Structural changes in the SARS-CoV-2 spike E406W mutant escaping a clinical monoclonal antibody cocktail
Amin Addetia,
Young-Jun Park,
Tyler Starr,
Allison J. Greaney,
Kaitlin R. Sprouse,
John E. Bowen,
Sasha W. Tiles,
Wesley C. Van Voorhis,
Jesse D. Bloom,
Davide Corti,
Alexandra C. Walls,
David Veesler
Affiliations
Amin Addetia
Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA; Department of Biochemistry, University of Washington, Seattle, WA, USA
Young-Jun Park
Department of Biochemistry, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA
Tyler Starr
Howard Hughes Medical Institute, Seattle, WA 98195, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Allison J. Greaney
Howard Hughes Medical Institute, Seattle, WA 98195, USA
Kaitlin R. Sprouse
Department of Biochemistry, University of Washington, Seattle, WA, USA
John E. Bowen
Department of Biochemistry, University of Washington, Seattle, WA, USA
Sasha W. Tiles
Center 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
Wesley C. Van Voorhis
Center 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
Jesse D. Bloom
Howard Hughes Medical Institute, Seattle, WA 98195, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Davide Corti
Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
Alexandra C. Walls
Department of Biochemistry, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA
David Veesler
Department of Biochemistry, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA; Corresponding author
Summary: Continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is eroding antibody responses elicited by prior vaccination and infection. The SARS-CoV-2 receptor-binding domain (RBD) E406W mutation abrogates neutralization mediated by the REGEN-COV therapeutic monoclonal antibody (mAb) COVID-19 cocktail and the AZD1061 (COV2-2130) mAb. Here, we show that this mutation remodels the receptor-binding site allosterically, thereby altering the epitopes recognized by these three mAbs and vaccine-elicited neutralizing antibodies while remaining functional. Our results demonstrate the spectacular structural and functional plasticity of the SARS-CoV-2 RBD, which is continuously evolving in emerging SARS-CoV-2 variants, including currently circulating strains that are accumulating mutations in the antigenic sites remodeled by the E406W substitution.
