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, Paul D. Bieniasz

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.
Original languageEnglish (US)
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 1 2023
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Chemistry
  • General Physics and Astronomy

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