theodora Hatziioanno and Durney, {Michael A.} and Xiebin Gu and Takuya Tada and Landau, {Nathaniel R.} and West, {Anthony P.} and Orit Rozenblatt-Rosen and Seaman, {Michael S.} and Baden, {Lindsey R.} and Graham, {Daniel B.} and Jacques Deguine and Bieniasz, {Paul D.} and Aviv Regev and Deborah Hung and Bjorkman, {Pamela J.} and Xavier, {Ramnik J.}",

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

year = "2021",

month = jun,

day = "10",

doi = "10.1016/j.cell.2021.04.032",

language = "אנגלית",

volume = "184",

pages = "3205--3221.e24",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

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}

Scheid, JF, Barnes, CO, Eraslan, B, Hudak, A, Keeffe, JR, Cosimi, LA, Brown, EM, Muecksch, F, Weisblum, Y, Zhang, S, Delorey, T, Woolley, AE, Ghantous, F, Park, SM, Phillips, D, Tusi, B, Huey-Tubman, KE, Cohen, AA, Gnanapragasam, PNP, Rzasa, K, Hatziioanno, T, Durney, MA, Gu, X, Tada, T, Landau, NR, West, AP, Rozenblatt-Rosen, O, Seaman, MS, Baden, LR, Graham, DB, Deguine, J, Bieniasz, PD, Regev, A, Hung, D, Bjorkman, PJ & Xavier, RJ 2021, 'B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV', Cell, vol. 184, no. 12, pp. 3205-3221.e24. https://doi.org/10.1016/j.cell.2021.04.032

TY - JOUR

T1 - B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV

AU - Scheid, Johannes F.

AU - Barnes, Christopher O.

AU - Eraslan, Basak

AU - Hudak, Andrew

AU - Keeffe, Jennifer R.

AU - Cosimi, Lisa A.

AU - Brown, Eric M.

AU - Muecksch, Frauke

AU - Weisblum, Yiska

AU - Zhang, Shuting

AU - Delorey, Toni

AU - Woolley, Ann E.

AU - Ghantous, Fadi

AU - Park, Sung Moo

AU - Phillips, Devan

AU - Tusi, Betsabeh

AU - Huey-Tubman, Kathryn E.

AU - Cohen, Alexander A.

AU - Gnanapragasam, Priyanthi N.P.

AU - Rzasa, Kara

AU - Hatziioanno, Theodora

AU - Durney, Michael A.

AU - Gu, Xiebin

AU - Tada, Takuya

AU - Landau, Nathaniel R.

AU - West, Anthony P.

AU - Rozenblatt-Rosen, Orit

AU - Seaman, Michael S.

AU - Baden, Lindsey R.

AU - Graham, Daniel B.

AU - Deguine, Jacques

AU - Bieniasz, Paul D.

AU - Regev, Aviv

AU - Hung, Deborah

AU - Bjorkman, Pamela J.

AU - Xavier, Ramnik J.

PY - 2021/6/10

Y1 - 2021/6/10

N2 - Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.

AB - Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.

KW - COVID-19

KW - cryo-electron microscopy

KW - disordered CDRH3

KW - memory B cells

KW - monoclonal antibodies

KW - SARS-CoV cross-neutralization

KW - single B cell genomics

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U2 - 10.1016/j.cell.2021.04.032

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VL - 184

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JO - Cell

JF - Cell

IS - 12

ER -

B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV

Abstract

Bibliographical note

Keywords

UN SDGs

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