Broad betacoronavirus neutralization by a stem helix–specific human antibody

Dora Pinto; Maximilian M. Sauer; Nadine Czudnochowski; Jun Siong Low; M. Alejandra Tortorici; Michael P. Housley; Julia Noack; Alexandra C. Walls; John E. Bowen; Barbara Guarino; Laura E. Rosen; Julia di Iulio; Josipa Jerak; Hannah Kaiser; Saiful Islam; Stefano Jaconi; Nicole Sprugasci; Katja Culap; Rana Abdelnabi; Caroline Foo; Lotte Coelmont; Istvan Bartha; Siro Bianchi; Chiara Silacci-Fregni; Jessica Bassi; Roberta Marzi; Eneida Vetti; Antonino Cassotta; Alessandro Ceschi; Paolo Ferrari; Pietro E. Cippà; Olivier Giannini; Samuele Ceruti; Christian Garzoni; Agostino Riva; Fabio Benigni; Elisabetta Cameroni; Luca Piccoli; Matteo S. Pizzuto; Megan Smithey; David Hong; Amalio Telenti; Florian A. Lempp; Johan Neyts; Colin Havenar-Daughton; Antonio Lanzavecchia; Federica Sallusto; Gyorgy Snell; Herbert W. Virgin; Martina Beltramello; Davide Corti; David Veesler

doi:10.1126/science.abj3321

Broad betacoronavirus neutralization by a stem helix–specific human antibody

Dora Pinto, Maximilian M. Sauer, Nadine Czudnochowski, Jun Siong Low, M. Alejandra Tortorici, Michael P. Housley, Julia Noack, Alexandra C. Walls, John E. Bowen, Barbara Guarino, Laura E. Rosen, Julia di Iulio, Josipa Jerak, Hannah Kaiser, Saiful Islam, Stefano Jaconi, Nicole Sprugasci, Katja Culap, Rana Abdelnabi, Caroline FooLotte Coelmont, Istvan Bartha, Siro Bianchi, Chiara Silacci-Fregni, Jessica Bassi, Roberta Marzi, Eneida Vetti, Antonino Cassotta, Alessandro Ceschi, Paolo Ferrari, Pietro E. Cippà, Olivier Giannini, Samuele Ceruti, Christian Garzoni, Agostino Riva, Fabio Benigni, Elisabetta Cameroni, Luca Piccoli, Matteo S. Pizzuto, Megan Smithey, David Hong, Amalio Telenti, Florian A. Lempp, Johan Neyts, Colin Havenar-Daughton, Antonio Lanzavecchia, Federica Sallusto, Gyorgy Snell, Herbert W. Virgin, Martina Beltramello, Davide Corti, David Veesler

Immunobiology

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

238 Scopus citations

Abstract

The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.

Original language	English (US)
Pages (from-to)	1109-1116
Number of pages	8
Journal	Science
Volume	373
Issue number	6559
DOIs	https://doi.org/10.1126/science.abj3321
State	Published - Sep 3 2021

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Pinto, D., Sauer, M. M., Czudnochowski, N., Low, J. S., Alejandra Tortorici, M., Housley, M. P., Noack, J., Walls, A. C., Bowen, J. E., Guarino, B., Rosen, L. E., di Iulio, J., Jerak, J., Kaiser, H., Islam, S., Jaconi, S., Sprugasci, N., Culap, K., Abdelnabi, R., ... Veesler, D. (2021). Broad betacoronavirus neutralization by a stem helix–specific human antibody. Science, 373(6559), 1109-1116. https://doi.org/10.1126/science.abj3321

Pinto, D, Sauer, MM, Czudnochowski, N, Low, JS, Alejandra Tortorici, M, Housley, MP, Noack, J, Walls, AC, Bowen, JE, Guarino, B, Rosen, LE, di Iulio, J, Jerak, J, Kaiser, H, Islam, S, Jaconi, S, Sprugasci, N, Culap, K, Abdelnabi, R, Foo, C, Coelmont, L, Bartha, I, Bianchi, S, Silacci-Fregni, C, Bassi, J, Marzi, R, Vetti, E, Cassotta, A, Ceschi, A, Ferrari, P, Cippà, PE, Giannini, O, Ceruti, S, Garzoni, C, Riva, A, Benigni, F, Cameroni, E, Piccoli, L, Pizzuto, MS, Smithey, M, Hong, D, Telenti, A, Lempp, FA, Neyts, J, Havenar-Daughton, C, Lanzavecchia, A, Sallusto, F, Snell, G, Virgin, HW, Beltramello, M, Corti, D & Veesler, D 2021, 'Broad betacoronavirus neutralization by a stem helix–specific human antibody', Science, vol. 373, no. 6559, pp. 1109-1116. https://doi.org/10.1126/science.abj3321

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abstract = "The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.",

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T1 - Broad betacoronavirus neutralization by a stem helix–specific human antibody

AU - Pinto, Dora

AU - Sauer, Maximilian M.

AU - Czudnochowski, Nadine

AU - Low, Jun Siong

AU - Alejandra Tortorici, M.

AU - Housley, Michael P.

AU - Noack, Julia

AU - Walls, Alexandra C.

AU - Bowen, John E.

AU - Guarino, Barbara

AU - Rosen, Laura E.

AU - di Iulio, Julia

AU - Jerak, Josipa

AU - Kaiser, Hannah

AU - Islam, Saiful

AU - Jaconi, Stefano

AU - Sprugasci, Nicole

AU - Culap, Katja

AU - Abdelnabi, Rana

AU - Foo, Caroline

AU - Coelmont, Lotte

AU - Bartha, Istvan

AU - Bianchi, Siro

AU - Silacci-Fregni, Chiara

AU - Bassi, Jessica

AU - Marzi, Roberta

AU - Vetti, Eneida

AU - Cassotta, Antonino

AU - Ceschi, Alessandro

AU - Ferrari, Paolo

AU - Cippà, Pietro E.

AU - Giannini, Olivier

AU - Ceruti, Samuele

AU - Garzoni, Christian

AU - Riva, Agostino

AU - Benigni, Fabio

AU - Cameroni, Elisabetta

AU - Piccoli, Luca

AU - Pizzuto, Matteo S.

AU - Smithey, Megan

AU - Hong, David

AU - Telenti, Amalio

AU - Lempp, Florian A.

AU - Neyts, Johan

AU - Havenar-Daughton, Colin

AU - Lanzavecchia, Antonio

AU - Sallusto, Federica

AU - Snell, Gyorgy

AU - Virgin, Herbert W.

AU - Beltramello, Martina

AU - Corti, Davide

AU - Veesler, David

PY - 2021/9/3

Y1 - 2021/9/3

N2 - The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.

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Broad betacoronavirus neutralization by a stem helix–specific human antibody

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