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Cited by 881SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections Studiesvaccines and immunoinformatics approaches

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Open access
Chen, Rita E., Zhang, Xianwen, Case, James Brett, Winkler, Emma S., Liu, Yang, VanBlargan, Laura A., Liu, Jianying, Errico, John M. +24 more·2021·Nature Medicine
DOI 10.1038/s41591-021-01294-wPMC PMC8058618

Published version of a preprint

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.

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Crossref · 10.1038/s41591-021-01294-w

Cites

59 of 60 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 14 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Wash SA-B.1.351 chimeric virus has South African spike gene with D80A, 242-244 deletion, R246I, K417N, E484K, N501Y, D614G, A701V.

    “We created a chimeric, fully-infectious SARS-CoV-2 with a South African spike gene (Wash SA-B.1.351; D80A, 242–244 deletion, R246I, K417N, E484K, N501Y, D614G, and A701V)”
    Quote in the paperSubstantial claim
  • Findingown data

    E484K plus N501Y caused 6-13 fold reductions in activity of class 1 mAbs COV2-2196, COV2-3025, COV2-2381, S2E12.

    “The combination of E484K and N501Y mutations, which is present in the circulating South African B.1.351 and Brazilian B.1.1.248 strains, showed even greater effects (6- to 13-fold reductions) on the activity of class 1 mAbs COV2–2196, COV2–3025, COV2–2381, and S2E12 mAbs”
    Quote in the paperSubstantial claim
  • Findingown data

    With D614G, neutralization by majority of class 1 and class 2 mAbs was similar in Vero-hACE2-TMPRSS2 and Vero-TMPRSS2 cells.

    “With the D614G strain, neutralization by the majority of class 1 and class 2 mAbs was similar in Vero-hACE2-TMPRSS2 and Vero-TMPRSS2 cells.”
    Quote in the paperSubstantial claim
  • Findingown data

    P681H and 69-70 deletion had marginal effects on neutralization potency of evaluated RBM and RBD mAbs.

    “The P681H mutation (in the C-terminal region of S1) and the 69–70 deletion (in the NTD) had marginal effects on neutralization potency of the RBM and RBD mAbs we evaluated.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Many highly neutralizing mAbs binding RBD or NTD, and most convalescent and mRNA vaccine-induced sera, showed reduced inhibition of viruses with E484K.

    “Many highly neutralizing mAbs engaging the receptor binding domain (RBD) or N-terminal domain (NTD), and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation.”
    Quote in the paperSubstantial claim
  • May combine two claims. 18
  • The quote only partly states this claim. 3
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data

    E484K reduced potency of class 1 antibodies: COV2-2196, COV2-3025, COV2-2381, S2E12 showed 4-5 fold reduced activity; COV2-2050, 1B07, COVOX-384, S2H58 lost virtually all neutralizing potential.

    “Compared to the D614G virus, mAbs COV2–2196, COV2–3025, COV2–2381 and S2E12 showed 4- to 5-fold reduced activity against the E484K virus, and COV2–2050, 1B07, COVOX-384, and S2H58 lost virtually all neutralizing potential”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    K417N caused ~27-fold reduction in neutralization by COVOX-40 but did not negatively affect other mAbs in panel.

    “The K417N mutation resulted in ~27-fold reduction in neutralization by mAb COVOX-40 but did not negatively affect other mAbs in our panel.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The N501Y substitution modestly lowered inhibition by COVOX-40, SARS2-31, and SARS2-10, while other mAbs were largely unaffected.

    “Mutation at N501Y reduced the neutralizing activity of COVOX-40, SARS2–31, and SARS2–10 slightly but did not alter the potency of other mAbs substantively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    B.1.1.7 isolate had spike changes including 69-70 and 144-145 deletions and N501Y, A570D, D614G, P681H.

    “A B.1.1.7 isolate had signature changes in the spike gene14 including the 69–70 and 144–145 deletions, and N501Y, A570D, D614G, and P681H substitutions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Leung, K., Shum, M.H., Leung, G.M., Lam, T.T. & Wu, J.T. Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, October to November 2020. Euro Surveill. https://doi.org/10.2807/1560-7917.ES.2020.26.1.2002106 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    S309 binds avidly to B.1.1.7 spike on cell surface and potently neutralizes VSV pseudotyped with B.1.1.7 spike in Vero E6 cells or WA1/2020 virus derived in Vero CCL81 cells tested on Vero-hACE2-TMPRSS2 or Vero-TMPRSS2 cells.

    “The reduced potency of S309 mAb against B.1.1.7 strain in Vero-hACE2-TMPRSS2 cells contrasts with data showing it binds avidly to the B.1.1.7 spike protein on the surface of cells and potently neutralizes a vesicular stomatitis virus (VSV) pseudotyped with B.1.1.7 spike protein in Vero E6 cells or a WA1/2020 virus derived in Vero CCL81 cells and tested on Vero-hACE2-TMPRSS2 or Vero-TMPRSS2 cells (”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    On Vero-TMPRSS2 cells, mAbs COV2-2381, S2E12, S2X259 showed small reductions (2.5-6 fold) against B.1.1.7 but remained highly neutralizing.

    “Nonetheless, we observed some small reductions in potency (2.5- to 6-fold) with mAbs COV2–2381, S2E12, and S2X259 on Vero-TMPRSS2 cells, although they remained highly neutralizing.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Hamster vaccine sera showed no statistically significant differences with K417N and B.1.1.7 viruses.

    “Statistically significant differences in neutralization were not observed with K417N and B.1.1.7 viruses (Fig 3f, g).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Human convalescent serum (n=10) showed smaller yet significant decrease (2.5-fold, P<0.01) in neutralization against Wash BR-B.1.1.248.

    “Nonetheless, we observed a smaller yet significant decrease (2.5-fold, P < 0.01) in neutralization potency of convalescent serum against Wash BR-B.1.1.248 (Fig 2g–h and Extended Data Fig 4).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    For some selected anti-SARS-CoV-2 human mAbs, neutralization of Wash BR-B.1.1.248 was virtually completely lost, with EC50 > 10,000 ng/mL.

    “Blue shading of cells shows virtually complete loss of neutralizing activity: EC50 > 10,000 ng/mL.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mouse vaccine sera showed decreases with E484K/N501Y (9-fold, P<0.001), K417N/E484K/N501Y (5-fold, P<0.01), and Wash SA-B.1.351 (5-fold, P<0.01).

    “decreases with E484K/N501Y (9-fold, P < 0.001; Fig 3c), K417N/E484K/N501Y (5-fold, P < 0.01; Fig 3d), and Wash SA-B.1.351 (5-fold, P < 0.01; Fig 3e)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BNT162b2 vaccine sera showed larger decrease against Wash SA-B.1.351 (10-fold, P<0.0001), with all subjects showing substantially reduced potency.

    “and larger decreases in activity against Wash SA-B.1.351 (10-fold, P < 0.0001; Fig 4d), with all subjects showing substantially reduced potency (Fig 4f)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Human convalescent sera had lower neutralization titers against E484K/N501Y (5-fold), K417N/E484K/N501Y (3.5-fold), and Wash SA-B.1.351 (4.6-fold) compared to WA1/2020 D614G.

    “serum neutralization titers were lower against E484K/N501Y (5-fold, P < 0.0001), K417N/E484K/N501Y (3.5-fold, P < 0.0001), and Wash SA-B.1.351 (4.6-fold, P < 0.0001) viruses (Fig 2c–e), all of which contain the E484K mutation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    S309 + S2E12 combination showed reduced (~10-fold) potency against E484K/N501Y/D614G but performed effectively against Wash SA-B.1.351.

    “Although the S309 + S2E12 combination showed reduced (~10-fold) potency against the E484K/N501Y/D614G strain, it performed effectively against the Wash SA-B.1.351 virus”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BNT162b2 vaccine sera showed moderate reductions against B.1.1.7 (2-fold, P<0.01) and E484K/N501Y (4-fold, P<0.0001).

    “we observed moderate reductions in neutralizing activity (GMTs) of B.1.1.7 (2-fold, P < 0.01; Fig 4a) and E484K/N501Y (4-fold, P < 0.0001; Fig 4c)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    All viruses were low passage and deep sequenced to confirm expected mutations and absence of cell type-dependent adaptations.

    “All viruses were used at low passage (p0 or p1) and deep sequenced to confirm the presence of expected mutations and an absence of cell type-dependent adaptations (Supplementary Table S1).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The human monoclonal antibodies analyzed in this work came from blood donated by people in North America or Europe who had previously had laboratory-confirmed symptomatic SARS-CoV or SARS-CoV-2 infection.

    “The human mAbs studied in this paper (COV2–2196, COV2–2072, COV2–2050, COV2–2381, COV2–2130, COVOX-384, COVOX-40, S309, S2E12, S2H58, S2X333, VIR-7381, and S2X259) were isolated from blood samples from individuals in North America or Europe with previous laboratory-confirmed symptomatic SARS-CoV or SARS-CoV-2 infection.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The p0 and p1 K417N/E484K/N501Y/D614G virus stocks used in the neutralization experiments were confirmed by deep sequencing.

    “deep-sequenced confirmed p0 (Vero cell-produced) or p1 (Vero-hACE2-TMPRSS2 cell-produced) versions of K417N/E484K/N501Y/D614G virus”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study focused exclusively on impact of spike sequence changes on antibody neutralization in cell culture.

    “These studies focused exclusively on the impact of sequence changes in the spike protein on antibody neutralization in cell culture.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The reduced potency was surprising because animal and human antibody responses are polyclonal and, in principle, ought to bypass resistance from single mutations.

    “This observation is unexpected given that antibody responses in animals and humans are polyclonal and in theory, should overcome resistance associated with individual mutations and loss of activity of particular B cell clones.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Animal and human antibody responses are polyclonal and, in principle, ought to bypass resistance from single mutations and loss of specific B cell clones.

  • May combine two claims.

    Premisecitation

    Neutralization measurement does not account for Fc effector functions; Fcγ receptor or complement engagement by antibodies could confer protection.

    “this measurement does not account for Fc effector functions; Fcγ receptor or complement protein engagement by non-, weakly-, or strongly- neutralizing antibodies that bind the SARS-CoV-2 spike protein on the surface of infected cells could confer substantial protection39–41.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Winkler, E. S. et al. Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic protection. Cell https://doi.org/10.1016/j.cell.2021.02.026 (2021). source

      Not checked in the free run.

    • cites [40] Zohar, T. et al. Compromised humoral functional evolution tracks with SARS-CoV-2 mortality. Cell 183, 1508–1519 (2020). source

      Not checked in the free run.

    • cites [41] Dan, J.M. et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science https://doi.org/10.1126/science.abf4063 (2021). source

      Not checked in the free run.

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

    Premisecitation

    Neutralizing antibody titers in serum are expected to correlate with protection.

    “Although serum neutralizing titers are an anticipated correlate of protection38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Schäfer, A. et al. Antibody potency, effector function, and combinations in protection and therapy for SARS-CoV-2 infection in vivo. J. Exp. Med. 218, e20201993 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    Adjustments to some therapeutic antibody cocktails or existing vaccine spike sequences might be necessary.

    “While our analysis of neutralizing antibody responses with authentic infectious SARS-CoV-2 variants on Vero-hACE2-TMPRSS2 and Vero-TMPRSS2 cells suggests that adjustments to some therapeutic antibody cocktails or existing spike sequences in vaccines might be necessary, corroborating in vivo studies are needed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Certain neutralizing antibodies against the RBD base or NTD had lower activity toward B.1.1.7, while others against RBM or NTD could not inhibit Wash SA-B.1.351, Wash BR-B.1.1.248, or E484K variants.

    “Some neutralizing mAbs targeting the base of the RBD or NTD showed reduced activity against the B.1.1.7 isolate, whereas others targeting the RBM or NTD failed to inhibit infection of Wash SA-B.1.351, Wash BR-B.1.1.248, or variants containing the E484K mutation.”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    This difference could be due to distinct NTD mutations/deletions or enhanced neutralization of B.1.1.248 by anti-RBD antibodies binding outside RBM.

    “While follow-up corroborating studies are warranted, this result could be due to the distinct set of mutations and/or deletions in the NTD region or enhanced neutralization of B.1.1.248 by anti-RBD antibodies that bind outside of the RBM (see Extended Data Fig 5c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Sera from convalescent people, BNT162b2 recipients, and vaccinated animals all neutralized E484K/N501Y viruses less potently.

    “Our studies with human sera from convalescent subjects and recipients of the BNT162b2 mRNA vaccine, and animal sera after immunization with a vaccine encoding a similar spike gene, demonstrate a lower potency of neutralization against E484K and N501Y-containing viruses”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The convalescent serum donors from the St. Louis cohort experienced mild SARS-CoV-2 infection, and none required intubation.

    “Convalescent serum samples were obtained from a cohort recruited from the St. Louis metropolitan area who experienced mild SARS-CoV-2 infection. None of those patients required intubation”
    Quote in the paperNot a substantial claim
26 of 26

  • The paper relies on this without support.

    SARS-CoV-2 variants with enhanced transmissibility have emerged in the UK, South Africa, Brazil, and elsewhere.

    “More recently, variants with enhanced transmissibility have emerged in the United Kingdom (B.1.1.7), South Africa (B.1.351), Brazil (B.1.1.248) and elsewhere with multiple substitutions in the spike protein including in the NTD and the receptor binding motif (RBM) of the RBD.”

  • The paper relies on this without support.

    The current antibody therapeutics and vaccines were designed using spike protein from strains circulating early in 2020.

    “The current suite of antibody therapeutics and vaccines was designed with a spike protein based on strains circulating during the early phases of the pandemic in 2020.”

  • The authors state this as an assumption.

    Animal and human antibody responses are polyclonal and, in principle, ought to bypass resistance from single mutations and loss of specific B cell clones.

    “This observation is unexpected given that antibody responses in animals and humans are polyclonal and in theory, should overcome resistance associated with individual mutations and loss of activity of particular B cell clones.”
3 of 3

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?

  • Recent studies have consistently reported lower neutralizing antibody titers against B.1.351 after vaccination but not against B.1.1.7.

    “Concerning neutralization of VOCs, recent studies have consistently reported lower neutralizing antibody titers against B.1.351 after vaccination but not against B.1.1.7 (39, 42, 48–59).”

    From SARS-CoV-2 variants of concern partially escape humoral but not T cell responses in COVID-19 convalescent donors and vaccine recipients (2021) · cites this paper as [52]

  • Viruses were passaged once in Vero-hACE2-TMPRSS2 cells and deep sequenced after RNA extraction to confirm the introduction and stability of substitutions.

    “All viruses were passaged once in Vero-hACE2-TMPRSS2 cells and subjected to deep sequencing after RNA extraction to confirm the introduction and stability of substitutions17.”

    From SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses (2021) · cites this paper as [17]

  • Of plasma samples from persons receiving one of the two authorized mRNA vaccines, about 60% had 3-fold to 10-fold and 5% had >10-fold reduced neutralizing activity to the Gamma variant.

    “Of plasma samples from persons receiving one of the two authorized mRNA vaccines, about 60% had 3-fold to 10-fold and 5% had >10-fold reduced neutralizing activity 97,103,117,167,217,230 (fIg.5).”

    From The biological and clinical significance of emerging SARS-CoV-2 variants (2021) · cites this paper as [117]

  • Of convalescent plasma samples obtained from persons infected with early pandemic variants or with the Alpha variant, about 20% had 3-fold to 10-fold and 10% had >10-fold reduced neutralizing activity to the Gamma variant.

    “Of convalescent plasma samples obtained from persons infected with early pandemic variants or with the Alpha variant, about 20% had 3-fold to 10-fold and 10% had >10-fold reduced neutralizing activity 97,103,117,203,217,228,229 (fIg.5).”

    From The biological and clinical significance of emerging SARS-CoV-2 variants (2021) · cites this paper as [117]

  • Of plasma samples obtained from persons receiving one of the mRNA vaccines, 45% had 3-fold to 10-fold and 30% had >10-fold reduced Beta variant neutralizing activity.

    “Of plasma samples obtained from persons receiving one of the mRNA vaccines, 45% had 3-fold to 10-fold and 30% had >10-fold reduced Beta variant neutralizing activity 97,104,117,121,151,204,208,209,222,223 (fIg.5).”

    From The biological and clinical significance of emerging SARS-CoV-2 variants (2021) · cites this paper as [117]

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.

  • Antibody identifier changes within one figure description

    Minor

    The Extended Data Fig. 3 description identifies the antibody used for binding analysis as VIR-7381 in one sentence and VIR-7831 in the next, leaving its identity inconsistent.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Bricker, T.L. et al. A single intranasal or intramuscular immunization with chimpanzee adenovirus vectored SARS-CoV-2 vaccine protects against pneumonia in hamsters. Preprint at bioRxiv https://doi.org/10.1101/2020.12.02.408823 (2020). · DOI

Cited by

Sorted by citations

Authors
Chen, R. E., Zhang, X., Case, J. B., Winkler, E. S., Liu, Y., VanBlargan, L. A., Liu, J., Errico, J. M., Xie, X., Suryadevara, N., Gilchuk, P., Zost, S. J., Tahan, S., Droit, L., Turner, J. S., Kim, W., Schmitz, A. J., Thapa, M., Wang, D., Boon, A. C. M., Presti, R. M., O’Halloran, J. A., Kim, A. H. J., Deepak, P., Pinto, D., Fremont, D. H., Crowe, J. E., Corti, D., Virgin, H. W., Ellebedy, A. H., Shi, P.-Y., & Diamond, M. S.
Affiliations
  • Washington University in St. Louis (US)
  • The University of Texas Medical Branch at Galveston (US)
  • Vanderbilt University Medical Center (US)
  • Vir Biotechnology (Switzerland) (CH)
Corresponding author
  • Ellebedy, Ali H.
  • Shi, Pei-Yong
  • Diamond, Michael S.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2021-03-04
Volume
27
Issue
4
Pages
717-726
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-021-01294-w
PMC
PMC8058618
OpenAlex
W3133782701
Cited by
881
References
60
Citations by year
2026: 19 · 2025: 24 · 2024: 73 · 2023: 109 · 2022: 283 · 2021: 369 · 2020: 2
FWCI
66.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (5T32CA009547, U01 AI151810, 75N93019C00074, R01 AI145617, HHSN272201400006C, HHSN272201400008C, UL1 TR001439)
  • United States Department of Defense | Defense Advanced Research Projects Agency (HR001117S0019)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
SARS-CoV-2 variants, antibody neutralization, monoclonal antibodies, B.1.351 variant, B.1.1.7 variant, receptor binding domain, BNT162b2 mRNA vaccine, convalescent sera, vaccine escape, COVID-19 pandemic

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