SARS-CoV-2 Omicron subvariants exhibit distinct fusogenicity, but similar sensitivity, to pan-CoV fusion inhibitors

ABSTRACT

Continuous emergence of the Omicron variant, along with its subvariants, has caused an increasing number of infections, reinfections, and vaccine-breakthrough infections, seriously threatening human health. Recently, several new Omicron subvariants, such as BA.5, BA.2.75, BA.4.6, and BF.7, bearing distinct mutation profiles in their spike (S) proteins, have significantly increased their capacity to evade vaccine-induced immunity and have shown enhanced infectivity and transmissibility, quickly becoming dominant sublineages. In this study, we found the S proteins of these Omicron subvariants to have 2- to 4-fold more efficient membrane fusion kinetics than that of the original Omicron variant (BA.1), indicating that these novel Omicron subvariants might possess increased pathogenicity. We also identified that peptide-based pan-CoV fusion inhibitors, EK1 and EK1C4, showed equal efficacy against membrane fusion mediated by S proteins of the noted Omicron subvariants and infection by their pseudoviruses. Additionally, either immune sera induced by wild-type (WT) SARS-CoV-2 RBD-based vaccine or BA.2 convalescent sera showed potent synergism with EK1 against both WT SARS-CoV-2 and various Omicron subvariants, further suggesting that EK1-based fusion inhibitors are promising candidates for development as clinical antiviral agents against the currently circulating Omicron subvariants.

KEYWORDS:

• SARS-CoV-2
• Omicron subvariants
• fusogenicity
• cell–cell fusion
• fusion inhibitor

Acknowledgements

The authors thank Qian Wang at FDU SHMC for technical support. L.L., S.J. and Q.M. conceived, planned and supervised the experiments; S.X., L.W., F.J., X.Y., W.X., Q.W., X.L., and Z.H. performed the experiments and analyzed the data; S.X., L.W., and F.J. wrote the draft, while L.L. S.J. and Q.M. Y.Z. revised the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Key R&D Program of China under Grant number [2021YFC2300703 to L.L.]; National Natural Science Foundation of China under Grant numbers [92169112 and 82161138002 to S.J.; 82002142 to S.X.]; and Shanghai Municipal Science and Technology Major Project under Grant number [ZD2021CY001 to L.L, S.J and S.X.]; Program of Shanghai Academic/Technology Research Leader under Grant number [20XD1420300 to L.L].