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Cited by 2,312SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections Studiesvaccines and immunoinformatics approaches

Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7

Open access
Wang, Pengfei, Nair, Manoj S., Liu, Lihong, Iketani, Sho, Luo, Yang, Guo, Yicheng, Wang, Maple, Yu, Jian +12 more·2021·Nature
DOI 10.1038/s41586-021-03398-2PMC PMC7852232

Published version of a preprint

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Abstract

The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization 1-3, and more treatments are under development 4-7. Furthermore, multiple vaccine constructs have shown promise 8, including two that have an approximately 95% protective efficacy against COVID-19 9,10. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK 11 and B.1.351 in South Africa 12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants 13,14 with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.

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Crossref · 10.1038/s41586-021-03398-2

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 19 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7

    B.1.1.7 is relatively resistant to a few monoclonal antibodies directed at the receptor-binding domain.

    “Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain.”
    Quote in the paperSubstantial claim
  • Findingown data

    The complete loss of activity of 2-15, LY-CoV555 and C121 against B.1.351 is mediated by the E484K substitution.

    “351 is mediated by the E484K substitution; the complete loss of activity of 910-30 is mediated by the K417N substitution; and the marked reduction in activity of REGN10933 is mediated by K417N and E484K, as has previously been reported 28 .”
    Quote in the paperSubstantial claim
  • Findingown data
    § Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7

    B.1.1.7 is refractory to neutralization by most monoclonal antibodies directed at the spike N-terminal domain.

    “Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain.”
    Quote in the paperSubstantial claim
  • Findingown data

    Both B.1.1.7 and B.1.351 are markedly resistant to neutralization by NTD-supersite antibodies 5-24, 4-8 and 4A8.

    “Both B.1.1.7 and B.1.351are markedly resistant to neutralization by antibodies 5-24 and 4-8 20 , as well as by 4A8 29 , all of which target the antigenic supersite in the NTD 18 (Fig. 2b).”
    Quote in the paperSubstantial claim
  • Findingown data

    Against authentic B.1.351, the neutralizing activities of 910-30, 2-15, LY-CoV555, C121 and REGN10933 were completely or markedly abolished.

    “For neutralization of B.1.351,however, the activities of 910-30, 2-15 20 , LY-CoV555 (bamlanivimab) 1,23 , C121 24 and REGN10933 (casirivimab) 2 are completely or markedly abolished.”
    Quote in the paperSubstantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingown data

    Eight plasma samples showed more than 2.5-fold decreased neutralizing activity against B.1.1.7Δ8, unlike the results for B.1.1.7.

    “Eight samples show a decrease of more than 2.5-fold in neutralizing activity against B.1.1.7Δ8,in contrast to the results for neutralization of B.1.1.7.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Most convalescent plasma samples (16 of 20) lost more than 2.5-fold neutralizing activity against B.1.351 while retaining activity against B.1.1.7.

    “Figure 3a shows that most (16 out of 20) plasma samples lost more than 2.5-fold neutralizing activity against B.1.351,while maintaining activity against B.1.1.7.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Brii-198 and COV2-2196 activities are diminished by 14.6-fold and 6.3-fold, respectively, against B.1.351 but not against B.1.1.7.

    “Brii-196 and COV2-2130 are essentially unaffected by the new variants; the activities of Brii-198 and COV2-2196 are diminished by 14.6-fold and 6.3-fold, respectively, against B.1.351but not against B.1.1.7.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    S309 and the Brii-196 plus Brii-198 combination are not significantly impaired, but their potencies are noticeably lower.

    “Although S309 and the combination of Brii-196 and Brii-198 are not significantly impaired, their potencies are noticeably lower”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    REGN10933 plus REGN10987 and COV2-2196 plus COV2-2130 appear unaffected against variant pseudoviruses but show noticeable activity decreases against authentic B.1.351.

    “Although REGN10933 and REGN10987 and COV2-2196 and COV2-2130 are seemingly unaffected against variant pseudoviruses, there are noticeable decreases in their activity against the B.1.351authentic virus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7

    B.1.351 and emergent variants carrying similar spike mutations create new difficulties for monoclonal antibody therapies and endanger the protective efficacy of current vaccines.

    “B.1.351and emergent variants 13,14 with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Faria, N. R. et al. Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings. Preprint at https://virological.org/t/genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-manaus-preliminary-findings/586 (2021).

      Not checked in the free run.

    • cites [14] Naveca, F. et al. Phylogenetic relationship of SARS-CoV-2 sequences from Amazonas with emerging Brazilian variants harboring mutations E484K and N501Y in the spike protein. Preprint at https://virological.org/t/phylogenetic-relationship-of-sars-cov-2-sequences-from-amazonas-with-emerging-brazilian-variants-harboring-mutations-e484k-and-n501y-in-the-spike-protein/585 (2021).

      Not checked in the free run.

    • Rests on an assumption: In vitro neutralization by monoclonal antibodies predicts clinical therapeutic efficacy.
    • Rests on an assumption: In vitro neutralization by vaccinee sera predicts vaccine protective efficacy.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Pseudovirus neutralization does not always faithfully reproduce live-virus neutralization.

    “These discrepant results highlight a previous observation 20 that pseudovirus neutralization does not always faithfully”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Liu, L. et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature 584, 450–456 (2020). source

      Not checked in the free run.

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

    Study design and conductnone given

    All cell lines used were obtained from authenticated vendors.

    “All cell lines were obtained from authenticated vendors.”
    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 study protocol was approved by the CUIMC Institutional Review Board and all participants provided written informed consent.

    “The study protocol was approved by the CUIMC Institutional Review Board (IRB) and all participants provided written informed consent.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    No statistical methods were used to predetermine the sample size.

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

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

    Study design and conductown data

    Cell viability was measured and found to be greater than 90%.

    “Viability was measured and found to be >90%.”
    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 conductreasoning

    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.”
    • Also stated in: § Additional information · plain
      “Randomization is not relevant as this is an observational study.”
    • Also stated in: § Additional information · plain
      “The investigators were not blinded as this is an observational study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    If widespread virus spread continues and more critical mutations accumulate, we may have to continually chase evolving SARS-CoV-2, as with influenza virus.

    “If the rampant spread of the virus continues and more critical mutations accumulate, then we may be condemned to chasing after the evolving SARS-CoV-2 continually, as we have long done for influenza virus.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The cell lines tested negative for mycoplasma contamination.

    “Mycoplasma is negative (Detected mycoplasma contamination using Mycoplasma PCR ELISA ,Sigma,catalog number is 11663925910)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Neutralizing activity of vaccinee sera against B.1.1.7 is largely intact, and no adverse effects on current vaccines are expected.

    “As for the ramifications of our findings for the protective efficacy of current SARS-CoV-2 vaccines, the neutralizing activity of sera from vaccinated individuals against B.1.1.7 is largely intact and no adverse effects on current vaccines are expected (Fig. 4c), consistent with conclusions that were reached by other studies 34,40,41 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [34] Wu, K. et al. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. Preprint at https://doi.org/10.1101/2021.01.25.427948 (2021). source

      Not checked in the free run.

    • cites [40] Collier, D. et al. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies. Preprint at https://doi.org/10.1101/2021.01.19.21249840 (2021). source

      Not checked in the free run.

    • cites [41] Muik, A. et al. Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera. Science https://doi.org/10.1126/science.abg6105 (2021). source

      Not checked in the free run.

    • Rests on an assumption: In vitro neutralization by vaccinee sera predicts vaccine protective efficacy.

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

    Study design and conductnone given

    Studies that were repeated are noted in figure captions and include all studies that demonstrated the key results reported in the manuscript.

    “Studies that were repeated are noted in figure captions and include all studies that demonstrated the key results reported in the manuscript.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    No data were excluded from the analysis.

    “No data were excluded from the analysis”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    E484K causes steric clashes and a charge change at antibody-binding sites, and thereby abolishes binding by RBM-directed monoclonal antibodies.

    “E484K causes not only steric clashes but also a charge change at antibody-binding sites, and thus abolishes binding by these RBM-directed monoclonal antibodies.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Cytopathogenic effects of viral infection were visually scored for each well in a blinded manner by two independent observers.

    “Cytopathogenic effects of viral infection were visually scored for each well in a blinded manner by two independent observers.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The sample size is appropriate within technical capability to compare the difference between groups.

    “The sample size is appropriate within technical capability to compare the difference between groups”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Eighteen mutant pseudoviruses were made as previously described, and each had a robust titre adequate for neutralization studies.

    “A total of 18 mutant pseudoviruses were made as previously described 20,21 , and each was found to have a robust titre (Extended Data Fig. 1c) that was adequate for neutralization studies.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Liu, L. et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature 584, 450–456 (2020). source

      Not checked in the free run.

    • cites [21] Wang, P. et al. SARS-CoV-2 neutralizing antibody responses are more robust in patients with severe disease. Emerg. Microbes Infect. 9, 2091–2093 (2020). source

      Not checked in the free run.

21 of 21

  • The paper relies on this without support.

    In vitro neutralization by monoclonal antibodies predicts clinical therapeutic efficacy.

    “These findings suggest that antibody treatment of this virus might need to be modified in localities in which B.1.351and related variants 13,14 are prevalent”
    “Decisions on the use of these monoclonal antibodies will depend heavily on the local prevalence of B.1.351or variants with an E484K substitution”

  • The paper relies on this without support.

    In vitro neutralization by vaccinee sera predicts vaccine protective efficacy.

    “the neutralizing activity of sera from vaccinated individuals against B.1.1.7 is largely intact and no adverse effects on current vaccines are expected”
    “threaten the protective efficacy of current vaccines”

  • The paper relies on this without support.

    Reduced neutralization of a variant by antibodies in vitro reflects reduced antibody-mediated protection against that variant in vivo.

    “Overall, the neutralizing activity against B.1.1.7 was essentially unchanged, but significantly lower against B.1.351(12.4-fold for the Moderna vaccine; 10.3-fold for the Pfizer vaccine).”

  • The paper relies on this without support.

    The convalescent plasma samples and vaccinee sera studied are representative of convalescent patients and of vaccine recipients generally.

    “B.1.351 is more resistant to neutralization by convalescent plasma from patients.”
    “B.1.351 is more resistant to neutralization by sera from individuals vaccinated with the Moderna or Pfizer vaccine.”
4 of 4

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Cites

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Research works printed but not linked: 2

  1. Faria, N. R. et al. Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings. Preprint at https://virological.org/t/genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-manaus-preliminary-findings/586 (2021).
  2. Naveca, F. et al. Phylogenetic relationship of SARS-CoV-2 sequences from Amazonas with emerging Brazilian variants harboring mutations E484K and N501Y in the spike protein. Preprint at https://virological.org/t/phylogenetic-relationship-of-sars-cov-2-sequences-from-amazonas-with-emerging-brazilian-variants-harboring-mutations-e484k-and-n501y-in-the-spike-protein/585 (2021).

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Related

Authors
Wang, P., Nair, M. S., Liu, L., Iketani, S., Luo, Y., Guo, Y., Wang, M., Yu, J., Zhang, B., Kwong, P. D., Graham, B. S., Mascola, J. R., Chang, J. Y., Yin, M. T., Sobieszczyk, M., Kyratsous, C. A., Shapiro, L., Sheng, Z., Huang, Y., & Ho, D. D.
Affiliations
  • Aaron Diamond AIDS Research Center (US)
  • National Institutes of Health (US)
  • Regeneron (United States) (US)
Corresponding author
  • Huang, Yaoxing
  • Ho, David D.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-03-08
Volume
593
Issue
7857
Pages
130-135
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03398-2
PMC
PMC7852232
OpenAlex
W3123551159
Cited by
2,312
References
51
Citations by year
2026: 34 · 2025: 101 · 2024: 136 · 2023: 299 · 2022: 750 · 2021: 984 · 2020: 6
FWCI
171.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Bill and Melinda Gates Foundation
  • JPB Foundation
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, SARS-CoV-2 variants, Beta variant, Alpha variant, antibody resistance, neutralizing antibodies, monoclonal antibodies, spike protein mutations, N-terminal domain, receptor binding domain, convalescent plasma, vaccine efficacy

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