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

The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index; none of the 19 sources its claims cite is checked for support yet.

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

Open access

Published version of a preprint

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.

Overview

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Crossref · 10.1038/s41586-021-03398-2

Cites

62 of 62 references verified0 citation errors · 0 not checkable

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Figures

Fig. 1 | Emerging SARS-CoV-2 variants identified in the UK and SA. a, Phylogenetic tree of SARS-CoV-2 variants, with B.1.351 and B.1.1.7 highlighted. b, Mutations in the viral spike identified in B.1.351 (SA) and B.1.1.7 (UK) in addition to D614G.
Fig. 1 | Emerging SARS-CoV-2 variants identified in the UK and SA. a, Phylogenetic tree of SARS-CoV-2 variants, with B.1.351 and B.1.1.7 highlighted. b, Mutations in the viral spike identified in B.1.351 (SA) and B.1.1.7 (UK) in addition to D614G.CC BY · PubMed Central
Fig. 2 | Susceptibility of UKΔ8 and SAΔ9 pseudoviruses to neutralization by mAbs. a, Footprints of neutralizing mAbs on the RBD. Left panel, top view of SARS-COV-2 spike with one RBD in the “up” conformation (pdb: 6zgg). RBD and NTD are colored green and peach, respectively. The positions of ‘inner’ and ‘outer’ sides are indicated on the “up” RBD with the ACE2-binding site colored yellow. The three panels to the right show the antibody footprints on RBD. b, Neutralization of UKΔ8, SAΔ9, and WT pseudoviruses by select RBD mAbs. c, Fold-change in IC50 of neutralizing mAbs against UKΔ8 and SAΔ9, as well as single-mutation pseudoviruses, relative to WT. MPI↓ denotes that maximum percent inhibition is substantially reduced, confounding IC50 calculations. d, Neutralization of UKΔ8, SAΔ9, and WT pseudoviruses by NTD-directed mAbs, the footprints of which are delineated by the color tracings in the insert. e, Changes in neutralization IC50 of authorized or investigational therapeutic mAbs against UKΔ8 and SAΔ9. Data in b and d are mean ± SEM of technical triplicates, and represent one of two independent experiments.
Fig. 2 | Susceptibility of UKΔ8 and SAΔ9 pseudoviruses to neutralization by mAbs. a, Footprints of neutralizing mAbs on the RBD. Left panel, top view of SARS-COV-2 spike with one RBD in the “up” conformation (pdb: 6zgg). RBD and NTD are colored green and peach, respectively. The positions of ‘inner’ and ‘outer’ sides are indicated on the “up” RBD with the ACE2-binding site colored yellow. The three panels to the right show the antibody footprints on RBD. b, Neutralization of UKΔ8, SAΔ9, and WT pseudoviruses by select RBD mAbs. c, Fold-change in IC50 of neutralizing mAbs against UKΔ8 and SAΔ9, as well as single-mutation pseudoviruses, relative to WT. MPI↓ denotes that maximum percent inhibition is substantially reduced, confounding IC50 calculations. d, Neutralization of UKΔ8, SAΔ9, and WT pseudoviruses by NTD-directed mAbs, the footprints of which are delineated by the color tracings in the insert. e, Changes in neutralization IC50 of authorized or investigational therapeutic mAbs against UKΔ8 and SAΔ9. Data in b and d are mean ± SEM of technical triplicates, and represent one of two independent experiments.CC BY · PubMed Central
Fig. 3 | UKΔ8 and SAΔ9 pseudoviruses are more resistant to neutralization by convalescent plasma from patients. a, Neutralization results for 20 convalescent plasma samples (P1-P20) against UKΔ8, SAΔ9, and WT. Data represent mean ± SEM of technical triplicates. The panels are arranged by IC50 values against the WT, from low to high. b, Fold change in neutralization IC50 of UKΔ8 and SAΔ9, as well as single-mutation pseudoviruses, relative to the WT presented as a heatmap with darker colors implying greater change. c, Change in reciprocal plasma neutralization IC50 values of convalescent plasma from severe and non-severe patients against UKΔ8 and SAΔ9, relative to the WT. Mean fold changes in IC50 values relative to the WT are written above the p values. Statistical analysis was performed using a two-tailed paired t test.
Fig. 3 | UKΔ8 and SAΔ9 pseudoviruses are more resistant to neutralization by convalescent plasma from patients. a, Neutralization results for 20 convalescent plasma samples (P1-P20) against UKΔ8, SAΔ9, and WT. Data represent mean ± SEM of technical triplicates. The panels are arranged by IC50 values against the WT, from low to high. b, Fold change in neutralization IC50 of UKΔ8 and SAΔ9, as well as single-mutation pseudoviruses, relative to the WT presented as a heatmap with darker colors implying greater change. c, Change in reciprocal plasma neutralization IC50 values of convalescent plasma from severe and non-severe patients against UKΔ8 and SAΔ9, relative to the WT. Mean fold changes in IC50 values relative to the WT are written above the p values. Statistical analysis was performed using a two-tailed paired t test.CC BY · PubMed Central
Fig. 4 | UKΔ8 and SAΔ9 pseudoviruses are more resistant to neutralization by vaccinee sera. a, Neutralization profiles for 22 serum samples obtained from persons who received SARS-CoV-2 vaccine made by Moderna (V1-V12) or Pfizer (V13-V22) against UKΔ8, SAΔ9, and WT pseudoviruses. The panels are arranged by IC50 values against the WT, from low to high for each set of vaccinees. Data are mean ± SEM of technical triplicates, and represent one of two independent experiments. b, Fold change in serum neutralization IC50 of UKΔ8 and SAΔ9, as well as single-mutation pseudoviruses, relative to the WT presented as a heatmap with darker colors implying greater change. c, Change in reciprocal serum IC50 values for Moderna and Pfizer vaccinees against UKΔ8 and SAΔ9, relative to the WT. Mean fold change in IC50 relative to the WT is written above the p values. Statistical analysis was performed using a two-tailed paired t test.
Fig. 4 | UKΔ8 and SAΔ9 pseudoviruses are more resistant to neutralization by vaccinee sera. a, Neutralization profiles for 22 serum samples obtained from persons who received SARS-CoV-2 vaccine made by Moderna (V1-V12) or Pfizer (V13-V22) against UKΔ8, SAΔ9, and WT pseudoviruses. The panels are arranged by IC50 values against the WT, from low to high for each set of vaccinees. Data are mean ± SEM of technical triplicates, and represent one of two independent experiments. b, Fold change in serum neutralization IC50 of UKΔ8 and SAΔ9, as well as single-mutation pseudoviruses, relative to the WT presented as a heatmap with darker colors implying greater change. c, Change in reciprocal serum IC50 values for Moderna and Pfizer vaccinees against UKΔ8 and SAΔ9, relative to the WT. Mean fold change in IC50 relative to the WT is written above the p values. Statistical analysis was performed using a two-tailed paired t test.CC BY · PubMed Central

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Claims the paper makes

38 Own result · 11 Not checked yet · 11 Own method · 9 Own interpretation

Verify all 19 references — free account
  • It may state two separate claims as one. 12
  • Probably not a substantial claim. 12
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.”
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Citations

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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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Metadata

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.
Venue
Nature
Published
2021-03-08
Volume
593
Issue
7857
Pages
130-135
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W3123551159
Cited by
2,312
References
51
Citations by year
2026: 34 · 2025: 101 · 2024: 136 · 2023: 299 · 2022: 750 · 2021: 984
FWCI
171.98
Type
journal article
Language
en
Open access
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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