SUMMARY
The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb1, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab2, S2X2593 and S2H974, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.
Competing Interest Statement
E.C., K.C., C.S., D.P., F.Z., A.D.M., A.L., L.P., M.S.P., D.C., H.K., J.N., N.F., J.diI., L.E.R., N.C., C.H.D., K.R.S., J.R.D., A.E.P., A.C., C.M., L.Y., D.S., L.S., L.A.P., C.H., A.T., H.W.V. and G.S. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. L.A.P. is a former employee and shareholder in Regeneron Pharmaceuticals. Regeneron provided no funding for this work. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. HYC reported consulting with Ellume, Pfizer, The Bill and Melinda Gates Foundation, Glaxo Smith Kline, and Merck. She has received research funding from Emergent Ventures, Gates Ventures, Sanofi Pasteur, The Bill and Melinda Gates Foundation, and support and reagents from Ellume and Cepheid outside of the submitted work. M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Footnotes
Live virus data are added to Figure 3 demonstrating that sotrovimab can effectively neutralize SARS-CoV-2 Omicron
