Long-term passaging of replication competent pseudo-typed SARS-CoV-2 reveals the antiviral breadth of monoclonal and bispecific antibody cocktails

Zhu, J.; Ma, H.; Zong, H.; Liu, J.; Yue, Y.; Ke, Y.; Liao, Y.; Tang, H.; Wang, L.; Wang, S.; Yuan, Y.; Wu, M.; Bian, Y.; Zhang, B.; Yin, H.; Jiang, H.; Sun, T.; Han, L.; Xie, Y.

doi:10.1101/2022.10.05.511057

bioRxiv · 10.1101/2022.10.05.511057

Long-term passaging of replication competent pseudo-typed SARS-CoV-2 reveals the antiviral breadth of monoclonal and bispecific antibody cocktails

Zhu, J.·Ma, H.·Zong, H.·Liu, J.·Yue, Y.·Ke, Y.·Liao, Y.·Tang, H.·Wang, L.·Wang, S.·Yuan, Y.·Wu, M.·Bian, Y.·Zhang, B.·Yin, H.·Jiang, H.·Sun, T.·Han, L.·Xie, Y.

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Abstract

The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses challenges to the effectiveness of neutralizing antibodies. Rational design of antibody cocktails is a realizable approach addressing viral immune evasion. However, evaluating the breadth of antibody cocktails is essential for understanding the development potential. Here, based on a replication competent vesicular stomatitis virus model that incorporates the spike of SARS-CoV-2 (VSV-SARS-CoV-2), we evaluated the breadth of a number of antibody cocktails consisting of monoclonal antibodies and bispecific antibodies by long-term passaging the virus in the presence of the cocktails. Results from over two-month passaging of the virus showed that 9E12+10D4+2G1 and 7B9-9D11+2G1 from these cocktails were highly resistant to random mutation, and there was no breakthrough after 30 rounds of passaging. As a control, antibody REGN10933 was broken through in the third passage. Next generation sequencing was performed and several critical mutations related to viral evasion were identified. These mutations caused a decrease in neutralization efficiency, but the reduced replication rate and ACE2 susceptibility of the mutant virus suggested that they might not have the potential to become epidemic strains. The 9E12+10D4+2G1 and 7B9-9D11+2G1 cocktails that picked from the VSV-SARS-CoV-2 system efficiently neutralized all current variants of concern and variants of interest including the most recent variants Delta and Omicron, as well as SARS-CoV-1. Our results highlight the feasibility of using the VSV-SARS-CoV-2 system to develop SARS-CoV-2 antibody cocktails and provide a reference for the clinical selection of therapeutic strategies to address the mutational escape of SARS-CoV-2.

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Zhu, J., Ma, H., Zong, H., Liu, J., Yue, Y., Ke, Y., Liao, Y., Tang, H., Wang, L., Wang, S., Yuan, Y., Wu, M., Bian, Y., Zhang, B., Yin, H., Jiang, H., Sun, T., Han, L., Xie, Y.. 2022-10-06. Long-term passaging of replication competent pseudo-typed SARS-CoV-2 reveals the antiviral breadth of monoclonal and bispecific antibody cocktails. https://doi.org/10.1101/2022.10.05.511057

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