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. 2022 Mar;28(3):490-495.
doi: 10.1038/s41591-021-01678-y. Epub 2022 Jan 19.

An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by therapeutic monoclonal antibodies

Laura A VanBlargan  1 , John M Errico  2 , Peter J Halfmann  3 , Seth J Zost  4   5 , James E Crowe Jr  4   5   6 , Lisa A Purcell  7 , Yoshihiro Kawaoka  3   8   9 , Davide Corti  10 , Daved H Fremont  2   11   12 , Michael S Diamond  13   14   15   16   17
Affiliations

An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by therapeutic monoclonal antibodies

Laura A VanBlargan et al. Nat Med. 2022 Mar.

Abstract

The emergence of the highly transmissible B.1.1.529 Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is concerning for antibody countermeasure efficacy because of the number of mutations in the spike protein. In this study, we tested a panel of anti-receptor-binding domain monoclonal antibodies (mAbs) corresponding to those in clinical use by Vir Biotechnology (S309, the parent mAb of VIR-7831 (sotrovimab)), AstraZeneca (COV2-2196 and COV2-2130, the parent mAbs of AZD8895 and AZD1061), Regeneron (REGN10933 and REGN10987), Eli Lilly (LY-CoV555 and LY-CoV016) and Celltrion (CT-P59) for their ability to neutralize an infectious B.1.1.529 Omicron isolate. Several mAbs (LY-CoV555, LY-CoV016, REGN10933, REGN10987 and CT-P59) completely lost neutralizing activity against B.1.1.529 virus in both Vero-TMPRSS2 and Vero-hACE2-TMPRSS2 cells, whereas others were reduced (COV2-2196 and COV2-2130 combination, ~12-fold decrease) or minimally affected (S309). Our results suggest that several, but not all, of the antibodies in clinical use might lose efficacy against the B.1.1.529 Omicron variant.

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Conflict of interest statement

M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences and Carnival Corporation and is 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. J.E.C. has served as a consultant for Luna Biologics and Merck Sharp & Dohme, is on the Scientific Advisory Board of Meissa Vaccines and is the founder of IDBiologics. The Crowe laboratory has received sponsored research agreements from Takeda Vaccines, AstraZeneca and IDBiologics. Vanderbilt University has applied for patents related to two antibodies discussed in this paper. L.A.P. and D.C. are employees of Vir Biotechnology and may hold stock shares in Vir Biotechnology. L.A.P. is a former employee and shareholder in Regeneron Pharmaceuticals. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Neutralizing mAb epitopes on B.1.1.529.
a, b, SARS-CoV-2 spike trimer (PDB: 7C2L and PDB: 6W41). One spike protomer is highlighted, showing the NTD in orange, RBD in green, RBM in magenta and S2 portion of the molecule in blue (a). Close-up view of the RBD with the RBM outlined in magenta (b). Amino acids that are changed in B.1.1.529 compared to WA1/2020 are indicated in light green (a, b), with the exception of N679K and P681H, which were not modeled in the structures used. c–k, SARS-CoV-2 RBD bound by EUA mAbs COV2-2196 (c, PDB: 7L7D); COV2-2130 (d, PDB: 7L7E); S309 (e, PDB: 6WPS); REGN10987 (f, PDB: 6XDG); REGN10933 (g, PDB: 6XDG); LY-CoV555 (h, PDB: 7KMG); LY-CoV016 (i, PDB: 7C01); CT-P59 (j PDB: 7CM4); and SARS2-38 (k, PDB: 7MKM). Residues mutated in the B.1.1.529 RBD and contained in these mAbsʼ respective epitopes are shaded red, whereas those outside the epitope are shaded green. l, Multiple sequence alignment showing the epitope footprints of each EUA mAb on the SARS-CoV-2 RBD highlighted in cyan. B.1.1.529 RBD is shown in the top row, with sequence changes relative to the wild-type RBD highlighted red. A green diamond indicates the location of the N-linked glycan at residue 343. Stars below the alignment indicate hACE2 contact residues on the SARS-CoV-2 RBD. Source data
Fig. 2
Fig. 2. Neutralization of SARS-CoV-2 B.1.1.529 Omicron strain by mAbs in Vero-TMPRSS2 cells.
a–f, Neutralization curves in Vero-TMPRSS2 cells comparing the sensitivity of SARS-CoV-2 strains with the indicated mAbs (COV2-2196, COV2-2130, REGN10933, REGN10987, LY-CoV555, LY-CoV016, S309, CT-P59 and SARS2-38) with WA1/2020 D614G and B.1.1.529. Also shown are the neutralization curves for antibody cocktails (COV2-2196/COV2-2130, REGN10933/REGN10987 or LY-CoV555/LY-CoV016). For data with mAb combinations, the x axis represents the total concentration of mAb used. One representative experiment of three performed in technical duplicate is shown. Error bars indicate the range of technical replicates. Data (% relative infection) are normalized to a no-mAb control. g, Summary of EC50 values (ng ml−1) of neutralization of SARS-CoV-2 viruses (WA1/2020 D614G and B.1.1.529) performed in Vero-TMPRSS2 cells. Data are the geometric mean of three experiments. Blue shading: light, EC50 > 5,000 ng ml−1; dark, EC50 > 10,000 ng ml−1. h, Comparison of EC50 values by mAbs against WA1/2020 D614G and B.1.1.529 (three experiments; NS, not significant; ****P < 0.0001; two-way ANOVA with Sidak’s post test). Each symbol represents neutralization data from an individual experiment. Bars indicate mean values. The dotted line indicates the upper limit of dosing of the assay. Source data
Fig. 3
Fig. 3. Neutralization of SARS-CoV-2 B.1.1.529 Omicron strain by mAbs in Vero-hACE2-TMPRSS2 cells.
a–f, Neutralization curves in Vero-hACE2-TMPRSS2 cells comparing the sensitivity of SARS-CoV-2 strains with the indicated mAbs (S309, COV2-2196, COV2-2130, REGN10933, REGN10987, LY-CoV555, LY-CoV016, CT-P59 and SARS2-38) with WA1/2020 D614G and B.1.1.529. Also shown are the neutralization curves for antibody cocktails (COV2-2196/COV2-2130, REGN10933/REGN10987 or LY-CoV555/LY-CoV016). For data with mAb combinations, the x axis represents the total concentration of mAb used. One representative experiment of three performed in technical duplicate is shown. Error bars indicate range of technical replicates. Data (% relative infection) are normalized to a no-mAb control. g, Summary of EC50 values (ng ml−1) of neutralization of SARS-CoV-2 viruses (WA1/2020 D614G and B.1.1.529) performed in Vero-hACE2-TMPRSS2 cells. Data are the geometric mean of three experiments. Blue shading: light, EC50 > 5,000 ng ml−1; dark, EC50 > 10,000 ng ml−1. h, Comparison of EC50 values by mAbs against WA1/2020 D614G and B.1.1.529. i, j, Neutralization curves in Vero-hACE2-TMPRSS2 cells comparing WA1/2020 D614G and B.1.1.529 infection in the presence of AZD1061, AZD8895 and the combination AZD7442. h, j, Three experiments; ****P < 0.0001; two-way ANOVA with Sidak’s post test. Each symbol represents neutralization data from an individual experiment. Bars indicate mean values. The dotted line indicates the upper limit of dosing of the assay.
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