Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape

Leander Witte, Viren A. Baharani, Fabian Schmidt, Zijun Wang, Alice Cho, Raphael Raspe, Camila Guzman-Cardozo, Frauke Muecksch, Marie Canis, Debby J. Park, Christian Gaebler, Marina Caskey, Michel C. Nussenzweig (), Theodora Hatziioannou () and Paul D. Bieniasz ()
Additional contact information
Leander Witte: The Rockefeller University
Viren A. Baharani: The Rockefeller University
Fabian Schmidt: The Rockefeller University
Zijun Wang: The Rockefeller University
Alice Cho: The Rockefeller University
Raphael Raspe: The Rockefeller University
Camila Guzman-Cardozo: The Rockefeller University
Frauke Muecksch: The Rockefeller University
Marie Canis: The Rockefeller University
Debby J. Park: The Rockefeller University
Christian Gaebler: The Rockefeller University
Marina Caskey: The Rockefeller University
Michel C. Nussenzweig: The Rockefeller University
Theodora Hatziioannou: The Rockefeller University
Paul D. Bieniasz: The Rockefeller University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Waves of SARS-CoV-2 infection have resulted from the emergence of viral variants with neutralizing antibody resistance mutations. Simultaneously, repeated antigen exposure has generated affinity matured B cells, producing broadly neutralizing receptor binding domain (RBD)-specific antibodies with activity against emergent variants. To determine how SARS-CoV-2 might escape these antibodies, we subjected chimeric viruses encoding spike proteins from ancestral, BA.1 or BA.2 variants to selection by 40 broadly neutralizing antibodies. We identify numerous examples of epistasis, whereby in vitro selected and naturally occurring substitutions in RBD epitopes that do not confer antibody resistance in the Wuhan-Hu-1 spike, do so in BA.1 or BA.2 spikes. As few as 2 or 3 of these substitutions in the BA.5 spike, confer resistance to nearly all of the 40 broadly neutralizing antibodies, and substantial resistance to plasma from most individuals. Thus, epistasis facilitates the acquisition of resistance to antibodies that remained effective against early omicron variants.

Date: 2023
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DOI: 10.1038/s41467-023-35927-0

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