A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies

Chunyan Wang; Rien van Haperen; Javier Gutiérrez-Álvarez; Wentao Li; Nisreen M.A. Okba; Irina Albulescu; Ivy Widjaja; Brenda van Dieren; Raul Fernandez-Delgado; Isabel Sola; Daniel L. Hurdiss; Olalekan Daramola; Frank Grosveld; Frank J.M. van Kuppeveld; Bart L. Haagmans; Luis Enjuanes; Dubravka Drabek; B.J. Bosch

doi:10.1038/s41467-021-21968-w

A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies

Chunyan Wang, Rien van Haperen, Javier Gutiérrez-Álvarez, Wentao Li, Nisreen M.A. Okba, Irina Albulescu, Ivy Widjaja, Brenda van Dieren, Raul Fernandez-Delgado, Isabel Sola, Daniel L. Hurdiss, Olalekan Daramola, Frank Grosveld, Frank J.M. van Kuppeveld, Bart L. Haagmans, Luis Enjuanes, Dubravka Drabek, B.J. Bosch^*

^*Corresponding author for this work

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

116 Citations (Scopus)

Abstract

The coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry and the focus for development of protective antibodies and vaccines. Structural studies show exposed sites on the spike trimer that might be targeted by antibodies with cross-species specificity. Here we isolated two human monoclonal antibodies from immunized humanized mice that display a remarkable cross-reactivity against distinct spike proteins of betacoronaviruses including SARS-CoV, SARS-CoV-2, MERS-CoV and the endemic human coronavirus HCoV-OC43. Both cross-reactive antibodies target the stem helix in the spike S2 fusion subunit which, in the prefusion conformation of trimeric spike, forms a surface exposed membrane-proximal helical bundle. Both antibodies block MERS-CoV infection in cells and provide protection to mice from lethal MERS-CoV challenge in prophylactic and/or therapeutic models. Our work highlights an immunogenic and vulnerable site on the betacoronavirus spike protein enabling elicitation of antibodies with unusual binding breadth.

Original language	English
Article number	1715
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21968-w
Publication status	Published - 17 Mar 2021

Bibliographical note

Funding Information:
We thank dr. Yoshiharu Matsuura (Osaka University, Japan) for providing the luciferase-encoding VSV-G pseudotyped VSVΔG-luc virus, Volker Thiel (University of Bern, Switzerland) for providing the HCoV-HKU1 spike protein encoding plasmid and Ale-jandra Tortorici (Institute Pasteur, France) for providing MERS-CoV S ectodomain. We thank Jaap Willem Back from PEPSCAN Presto BV, Lelystad, the Netherlands for his assistance with the spike protein peptide microarray analysis. We thank Ludo Broos for technical support. This study was done within the framework of the Utrecht Molecular Immunology Hub - Utrecht University. Funding: The project was co-financed by a grant from the Zoonotic Anticipation and Preparedness Initiative [ZAPI project; Innovative Medicines Initiative (IMI) grant agreement no. 115760], with the assistance and financial support of IMI and the European Commission, and in-kind contributions from European Federation of Pharmaceutical Industries and Associations partners. This manuscript was part of the research programme of the Netherlands Centre for One Health (www.ncoh.nl). The collaboration project is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study was also partially financed by grants from the Ministry of Science and Innovation of Spain (BIO2016-75549-R AEI/FEDER, UE) and NIH (2PO1AIO6O699). The mice used to generate the mAbs produced in this study were provided by Harbour Antibodies BV, a daughter company of Harbour Biomed (http://www.harbourbiomed.com). Chunyan Wang was supported by a grant from the China Scholarship Council.

Publisher Copyright:
© 2021, The Author(s).

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Wang, C., van Haperen, R., Gutiérrez-Álvarez, J., Li, W., Okba, N. M. A., Albulescu, I., Widjaja, I., van Dieren, B., Fernandez-Delgado, R., Sola, I., Hurdiss, D. L., Daramola, O., Grosveld, F., van Kuppeveld, F. J. M., Haagmans, B. L., Enjuanes, L., Drabek, D., & Bosch, B. J. (2021). A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies. Nature Communications, 12(1), Article 1715. https://doi.org/10.1038/s41467-021-21968-w

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abstract = "The coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry and the focus for development of protective antibodies and vaccines. Structural studies show exposed sites on the spike trimer that might be targeted by antibodies with cross-species specificity. Here we isolated two human monoclonal antibodies from immunized humanized mice that display a remarkable cross-reactivity against distinct spike proteins of betacoronaviruses including SARS-CoV, SARS-CoV-2, MERS-CoV and the endemic human coronavirus HCoV-OC43. Both cross-reactive antibodies target the stem helix in the spike S2 fusion subunit which, in the prefusion conformation of trimeric spike, forms a surface exposed membrane-proximal helical bundle. Both antibodies block MERS-CoV infection in cells and provide protection to mice from lethal MERS-CoV challenge in prophylactic and/or therapeutic models. Our work highlights an immunogenic and vulnerable site on the betacoronavirus spike protein enabling elicitation of antibodies with unusual binding breadth.",

author = "Chunyan Wang and {van Haperen}, Rien and Javier Guti{\'e}rrez-{\'A}lvarez and Wentao Li and Okba, {Nisreen M.A.} and Irina Albulescu and Ivy Widjaja and {van Dieren}, Brenda and Raul Fernandez-Delgado and Isabel Sola and Hurdiss, {Daniel L.} and Olalekan Daramola and Frank Grosveld and {van Kuppeveld}, {Frank J.M.} and Haagmans, {Bart L.} and Luis Enjuanes and Dubravka Drabek and B.J. Bosch",

note = "Funding Information: We thank dr. Yoshiharu Matsuura (Osaka University, Japan) for providing the luciferase-encoding VSV-G pseudotyped VSVΔG-luc virus, Volker Thiel (University of Bern, Switzerland) for providing the HCoV-HKU1 spike protein encoding plasmid and Ale-jandra Tortorici (Institute Pasteur, France) for providing MERS-CoV S ectodomain. We thank Jaap Willem Back from PEPSCAN Presto BV, Lelystad, the Netherlands for his assistance with the spike protein peptide microarray analysis. We thank Ludo Broos for technical support. This study was done within the framework of the Utrecht Molecular Immunology Hub - Utrecht University. Funding: The project was co-financed by a grant from the Zoonotic Anticipation and Preparedness Initiative [ZAPI project; Innovative Medicines Initiative (IMI) grant agreement no. 115760], with the assistance and financial support of IMI and the European Commission, and in-kind contributions from European Federation of Pharmaceutical Industries and Associations partners. This manuscript was part of the research programme of the Netherlands Centre for One Health (www.ncoh.nl). The collaboration project is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study was also partially financed by grants from the Ministry of Science and Innovation of Spain (BIO2016-75549-R AEI/FEDER, UE) and NIH (2PO1AIO6O699). The mice used to generate the mAbs produced in this study were provided by Harbour Antibodies BV, a daughter company of Harbour Biomed (http://www.harbourbiomed.com). Chunyan Wang was supported by a grant from the China Scholarship Council. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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Wang, C, van Haperen, R, Gutiérrez-Álvarez, J, Li, W, Okba, NMA, Albulescu, I, Widjaja, I, van Dieren, B, Fernandez-Delgado, R, Sola, I, Hurdiss, DL, Daramola, O, Grosveld, F, van Kuppeveld, FJM, Haagmans, BL, Enjuanes, L, Drabek, D & Bosch, BJ 2021, 'A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies', Nature Communications, vol. 12, no. 1, 1715. https://doi.org/10.1038/s41467-021-21968-w

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T1 - A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies

AU - Wang, Chunyan

AU - van Haperen, Rien

AU - Gutiérrez-Álvarez, Javier

AU - Li, Wentao

AU - Okba, Nisreen M.A.

AU - Albulescu, Irina

AU - Widjaja, Ivy

AU - van Dieren, Brenda

AU - Fernandez-Delgado, Raul

AU - Sola, Isabel

AU - Hurdiss, Daniel L.

AU - Daramola, Olalekan

AU - Grosveld, Frank

AU - van Kuppeveld, Frank J.M.

AU - Haagmans, Bart L.

AU - Enjuanes, Luis

AU - Drabek, Dubravka

AU - Bosch, B.J.

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AB - The coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry and the focus for development of protective antibodies and vaccines. Structural studies show exposed sites on the spike trimer that might be targeted by antibodies with cross-species specificity. Here we isolated two human monoclonal antibodies from immunized humanized mice that display a remarkable cross-reactivity against distinct spike proteins of betacoronaviruses including SARS-CoV, SARS-CoV-2, MERS-CoV and the endemic human coronavirus HCoV-OC43. Both cross-reactive antibodies target the stem helix in the spike S2 fusion subunit which, in the prefusion conformation of trimeric spike, forms a surface exposed membrane-proximal helical bundle. Both antibodies block MERS-CoV infection in cells and provide protection to mice from lethal MERS-CoV challenge in prophylactic and/or therapeutic models. Our work highlights an immunogenic and vulnerable site on the betacoronavirus spike protein enabling elicitation of antibodies with unusual binding breadth.

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A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies

Abstract

Bibliographical note

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