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Cited by 1,290SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesAnimal Virus Infections Studies

Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2

Open access
Liu, Lihong, Iketani, Sho, Guo, Yicheng, Chan, Jasper F.-W., Wang, Maple, Liu, Liyuan, Luo, Yang, Chu, Hin +15 more·2022·Nature
DOI 10.1038/s41586-021-04388-0

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

The B.1.1.529/Omicron variant of SARS-CoV-2 was only recently detected in southern Africa, but its subsequent spread has been extensive, both regionally and globally 1. It is expected to become dominant in the coming weeks 2, probably due to enhanced transmissibility. A striking feature of this variant is the large number of spike mutations 3 that pose a threat to the efficacy of current COVID-19 vaccines and antibody therapies 4. This concern is amplified by the findings of our study. Here we found that B.1.1.529 is markedly resistant to neutralization by serum not only from patients who recovered from COVID-19, but also from individuals who were vaccinated with one of the four widely used COVID-19 vaccines. Even serum from individuals who were vaccinated and received a booster dose of mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies against all known epitope clusters on the spike protein, we noted that the activity of 17 out of the 19 antibodies tested were either abolished or impaired, including ones that are currently authorized or approved for use in patients. Moreover, we also identified four new spike mutations (S371L, N440K, G446S and Q493R) that confer greater antibody resistance on B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.

AI snapshot

Written from the paper’s full text.

TL;DR

The Omicron (B.1.1.529) variant of SARS-CoV-2 shows marked resistance to neutralization by convalescent and vaccinee sera and by most tested monoclonal antibodies, including authorized therapies. The study identifies four spike mutations—S371L, N440K, G446S, and Q493R—that contribute to this antibody escape.

Key findings

  • Convalescent sera from 10 individuals showed a >32-fold drop in ID50 against B.1.1.529 versus D614G, with only 2 samples above the limit of detection.
  • Vaccinee sera showed substantial losses: >21-fold for BNT162b2 and >8.6-fold for mRNA-1273; all Ad26.COV2.S and ChAdOx1 nCoV-19 samples were below the limit of detection except two Ad26.COV2.S samples from previously infected individuals. Boosted mRNA vaccinees showed a mean 6.5-fold decrease against B.1.1.529.
  • Among 19 monoclonal antibodies, 17 lost neutralizing activity completely or partially; class 1 and class 2 RBD antibodies decreased by more than 100-fold, while S309 and Brii-198 were spared. All four combination monoclonal antibody drugs in clinical use lost substantial activity.
  • Four previously undescribed mutations—S371L, N440K, G446S, and Q493R—conferred greater antibody resistance; S371L broadly affected neutralization by monoclonal antibodies in all four RBD classes.

Methods

  • Serum neutralization was tested using pseudoviruses and authentic SARS-CoV-2 isolates. Convalescent samples were collected in spring 2020 (9–120 days after symptoms); vaccinee samples included BNT162b2, mRNA-1273, Ad26.COV2.S, ChAdOx1 nCoV-19, and boosted mRNA recipients.
  • A panel of 19 monoclonal antibodies (17 RBD-directed, 2 NTD-directed) was tested against B.1.1.529 and B.1.1.529+R346K pseudoviruses, and against pseudoviruses carrying each of 34 individual spike mutations.
  • Neutralization curves and IC50 values were derived by nonlinear five-parameter dose-response fitting; P values were determined using two-tailed Wilcoxon matched-pairs signed-rank tests.

Limitations

  • The paper states that no statistical methods were used to predetermine sample size, experiments were not randomized, and investigators were not blinded to allocation during experiments and outcome assessment.
  • The paper notes that for BNT162b2 and mRNA-1273 groups, samples with high titres were specifically chosen so fold changes could be better quantified, and the difference in samples above the limit of detection may therefore be favourably biased.
  • Evident from the text: the study reports in vitro neutralization only and does not measure clinical protection, in vivo efficacy, or reinfection/breakthrough outcomes directly.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41586-021-04388-0

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 13 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    S371L broadly affected neutralization by monoclonal antibodies in all four RBD classes.

    “The most striking and perhaps unexpected finding was that S371L broadly affected neutralization by monoclonal antibodies in all four RBD classes”
    Quote in the paperSubstantial claim
  • Findingown data

    Convalescent serum from patients infected with WT SARS-CoV-2 showed a >32-fold reduction in neutralizing ID50 against B.1.1.529 compared with D614G, with only 2 of 10 samples above the limit of detection.

    “a significant drop (>32-fold) in 50% infectious dose (ID 50 ) titres was observed against B.1.1.529,with only two samples showing titres above the limit of detection (LOD)”
    • Also stated in: § Abstract · plain
      “Here we found that B.1.1.529is markedly resistant to neutralization by serum not only from patients who recovered from COVID-19, but also from individuals who were vaccinated with one of the four widely used COVID-19 vaccines.”
    Quote in the paperSubstantial claim
  • Findingown data

    Previous variants developed resistance to only NTD antibodies and class 1 and class 2 RBD antibodies.

    “previous variants developed resistance to only NTD antibodies and class 1 and class 2 RBD antibodies”
    Quote in the paperSubstantial claim
  • Findingown data

    Sera from individuals vaccinated with mRNA-1273 showed a >8.6-fold decrease in ID50 against B.1.1.529.

    “For the two mRNA-based vaccines, BNT162b2 and mRNA-1273, a >21-fold and >8.6-fold decrease in ID 50 was observed, respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    The activities of S309 and Brii-198 were spared against B.1.1.529.

    “The activities of S309 and Brii-198 were spared.”
    Quote in the paperSubstantial claim
  • May combine two claims. 6
  • The quote only partly states this claim. 3
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Using authentic SARS-CoV-2 isolates, neutralization of B.1.1.529 decreased >6.0-fold for fully vaccinated and >4.1-fold for boosted individuals.

    “Again, a substantial decrease in the neutralization of B.1.1.529was observed, with mean decreases of >6.0-fold and >4.1-fold for the fully vaccinated group and the boosted group, respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Q493R mediates resistance to CB6 (class 1) and to LY-CoV555 and 2-15 (class 2).

    “Q493R, which was previously shown to affect binding of CB6 and LY-CoV555 (ref.28 ) as well as polyclonal sera 29 , mediated resistance to CB6 (class 1) as well as to LY-CoV555 and 2-15 (class 2)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Starr, T. N., Greaney, A. J., Dingens, A. S. & Bloom, J. D. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016. Cell Rep. Med. 2, 100255 (2021). source

      Not checked in the free run.

    • cites [29] Amanat, F. et al. SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD, and S2. Cell 184, 3936–3948 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The B.1.1.529 spike protein contains >30 mutations, including at least 15 in the RBD.

    “its spike protein contains an alarming number of mutations (>30) (Fig. 1b and Extended Data Fig. 1), including at least 15 in the receptor-binding domain (RBD)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    B.1.1.529, with or without R346K, is nearly completely resistant to class 1 and class 2 RBD antibodies and substantially resistant to class 3 and class 4 RBD antibodies.

    “B.1.1.529,with or without R346K, has made a big mutational leap by becoming not only nearly completely resistant to class 1 and class 2 RBD antibodies, but also substantially resistant to both class 3 and class 4 RBD antibodies.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    B.1.1.529 has key spike mutations.

    “Key spike mutations found in the viruses isolated in the major lineage of B.1.1.529.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    B.1.1.529+R346K is resistant to neutralization by monoclonal antibodies.

    “Neutralization of D614G and B.1.1.529+R346Kpseudoviruses by RBD-directed and NTD-directed monoclonal antibodies.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The four new mutations were not previously known to have functional importance to neutralization.

    “revealed several mutations that were not previously known to have functional importance to neutralization”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    R346K is the defining mutation for the B.1.621/Mu variant.

    “which is the defining mutation for the B.1.621/Muvariant 27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Uriu, K. et al. Neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine serum. N. Engl. J. Med. 385, 2397–2399 (2021). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All viruses were first titrated to normalize the viral input between assays.

    “All viruses were first titrated to normalize the viral input between assays.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No statistical methods were used to predetermine sample size.

    “No statistical methods were used to predetermine sample size.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Authentic B.1.1.529 virus sequence was confirmed by next-generation sequencing before use.

    “Viruses were propagated in Vero-E6-TMPRSS2 cells and the sequence was confirmed by next-generation sequencing before use.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All participants provided written informed consent.

    “All of the participants provided written informed consent.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Samples with high titres against WT SARS-CoV-2 were specifically chosen to better quantify loss in activity against B.1.1.529.

    “Note that, whenever possible, we specifically chose samples with high titres against the WT strain of SARS-CoV-2 such that the loss in activity against B.1.1.529could be better quantified and the titres observed here should therefore be considered in that context.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All collections were conducted under protocols reviewed and approved by the Institutional Review Board of Columbia University.

    “All collections were conducted under protocols reviewed and approved by the Institutional Review Board of Columbia University.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The experiments were not randomized and the investigators were not blinded to allocation during experiments and outcome assessment.

    “The experiments were not randomized and the investigators were not blinded to allocation during experiments and outcome assessment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The data represent one out of two independent experiments.

    “Data represent one out of two independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Cytopathic effects were scored by plaque assay in a blinded manner.

    “Cytopathic effects were then scored by plaque assay in a blinded manner.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Q493R was previously shown to affect binding of CB6 and LY-CoV555 as well as polyclonal sera.

    “Q493R, which was previously shown to affect binding of CB6 and LY-CoV555 (ref.28 ) as well as polyclonal sera 29”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Starr, T. N., Greaney, A. J., Dingens, A. S. & Bloom, J. D. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016. Cell Rep. Med. 2, 100255 (2021). source

      Not checked in the free run.

    • cites [29] Amanat, F. et al. SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD, and S2. Cell 184, 3936–3948 (2021). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Variant sequences were verified by next-generation sequencing and manual inspection.

    “To verify the sequences of variants, next-generation sequencing libraries were prepared according to a low-volume Nextera sequencing protocol 43 and sequenced on the Illumina Miseq platform (single-end mode with 50 bp R1).”
    • Also stated in: § Additional information · plain
      “The resulting reads alignments were then visualized in the Integrative Genomics Viewer 46 and manually inspected to verify the fidelity of variants.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Baym, M. et al. Inexpensive multiplexed library preparation for megabase-sized genomes. PLoS ONE 10, e0128036 (2015). source

      Not checked in the free run.

    • cites [46] Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Cells were purchased from authenticated vendors and morphology was confirmed visually before use.

    “Cells were purchased from authenticated vendors and morphology was confirmed visually before use.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All cell lines tested mycoplasma negative.

    “All cell lines tested mycoplasma negative.”
    Quote in the paperNot a substantial claim
21 of 21

  • The authors state this as an assumption.

    Patients with COVID-19 in spring 2020 were infected with WT SARS-CoV-2.

    “who were presumably infected with the wild-type (WT) SARS-CoV-2”

  • The paper relies on this without support.

    In vitro neutralization activity of monoclonal antibodies predicts their clinical efficacy in patients.

    “probably abolishing or impairing their efficacy in patients”

  • The paper relies on this without support.

    Neutralizing antibody titres are a correlate of protection against SARS-CoV-2 infection.

    “Collectively, these results suggest that individuals who were previously infected or fully vaccinated remain at risk for B.1.1.529infection.”

  • The authors state this as an assumption.

    Convalescent plasma samples were infected by the WT strain of SARS-CoV-2.

    “These samples were collected at the beginning of the pandemic in early 2020 at Columbia University Irving Medical Center and are therefore assumed to be infection by the WT strain of SARS-CoV-2 (ref. 4 ).”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Vaccination with three doses of BNT162b2 may protect against Omicron-mediated COVID-19.

    “Similar findings suggest that vaccination with three doses of the mRNA vaccine BNT162b2 may protect against Omicron-mediated COVID-19.407,408”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [407]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Omicron doubling time conflicts with the cited reference title

    Minor

    The text gives a doubling time of 2-3 days and cites reference 2, whose title gives 3.2-3.6 days. The two ranges do not overlap.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Grabowski, F., Kochańczyk, M. & Lipniacki, T. Omicron strain spreads with the doubling time of 3.2—3.6 days in South Africa province of Gauteng that achieved herd immunity to Delta variant. Preprint at https://doi.org/10.1101/2021.12.08.21267494 (2021). · DOI

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Authors
Liu, L., Iketani, S., Guo, Y., Chan, J. F.-W., Wang, M., Liu, L., Luo, Y., Chu, H., Huang, Y., Nair, M. S., Yu, J., Chik, K. K.-H., Yuen, T. T.-T., Yoon, C., To, K. K.-W., Chen, H., Yin, M. T., Sobieszczyk, M. E., Huang, Y., Wang, H. H., Sheng, Z., Yuen, K.-Y., & Ho, D. D.
Affiliations
  • Aaron Diamond AIDS Research Center (US)
  • University of Hong Kong (HK)
  • Columbia University (US)
Corresponding author
Ho, David D.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-12-23
Volume
602
Issue
7898
Pages
676-681
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-04388-0
OpenAlex
W4220904663
Cited by
1,290
References
47
Citations by year
2026: 60 · 2025: 107 · 2024: 179 · 2023: 341 · 2022: 598 · 2021: 5
FWCI
89.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation (2032259)
  • Bill and Melinda Gates Foundation
  • JPB Foundation
  • Regeneron Pharmaceuticals
  • Irving Medical Center, Columbia University
  • National Institute of Allergy and Infectious Diseases
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
Keywords
Omicron variant, SARS-CoV-2, antibody escape, neutralizing antibodies, spike protein mutations, vaccine escape, COVID-19 vaccines, monoclonal antibodies, booster vaccination, serum neutralization
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, Antibodies, Monoclonal, Antibodies, Viral, Cell Line, Convalescence, Humans, Immune Sera, Models, Molecular, Mutation, Neutralization Tests, Evolution, Molecular, Inhibitory Concentration 50, Immune Evasion, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus

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