Impaired potency of neutralizing antibodies against cell–cell fusion mediated by SARS-CoV-2

ABSTRACT

The SARS-CoV-2 Omicron subvariants have dominated the pandemic due to their high transmissibility and immune evasion conferred by the spike mutations. The Omicron subvariants can spread by cell-free virus infection and cell–cell fusion, the latter of which is more effective but has not been extensively investigated. In this study, we developed a simple and high-throughput assay that provides a rapid readout to quantify cell–cell fusion mediated by the SARS-CoV-2 spike proteins without using live or pseudotyped virus. This assay can be used to identify variants of concern and to screen for prophylactic and therapeutic agents. We further evaluated a panel of monoclonal antibodies (mAbs) and vaccinee sera against D614G and Omicron subvariants, finding that cell–cell fusion is substantially more resistant to mAb and serum inhibition than cell-free virus infection. Such results have important implications for the development of vaccines and antiviral antibody drugs against cell–cell fusion induced by SARS-CoV-2 spikes.

KEYWORDS:

• SARS-CoV-2
• omicron subvariants
• spike protein
• cell–cell fusion
• monoclonal antibody
• polyclonal serum
• neutralization
• antibody evasion

Acknowledgements

We thank C. Lu and the Columbia Center for Translational Immunology (CCTI) Flow Cytometry Core for their help with cell sorting.

Disclosure statement

L.L., and D.D.H. are inventors on patent applications (WO2021236998) or provisional patent applications (63/271,627) filed by Columbia University. D.D.H. is a co-founder of TaiMed Biologics and RenBio, consultant to WuXi Biologics and Brii Biosciences, and board director for Vicarious Surgical.

Additional information

Funding

This study was supported financially by the National Institutes of Health (Subcontract No. 0258-A709-4609 under Federal Contract No. 75N93021C00014).