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Cited by 1,343SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesAnimal Virus Infections Studies

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Open access
Wang, Zijun, Schmidt, Fabian, Weisblum, Yiska, Muecksch, Frauke, Barnes, Christopher O., Finkin, Shlomo, Schaefer-Babajew, Dennis, Cipolla, Melissa +26 more·2021·Nature
DOI 10.1038/s41586-021-03324-6PMC PMC8503938

Published version of a preprint

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Abstract

Here we report on the antibody and memory B cell responses of a cohort of 20 volunteers who received the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccine against SARS-CoV-2 1-4. Eight weeks after the second injection of vaccine, volunteers showed high levels of IgM and IgG anti-SARS-CoV-2 spike protein (S) and receptor-binding-domain (RBD) binding titre. Moreover, the plasma neutralizing activity and relative numbers of RBD-specific memory B cells of vaccinated volunteers were equivalent to those of individuals who had recovered from natural infection 5,6. However, activity against SARS-CoV-2 variants that encode E484K-, N501Y- or K417N/E484K/N501-mutant S was reduced by a small-but significant-margin. The monoclonal antibodies elicited by the vaccines potently neutralize SARS-CoV-2, and target a number of different RBD epitopes in common with monoclonal antibodies isolated from infected donors 5-8. However, neutralization by 14 of the 17 most-potent monoclonal antibodies that we tested was reduced or abolished by the K417N, E484K or N501Y mutation. Notably, these mutations were selected when we cultured recombinant vesicular stomatitis virus expressing SARS-CoV-2 S in the presence of the monoclonal antibodies elicited by the vaccines. Together, these results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid a potential loss of clinical efficacy.

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Crossref · 10.1038/s41586-021-03324-6

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Claims the paper makes

0 of 85 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The same mutations were selected when rVSV/SARS-CoV-2 S was cultured with vaccine-elicited mAbs.

    “Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs.”
    Quote in the paperSubstantial claim
  • Findingown data

    For 14 of the 17 strongest mAbs tested, the K417N, E484K, or N501Y mutations lowered or eliminated neutralizing activity.

    “However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations.”
    Quote in the paperSubstantial claim
  • Findingown data

    All vaccinated individuals tested had reactivity to S and RBD significantly higher than pre-COVID-19 historic controls.

    “All individuals tested showed reactivity to S and RBD that was significantly higher compared to pre-COVID-19 historic controls (Extended Data Fig 1a–f).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the volunteer plasma samples, neutralization fell by 1- to 3-fold for E484K, N501Y, and the triple K417N:E484K:N501Y mutant (p=0.0033, p=0.0002, p<0.0001).

    “Among the volunteer plasmas tested there was a 1- to 3-fold decrease in neutralizing activity against E484K, N501Y and the K417N:E484K:N501Y combination (p=0.0033, p=0.0002, and p<0.0001, respectively, Fig. 1h and i).”
    Quote in the paperSubstantial claim
  • Findingcitation

    Plasma neutralizing activity directly correlated with anti-S and anti-RBD binding titers in ELISAs.

    “As expected, plasma neutralizing activity was directly correlated to anti-S and -RBD binding titers in ELISAs7,8 (Fig. 1c, d, and Extended Data Fig. 2a–d).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Barnes, C. O. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). source

      Not checked in the free run.

    • cites [8] Barnes, C. O. et al. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182, 828–842 (2020). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 17
  • May combine two claims. 27
  • The quote only partly states this claim. 2

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

    Findingnone given

    Anti-S and anti-RBD IgG levels were higher than IgM or IgA.

    “As might be expected anti-S and -RBD IgG levels were higher than IgM or IgA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Binding to RBD and S and neutralizing activity all correlated with the interval from first dose to blood draw, and all three declined significantly over time.

    “Finally, RBD and S binding, and neutralizing activities were directly correlated to the time between the first vaccine dose and blood donation with significantly reduced levels in all 3 measurements with time (Fig. 1e, f and g, and Extended Data Fig. 2e–h)11.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Schmidt, F. et al. Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses. J. Exp. Med. 217, e20201181 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Vaccine-elicited monoclonal antibodies potently neutralize SARS-CoV-2 and target several RBD epitopes shared with mAbs from infected donors.

    “Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes in common with mAbs isolated from infected donors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Vaccinees had significantly higher IgG and IgM than convalescent patients tested 1.3 and 6.2 months after infection; IgA was comparable.

    “In line with previous reports3,6,9, IgG and IgM levels were significantly higher in the vaccinated group compared to a cohort of convalescent patients assayed 1.3 and 6.2 months after infection, while IgA levels were similar (Extended Data Fig 1j–l).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Krammer, F. SARS-CoV-2 vaccines in development. Nature 586, 516–527 (2020). source

      Not checked in the free run.

    • cites [6] Robbiani, D. F. et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 584, 437–442 (2020). source

      Not checked in the free run.

    • cites [9] Corbett, K. S. et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N. Engl. J. Med. 383, 1544–1555 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Neutralizing activity in plasma varied widely 3-14 weeks after the second dose; it resembled that in convalescent individuals at 1.3 months and exceeded that at 6.2 months.

    “In agreement with previous reports3,6,9, there was a broad range of plasma neutralizing activity 3–14 weeks after the second vaccine dose that was similar to that elicited by natural infection in a convalescent cohort after 1.3 months, and greater than the activity at 6.2 months after infection (Fig. 1a, Extended Data Table 1).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Krammer, F. SARS-CoV-2 vaccines in development. Nature 586, 516–527 (2020). source

      Not checked in the free run.

    • cites [6] Robbiani, D. F. et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 584, 437–442 (2020). source

      Not checked in the free run.

    • cites [9] Corbett, K. S. et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N. Engl. J. Med. 383, 1544–1555 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In vaccine recipients, the ability of plasma to neutralize virus and the proportion of memory B cells specific for RBD matched those seen in people who had recovered from natural infection.

    “Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection7,8.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Barnes, C. O. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). source

      Not checked in the free run.

    • cites [8] Barnes, C. O. et al. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182, 828–842 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In vaccinees, antibodies with identical IGHV-IGLV gene pairings accounted for 39% of clonal sequences; adding naturally infected individuals raised this to 59%.

    “In addition, antibodies that share the same combination of IGHV and IGLV genes in vaccinees comprised 39% of all the clonal sequences (Extended Data Fig. 4b) and 59% when combined with naturally infected individuals7,8 (Fig. 2f), and some of these antibodies were nearly identical (Extended Data Table 3 and 4).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Barnes, C. O. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). source

      Not checked in the free run.

    • cites [8] Barnes, C. O. et al. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182, 828–842 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Geometric mean neutralization IC50 of Pfizer-BioNTech and Moderna vaccinee antibodies were not significantly different from each other or from antibody collections from naturally infected individuals at 1.3 or 6.2 months.

    “Consistent with the plasma neutralization results, the geometric mean neutralization half-maximal inhibitory concentration of the Pfizer-BioNTech and Moderna vaccinee antibodies were not significantly different from each other or to antibody collections obtained from naturally infected individuals 1.3 or 6.2 months after infection (Fig. 3a and 7,8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Barnes, C. O. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). source

      Not checked in the free run.

    • cites [8] Barnes, C. O. et al. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182, 828–842 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Vaccinees had a significantly higher proportion of RBD-binding memory B cells than naturally infected people sampled at 1.3 months, but a similar proportion to those same people at 6.2 months.

    “Notably, the percentage of RBD-binding memory B cells in vaccinees was significantly greater than in naturally infected individuals assayed after 1.3 months, but similar to the same individuals assayed after 6.2 months (Fig. 2b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IgH CDR3 length was comparable between naturally infected people and vaccinees, and hydrophobicity was lower than average.

    “The length of the IgH CDR3 was similar in both natural infected individuals and vaccinees and hydrophobicity was below average27 (Fig. 2h and Extended Data Fig. 5a and b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Zost, S. J. et al. Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 584, 443–449 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Among 127 representative antibodies from 8 people, 98% (124/127) bound RBD, showing that flow-cytometric single-cell sorting efficiently found B cells making anti-RBD antibodies.

    “Of the antibodies tested 98% (124 out of the 127) bound to RBD indicating that single cell sorting by flow cytometry efficiently identified B cells producing anti-RBD antibodies (Extended Data Fig. 6a–c and Table 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    By anti-RBD ELISA, vaccinee antibodies had a higher mean EC50 than antibodies from infected people at 6.2 months, but this value did not differ significantly from antibodies at 1.3 months.

    “In anti-RBD ELISAs the mean half-maximal effective concentration (EC50) was higher than that observed in infected individuals after 6.2 months but not significantly different from antibodies obtained 1.3 months after infection (Extended Data Fig. 6a, and Table 5 and 7,8).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Barnes, C. O. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). source

      Not checked in the free run.

    • cites [8] Barnes, C. O. et al. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182, 828–842 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The number of V gene nucleotide mutations in vaccinees was greater than in naturally infected individuals at 1.3 months, but lower than in the same individuals at 6.2 months.

    “The number of V gene nucleotide mutations in vaccinees is greater than in naturally infected individuals assayed after 1.3 months, but lower than that in the same individuals assayed after 6.2 months (Fig. 2g and Extended Data Fig. 5a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For K417N, five antibodies showed at least a ten-fold drop; for N501Y, four did.

    “In addition, 5 of the antibodies were less potent against K417N and 4 against N501Y by ten-fold or more (Fig. 3b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Selection involved K417N/E/T for six antibodies, E484K for five, and N501Y/T/H for three; these match mutations in circulating B.1.1.17/501Y.V1, B.1.351/501Y.V2, and B1.1.28/501.V3 (P.1) variants.

    “Notably, 6 of the antibodies selected for K417N, E or T, 5 selected for E484K and 3 selected for N501Y, T or H, which coincide with mutations present in the circulating B.1.1.17/501Y.V1, B.1.351/501Y.V2 and B1.1.28/501.V3 (P.1) variants that have been associated with rapidly increasing case numbers in particular locales14,17,18,36.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [14] Baum, A. et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014–1018 (2020). source

      Not checked in the free run.

    • cites [17] Greaney, A. J. et al. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. Cell Host Microbe 29, 44–57 (2021). source

      Not checked in the free run.

    • cites [18] National Institute of Infectious Diseases. Brief report: new variant strain of SARS-CoV-2 identified in travelers from Brazil. https://www.niid.go.jp/niid/en/2019-ncov-e/10108-covid19-33-en.html (2021).

      Not checked in the free run.

    • cites [36] Hsieh, C. L. et al. Structure-based design of prefusion-stabilized SARS-CoV-2 spikes. Science 369, 1501–1505 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    C627, classified as class 2 because E484K reduced its activity, caused E484K to emerge in culture.

    “For example, antibody C627, which was assigned to class 2 based on sensitivity to the E484K mutation, selected for the emergence of the E484K mutation in vitro (Fig 3c).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Findingown data

    The distribution of hydrophobicity GRAVY scores at the IGH CDR3 differed significantly between the study's sequences and a public database (p<0.0001).

    “Statistical significance was determined using two-tailed Wilcoxon matched-pairs signed rank test (**** = p < 0.0001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Rubelt, F. et al. Onset of immune senescence defined by unbiased pyrosequencing of human immunoglobulin mRNA repertoires. PLoS ONE 7, e49774 (2012). source

      Not checked in the free run.

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

    Findingown data

    In vaccinees, NT50 did not correlate with the time between doses (r=0.03, p=0.89).

    “f, NT50 (Y axis) plotted against time between doses (X axis) r=0.03 p=0.89.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    In vaccinees, age did not correlate with NT50 (r=−0.06, p=0.82).

    “i, Age (Y axis) plotted against NT50 (X axis) r=−0.06 p=0.82.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    The frequency distributions of human IGVK and IgVL genes differed significantly between vaccinees and the Sequence Read Archive dataset SRP010970.

    “Two-sided binomial tests with unequal variance were used to compare the frequency distributions., significant differences are denoted with stars (* p < 0.05, ** p < 0.01, *** p < 0.001, **** = p < 0.0001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Baum, A. et al. REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters. Science 370, 1110–1115 (2020). source

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

    Findingown data

    In vaccinees, the percentage of RBD-binding memory B cells did not correlate significantly with the time between the first dose and blood draw (r=0.40, p=0.087).

    “c, the percentage of RBD-binding memory B cells in vaccinees (Y axis) plotted against time between first dose and blood draw (X axis) r=0.40 p=0.087 (left panel)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Antibody levels from plasma cells decline with time, yet durable immune memory can remain in expanded memory B cell clones.

    “Although circulating antibodies derived from plasma cells wane over time, long-lived immune memory can persist in expanded clones of memory B cells7,20.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Barnes, C. O. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). source

      Not checked in the free run.

    • cites [20] Lauring, A. S. & Hodcroft, E. B. Genetic variants of SARS-CoV-2–what do they mean? J. Am. Med. Assoc. 325, 529–531 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Cryo-EM structures of antibody-spike complexes indicate that S produced from vaccine and from virus takes on comparable shapes, leading to similar anti-RBD antibodies.

    “Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Several circulating variants linked to rapidly rising case counts are especially prevalent in the UK (B.1.1.7/501Y.V1), South Africa (B.1.351/501Y.V2), and Brazil (P.1).

    “A number of circulating SARS-CoV-2 variants that have been associated with rapidly increasing case numbers and have particular prevalence in the UK (B.1.1.7/501Y.V1), South Africa (B.1.351/501Y.V2) and Brazil (P.1)14,17,18,36.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [14] Baum, A. et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014–1018 (2020). source

      Not checked in the free run.

    • cites [17] Greaney, A. J. et al. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. Cell Host Microbe 29, 44–57 (2021). source

      Not checked in the free run.

    • cites [18] National Institute of Infectious Diseases. Brief report: new variant strain of SARS-CoV-2 identified in travelers from Brazil. https://www.niid.go.jp/niid/en/2019-ncov-e/10108-covid19-33-en.html (2021).

      Not checked in the free run.

    • cites [36] Hsieh, C. L. et al. Structure-based design of prefusion-stabilized SARS-CoV-2 spikes. Science 369, 1501–1505 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations at K417, E484, and N501 often reduce their activity, and these antibodies select K417N, E484K, and N501Y in yeast and VSV S libraries.

    “They are frequently sensitive to mutation in these residues and select for K417N, E484K and N501Y mutations in SARS-CoV-2 S protein expression libraries in yeast and VSV 12,15,33.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Widge, A. T. et al. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N. Engl. J. Med. 384, 80–82 (2021). source

      Not checked in the free run.

    • cites [15] Davies, N. G. et al. Estimated transmissibility and severity of novel SARS-CoV-2 variant of concern 202012/01 in England. Preprint at https://doi.org/10.1101/2020.12.24.20248822 (2020). source

      Not checked in the free run.

    • cites [33] Singer, J., Gifford, R., Cotten, M. & Robertson, D. CoV-GLUE: a web application for tracking SARS-CoV-2 genomic variation. Preprint at https://doi.org/10.20944/preprints202006.0225.v1 (2020). source

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

    Premisecitation

    The panel also included circulating variant residues K417N, Y453F, S477R, N501Y, and D614G, some linked to rapidly rising case counts.

    “Additionally, K417N, Y453F, S477R, N501Y, and D614G represent circulating variants some of which have been associated with rapidly increasing case numbers14,15,19,33–35.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [14] Baum, A. et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014–1018 (2020). source

      Not checked in the free run.

    • cites [15] Davies, N. G. et al. Estimated transmissibility and severity of novel SARS-CoV-2 variant of concern 202012/01 in England. Preprint at https://doi.org/10.1101/2020.12.24.20248822 (2020). source

      Not checked in the free run.

    • cites [19] Tegally, H. et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. Preprint at https://doi.org/10.1101/2020.12.21.20248640 (2020). source

      Not checked in the free run.

    • cites [33] Singer, J., Gifford, R., Cotten, M. & Robertson, D. CoV-GLUE: a web application for tracking SARS-CoV-2 genomic variation. Preprint at https://doi.org/10.20944/preprints202006.0225.v1 (2020). source

      Not checked in the free run.

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      Not checked in the free run.

    • cites [35] Voloch, C. M. et al. Genomic characterization of a novel SARS-CoV-2 lineage from Rio de Janeiro, Brazil. Preprint at https://doi.org/10.1101/2020.12.23.20248598 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antibodies in classes 1 and 2 are both highly potent and highly abundant.

    “Class 1 and 2 antibodies are among the most potent and also the most abundant antibodies7,8,21,22,25,39.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [7] Barnes, C. O. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). source

      Not checked in the free run.

    • cites [8] Barnes, C. O. et al. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182, 828–842 (2020). source

      Not checked in the free run.

    • cites [21] Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007). source

      Not checked in the free run.

    • cites [22] Brouwer, P. J. M. et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science 369, 643–650 (2020). source

      Not checked in the free run.

    • cites [25] 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 [39] 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.

  • May combine two claims.

    Premisecitation

    Class 1 antibodies are resisted by A475V; class 2 by E484K and Q493R; class 3 by R346S, N439K, and N440K.

    “A475V is resistant to class 1 antibodies (structurally defined as described29); E484K and Q493R are resistant to class 2 antibodies7,8,12,13,29,30,32,33; while R346S, N439K, and N440K are resistant to class 3 antibodies7,8,12,13,29,33.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [29] Andreano, E. et al. SARS-CoV-2 escape in vitro from a highly neutralizing COVID-19 convalescent plasma. Preprint at https://doi.org/10.1101/2020.12.28.424451 (2020). source

      Not checked in the free run.

    • cites [7] Barnes, C. O. et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687 (2020). source

      Not checked in the free run.

    • cites [8] Barnes, C. O. et al. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182, 828–842 (2020). source

      Not checked in the free run.

    • cites [12] Widge, A. T. et al. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N. Engl. J. Med. 384, 80–82 (2021). source

      Not checked in the free run.

    • cites [13] Weisblum, Y. et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. eLife 9, e61312 (2020). source

      Not checked in the free run.

    • cites [30] Thomson, E. C. et al. Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity. Cell, https://doi.org/10.1016/j.cell.2021.01.037 (2021). source

      Not checked in the free run.

    • cites [32] Starr, T. N. et al. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Science 371, 850–854 (2021). source

      Not checked in the free run.

    • cites [33] Singer, J., Gifford, R., Cotten, M. & Robertson, D. CoV-GLUE: a web application for tracking SARS-CoV-2 genomic variation. Preprint at https://doi.org/10.20944/preprints202006.0225.v1 (2020). source

      Not checked in the free run.

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

    Premisecitation

    Neutralizing human mAbs against SARS-CoV-2 RBD fall into four classes according to their RBD target regions.

    “Human neutralizing monoclonal antibodies to the SARS-CoV-2 RBD can be categorized as belonging to 4 different classes based on their target regions on the RBD29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Andreano, E. et al. SARS-CoV-2 escape in vitro from a highly neutralizing COVID-19 convalescent plasma. Preprint at https://doi.org/10.1101/2020.12.28.424451 (2020). source

      Not checked in the free run.

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

    Study design and conductown data

    The overall resolutions of the cryo-EM reconstructions were determined using gold-standard Fourier shell correlation calculations.

    “Overall resolutions were reported based on gold standard FSC calculations.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Sample size was not set in advance using statistical methods.

    “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). May combine two claims.

    Study design and conductown data

    All participants gave informed consent, and the study followed Good Clinical Practice.

    “Informed consent was obtained from all participants and the study was conducted in accordance with Good Clinical Practice.”
    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 conductown data

    Neither randomization nor blinding of investigators to allocation was used in the experiments or 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

  • May combine two claims.

    Premisecitation

    The common cold coronavirus HCoV-229E generates antigenic variants that resist older sera yet stay sensitive to current sera.

    “but the common cold coronavirus HCoV-229E evolves antigenic variants that are comparatively resistant to the older sera but remain sensitive to contemporaneous sera50.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Amanat, F. et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. Nat. Med. 26, 1033–1036 (2020). source

      Not checked in the free run.

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

    Study design and conductown data

    Positive and negative controls were included in the ELISA validation.

    “Positive and negative controls were included for validation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Findings imply that vaccines and antibody treatments against SARS-CoV-2 might require updates, with immune monitoring, to keep pace with viral evolution.

    “The data suggests that SARS-CoV-2 vaccines and antibody therapies may need to be updated and immunity monitored in order to compensate for viral evolution.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The data shown in Extended Data Fig. 7 are the mean of two independent experiments.

    “Data are the mean of 2 independent experiments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because vaccinee plasma contains polyclonal neutralizing antibodies, the mutations have relatively modest effects on viral sensitivity.

    “The comparatively modest effects of the mutations on viral sensitivity to plasma reflects the polyclonal nature of the neutralizing antibodies in vaccinee plasma.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The ELISA results shown are the average of two or more experiments.

    “Average of two or more experiments.”
    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 shown in Extended Data Fig. 6 are representative of two independent experiments.

    “Data are representative of two independent experiments.”
    Quote in the paperNot a substantial claim
40 of 40

  • The paper relies on this without support.

    The 20 volunteers had no prior SARS-CoV-2 infection.

    “None of the volunteers had a history of prior SARS-CoV-2 infection”
    “did not report prior history of SARS-CoV-2 infection”
1 of 1

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?

  • The majority of COVID-19 vaccines evoke humoral and cellular immune responses against the SARS-CoV-2 spike protein; these responses may not prevent infection but robustly protect against severe COVID-19 for certain periods of time.

    “The majority of COVID-19 vaccines are designed to evoke humoral and cellular immune responses against the SARS-CoV-2 spike protein — responses that may not prevent infection but robustly protect against severe COVID-19, at least for certain periods of time11,150–157.”

    From COVID-19 and cellular senescence (2023) · cites this paper as [156]

  • These variants are partially resistant to neutralization by monoclonal antibodies against spike, convalescent plasma, and sera from vaccinated participants.

    “recent reports suggest that these variants are partially resistant to neutralization by monoclonal antibodies against spike protein, by convalescent plasma and, notably, by sera from participants who have received severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines91,94,95.”

    From Prospects for durable immune control of SARS-CoV-2 and prevention of reinfection (2021) · cites this paper as [91]

  • The 10.3-12.4-fold loss of activity against B.1.351 is larger than reported results using mutant pseudoviruses.

    “On the other hand, the loss in activity by 10.3-12.4-foldagainst B.1.351 is larger than results that were reported using mutant pseudoviruses 34,42,43 .”

    From Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7 (2021) · cites this paper as [42]

  • Mutations in B.1.351 and P.1 variants are associated with the more pronounced loss of neutralizing capacity.

    “In contrast, mutations in B.1.351 and P.1 variants are associated with the more pronounced loss of neutralizing capacity.15,16,22,23,25”

    From Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals (2021) · cites this paper as [22]

  • Robust CD4+ and CD8+ T cell memory is induced after COVID-19, and multiple COVID-19 vaccines elicit CD4+ and CD8+ T cell responses.

    “Robust CD4+ and CD8+ T cell memory is induced after COVID-19,22,39, 40, 41 and multiple COVID-19 vaccines elicit CD4+ and CD8+ T cell responses.26,42, 43, 44, 45”

    From Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals (2021) · cites this paper as [22]

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.

  • Nine mutant RBDs are listed as eight

    Minor

    The methods state that there were eight additional mutant RBD proteins, but the parenthetical list names nine.

1 of 1

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 68 · Cited by 1,343

Authors
Wang, Z., Schmidt, F., Weisblum, Y., Muecksch, F., Barnes, C. O., Finkin, S., Schaefer-Babajew, D., Cipolla, M., Gaebler, C., Lieberman, J. A., Oliveira, T. Y., Yang, Z., Abernathy, M. E., Huey-Tubman, K. E., Hurley, A., Turroja, M., West, K. A., Gordon, K., Millard, K. G., Ramos, V., Da Silva, J., Xu, J., Colbert, R. A., Patel, R., Dizon, J., Unson-O’Brien, C., Shimeliovich, I., Gazumyan, A., Caskey, M., Bjorkman, P. J., Casellas, R., Hatziioannou, T., Bieniasz, P. D., & Nussenzweig, M. C.
Affiliations
  • Rockefeller University (US)
  • California Institute of Technology (US)
  • National Institutes of Health (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Casellas, Rafael
  • Bieniasz, Paul D.
  • Nussenzweig, Michel C.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-02-10
Volume
592
Issue
7855
Pages
616-622
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03324-6
PMC
PMC8503938
OpenAlex
W3126729284
Cited by
1,343
References
68
Citations by year
2026: 31 · 2025: 51 · 2024: 84 · 2023: 167 · 2022: 396 · 2021: 610 · 2020: 2
FWCI
99.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute (UL1TR001866)
  • George Mason University
  • California Institute of Technology
  • Wellcome Trust
  • National Institutes of Health (P01-AI138398-S1, AI150464, TR001866, UL1TR001866)
  • Beckman Institute, California Institute of Technology
  • National Institute of Allergy and Infectious Diseases (R01AI078788, P50AI150464, U19AI111825, P01AI138938, R37AI064003)
  • National Center for Advancing Translational Sciences (TR001866)
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
mRNA vaccines, SARS-CoV-2, COVID-19 pandemic, Moderna mRNA-1273, BNT162b2, spike protein, receptor binding domain, neutralizing antibodies, memory B cells, SARS-CoV-2 variants of concern, E484K mutation, N501Y mutation, monoclonal antibodies, vaccine update

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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