Cell Reports 42, 112014 | 11 JAN 2023

Heather M. Callaway, Kathryn M. Hastie, Sharon L. Schendel, Haoyang Li, Xiaoying Yu, Jeremy Shek, Tierra Buck, Sean Hui, Dan Bedinger, Camille Troup, S. Moses Dennison, Kan Li, Michael Alpert, Charles C. Bailey, Sharon Benzeno, Jody L. Bonnevier, Jin-Qiu Chen, Charm Chen, Hyeseon Cho, Peter D. Crompton, Vincent Dussupt, Kevin C. Entzminger, Yassine Ezzyat, Jonathan K. Fleming, Nick Geukens, Amy E. Gilbert, Yongjun Guan, Xiaojian Han, Christopher J. Harvey, Julia M. Hatler, Bryan Howie, Chao Hu, Ailong Huang, Maya Imbrechts, Aishun Jin, Nik Kamachi, Gladys Keitany, Mark Klinger, Jay K. Kolls, Shelly J. Krebs, Tingting Li, Feiyan Luo, Toshiaki Maruyama, Michael A. Meehl, Letzibeth Mendez-Rivera, Andrea Musa, C.J. Okumura, Benjamin E.R. Rubin, Aaron K. Sato, Meiying Shen, Anirudh Singh, Shuyi Song, Joshua Tan, Jeffrey M. Trimarchi, Dhruvkumar P. Upadhyay, Yingming Wang, Lei Yu, Tom Z. Yuan, Erik Yusko, Bjoern Peters, Georgia Tomaras, Erica Ollmann Saphire


  • 66/397 of CoVIC IgGs raised against earlier SARS-CoV-2 also neutralize Omicron
  • 14 of these recognize epitopes conserved in Omicron
  • Most others recognize highly mutated epitopes, retaining activity by binding bivalently
  • Cleavage of bivalent binding IgGs to Fabs abolishes Omicron neutralization


The SARS-CoV-2 Omicron Variant of Concern (VoC) and its sublineages contain 31-36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural IgGs, especially those in the receptor binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22-50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organization identical to trimeric spike.

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