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Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

Matthew McCallum, Alexandra C. Walls, Kaitlin R. Sprouse, John E. Bowen, Laura Rosen, Ha V. Dang, Anna deMarco, Nicholas Franko, Sasha W Tilles, Jennifer Logue, Marcos C. Miranda, Margaret Ahlrichs, Lauren Carter, Gyorgy Snell, Matteo Samuele Pizzuto, Helen Y. Chu, Wesley C. Van Voorhis, Davide Corti, David Veesler
doi: https://doi.org/10.1101/2021.08.11.455956
Matthew McCallum
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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Alexandra C. Walls
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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Kaitlin R. Sprouse
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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John E. Bowen
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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Laura Rosen
2Vir Biotechnology, San Francisco, CA 94158, USA
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Ha V. Dang
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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Anna deMarco
3Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Nicholas Franko
4Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195, USA
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Sasha W Tilles
5Center for Emerging and Re-emerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
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Jennifer Logue
4Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195, USA
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Marcos C. Miranda
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
6Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Margaret Ahlrichs
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
6Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Lauren Carter
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
6Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Gyorgy Snell
2Vir Biotechnology, San Francisco, CA 94158, USA
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Matteo Samuele Pizzuto
3Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Helen Y. Chu
4Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195, USA
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Wesley C. Van Voorhis
5Center for Emerging and Re-emerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
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Davide Corti
3Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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David Veesler
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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  • For correspondence: dveesler@uw.edu
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Abstract

Worldwide SARS-CoV-2 transmission leads to the recurrent emergence of variants, such as the recently described B.1.617.1 (kappa), B.1.617.2 (delta) and B.1.617.2+ (delta+). The B.1.617.2 (delta) variant of concern is causing a new wave of infections in many countries, mostly affecting unvaccinated individuals, and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing the impact of individual mutations on immune evasion. Mutations in the B.1.617.1 (kappa) and B.1.617.2 (delta) spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including an unexpected remodeling of the B.1.617.2 (delta) N-terminal domain. The binding affinity of the B.1.617.1 (kappa) and B.1.617.2 (delta) receptor-binding domain for ACE2 is comparable to the ancestral virus whereas B.1.617.2+ (delta+) exhibits markedly reduced affinity. We describe a previously uncharacterized class of N-terminal domain-directed human neutralizing monoclonal antibodies cross-reacting with several variants of concern, revealing a possible target for vaccine development.

Competing Interest Statement

A.D.M, M.S.P. and D.C. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. D.V. is a consultant for Vir Biotechnology Inc. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 12, 2021.
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Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants
Matthew McCallum, Alexandra C. Walls, Kaitlin R. Sprouse, John E. Bowen, Laura Rosen, Ha V. Dang, Anna deMarco, Nicholas Franko, Sasha W Tilles, Jennifer Logue, Marcos C. Miranda, Margaret Ahlrichs, Lauren Carter, Gyorgy Snell, Matteo Samuele Pizzuto, Helen Y. Chu, Wesley C. Van Voorhis, Davide Corti, David Veesler
bioRxiv 2021.08.11.455956; doi: https://doi.org/10.1101/2021.08.11.455956
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Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants
Matthew McCallum, Alexandra C. Walls, Kaitlin R. Sprouse, John E. Bowen, Laura Rosen, Ha V. Dang, Anna deMarco, Nicholas Franko, Sasha W Tilles, Jennifer Logue, Marcos C. Miranda, Margaret Ahlrichs, Lauren Carter, Gyorgy Snell, Matteo Samuele Pizzuto, Helen Y. Chu, Wesley C. Van Voorhis, Davide Corti, David Veesler
bioRxiv 2021.08.11.455956; doi: https://doi.org/10.1101/2021.08.11.455956

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