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Cited by 1,009SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesCOVID-19 epidemiological studies

The biological and clinical significance of emerging SARS-CoV-2 variants

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Tao, Kaiming, Tzou, Philip L., Nouhin, Janin, Gupta, Ravindra K., de Oliveira, Tulio, Kosakovsky Pond, Sergei L., Fera, Daniela, Shafer, Robert W.·2021·Nature Reviews Genetics
DOI 10.1038/s41576-021-00408-xPMC PMC8447121
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Abstract

The past several months have witnessed the emergence of SARS-CoV-2 variants with novel spike protein mutations that are influencing the epidemiological and clinical aspects of the COVID-19 pandemic. These variants can increase rates of virus transmission and/or increase the risk of reinfection and reduce the protection afforded by neutralizing monoclonal antibodies and vaccination. These variants can therefore enable SARS-CoV-2 to continue its spread in the face of rising population immunity while maintaining or increasing its replication fitness. The identification of four rapidly expanding virus lineages since December 2020, designated variants of concern, has ushered in a new stage of the pandemic. The four variants of concern, the Alpha variant (originally identified in the UK), the Beta variant (originally identified in South Africa), the Gamma variant (originally identified in Brazil) and the Delta variant (originally identified in India), share several mutations with one another as well as with an increasing number of other recently identified SARS-CoV-2 variants. Collectively, these SARS-CoV-2 variants complicate the COVID-19 research agenda and necessitate additional avenues of laboratory, epidemiological and clinical research. In this Review, the authors describe our latest understanding of the emergence and properties of SARS-CoV-2 genetic variants, particularly those designated as WHO (World Health Organization) ‘variants of concern’. They focus on the consequences of these variants for antibody-mediated virus neutralization, with important implications for reinfection risk and for vaccine effectiveness.

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Written from the paper’s full text.

TL;DR

This review synthesizes SARS-CoV-2 evolution, spike structure and the biological/clinical significance of the four WHO variants of concern as of June 2021: Alpha, Beta, Gamma and Delta. It shows that recurrent spike mutations increase transmissibility and immune evasion, reducing neutralization by monoclonal antibodies and vaccinee plasma, and calls for integrated genomic, neutralization and vaccine-efficacy surveillance.

Key findings

  • Four VOCs emerged independently: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2). Alpha was estimated to be ~50% more transmissible than prior UK variants and associated with an estimated 50% increased mortality; Beta was estimated to be 50% more transmissible than preceding lineages; Gamma was estimated to cause 3–4 times higher virus levels and 1.1-fold to 1.8-fold higher mortality; Delta spread to 54 countries and replaced Alpha in the UK and USA.
  • Neutralization escape varied by variant. Beta showed 3-fold to 10-fold reduced susceptibility to 46% and >10-fold reduced susceptibility to 22% of convalescent plasma samples; mRNA vaccinee plasma showed 45% with 3-fold to 10-fold and 30% with >10-fold reduced Beta neutralization. Delta showed 3-fold to 10-fold reduced susceptibility to 45% and >10-fold to 5% of convalescent plasma samples, while ~15% of BNT162b vaccinee plasma had 3-fold to 10-fold reduced Delta neutralization. Alpha was rarely associated with reduced convalescent plasma susceptibility but showed 3-fold to 10-fold reduced susceptibility to ~15% of mRNA vaccinee plasma samples.
  • Vaccine efficacy against VOCs was reduced in several studies: BNT162b retained >90% efficacy against Alpha in Israel and Qatar; Beta efficacy was 72% in a Qatar cohort and 75% in a test-negative case-control study; Delta efficacy was ~85% for BNT162b and ~60% for AZD1222 in UK case-control studies. In trials, AZD1222 efficacy against Beta was 10% in South Africa, and NVX-CoV2373 efficacy was 49% against Beta and 86.3% against Alpha versus 96.4% against non-Alpha variants.
  • Key mutations include D614G, which rose to near 100% global prevalence by June 2020; N501Y, which increases ACE2 affinity; E484K, which reduces susceptibility to several monoclonal antibodies and plasma; and non-spike mutations that antagonize innate immunity, with Alpha and Beta showing mean 112-fold and 8-fold reduced susceptibility to type I interferons, respectively, compared with an early pandemic virus.

Methods

  • Narrative review creating a framework for SARS-CoV-2 variants by describing evolution, spike protein structure/function, laboratory characterization methods, biological and epidemiological properties of VOCs/VOIs, and required research responses; data summarized as of June 2021.
  • Synthesizes genomic surveillance data from more than two million partially or fully sequenced virus isolates, in vitro selection and neutralization experiments using pseudotyped viruses, VSV-based chimeric viruses, full-length recombinant SARS-CoV-2 and cultured isolates, deep mutational scanning, and vaccine efficacy trials, test-negative case-control studies and cohort studies.
  • Neutralization results were pooled in the Stanford University Coronavirus Antiviral & Resistance Database and summarized as <3-fold, 3–10-fold and >10-fold reductions compared with control viruses.

Limitations

  • The paper states that as of June 2021 it is uncertain whether current lineage-based variant classification will be sustainable, and that classifying variants by component mutations may become challenging if recurrent mutations increase.
  • The paper notes unresolved questions, including whether neutralizing antibodies are the most important protective mechanism versus memory B cells, Fc-effector functions and T cell immunity, and whether updated immunogens can broaden responses in animal models more predictive of humans.
  • Evident from the text: this is a synthesis as of June 2021, so later variants and data are not included; neutralization estimates pool results across pseudotyped, chimeric and infectious virus assays, and some distributions are approximate because they include results reported only as aggregate mean fold reductions.

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Registry

Crossref · 10.1038/s41576-021-00408-x

Cites

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  • Premisecitation
    § Abstract

    Four SARS-CoV-2 variants of concern (Alpha, Beta, Gamma and Delta) emerged in the past several months.

    “The past several months have witnessed the emergence of four SArS-cov-2 variants of concern (Alpha, beta, Gamma and Delta)”
    • Also stated in: § SARS-CoV-2 evolution · plain
      “The four variants of concern, the Alpha variant (originally identified in the UK), the Beta variant (originally identified in South Africa), the Gamma variant (originally identified in Brazil) and the Delta variant (originally identified in India)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Rambaut, A. et al. Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. Virological https://virological.org/t/563 (2020).

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    • cites [16] Tegally, H. et al. Detection of a SARS-CoV-2 variant of concern in South Africa. Nature 592, 438–443 (2021). This molecular epidemiological study charts the spread of the beta variant in South Africa and shows that it resulted from selective evolutionary forces. source

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    • cites [19] Faria, N. R. et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science 372, 815–821 (2021). This paper presents an analysis showing that the Gamma variant is about twofold more transmissible than previous variants in Manaus, Brazil, and that it poses an increased risk of reinfection compared with previous variants. source

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  • Interpretationnone given
    § Abstract

    The increasing number of SARS-CoV-2 variants share a repertoire of mutations that is enabling the virus to spread despite rising population immunity while maintaining or increasing its replication fitness.

    “The increasing number of SArS-cov-2 variants share a repertoire of mutations that is enabling the virus to spread despite rising population immunity while maintaining or increasing its replication fitness.”
    Quote in the paperNot a substantial claim
  • Premisecitation
    § Secondary attack rate

    In a post-hoc analysis of a NVX-CoV2373 clinical trial, vaccine efficacy was 86.3% against Alpha variants compared with 96.4% against non-Alpha variants.

    “In a post-hoc analysis of a NVX-CoV2373 clinical trial, vaccine efficacy was 86.3% against Alpha variants compared with 96.4% against non-Alpha variants 212 (TABLe 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [212] Heath, P. T. et al. Safety and efficacy of NVX-CoV2373 Covid-19 vaccine. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2107659 (2021). source

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  • Premisecitation
    § Secondary attack rate

    By the second quarter of 2021, the Alpha variant accounted for the majority of infections in the USA and many European countries.

    “By the second quarter of 2021, the Alpha variant accounted for the majority of infections in the USA and many European countries 23,196 .”
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    • cites [23] Hodcroft, E. CoVariants: SARS-CoV-2 mutations and variants of interest (NextStrain). CoVariants https://covariants.org/ (2021).

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    • cites [196] Mullen, J. L. et al. Outbreak.info https://outbreak.info/citation (2020).

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  • Premisecitation
    § Secondary attack rate

    The Alpha variant was associated with threefold to eightfold higher upper-airway levels.

    “It was also associated with threefold to eightfold higher upper-airway levels [199][200][201]”
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    • cites [199] Golubchik, T. et al. Early analysis of a potential link between viral load and the N501Y mutation in the SARS-COV-2 spike protein. Preprint at bioRxiv https://doi.org/10.1101/2021.01.12.20249080 (2021). source

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    • cites [200] Kidd, M. et al. S-variant SARS-CoV-2 lineage B1.1.7 is associated with significantly higher viral loads in samples tested by ThermoFisher TaqPath RT-qPCR. J. Infect. Dis. 223, 1666–1670 (2021). source

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    • cites [201] Borges, V. et al. Tracking SARS-CoV-2 lineage B.1.1.7 dissemination: insights from nationwide spike gene target failure (SGTF) and spike gene late detection (SGTL) data, Portugal, week 49 2020 to week 3 2021. Eur. Surveill. 26, 2100131 (2021). source

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  • May combine two claims. 33
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    Premisecitation
    § Secondary attack rate

    The Alpha variant is susceptible to neutralization by most neutralizing mAbs as well as by most plasma samples from previously infected persons.

    “The Alpha variant is susceptible to neutralization by most neutralizing mAbs as well as by most plasma samples from previously infected persons 97,102,121,149,159,[203][204][205][206] (fIg.5).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [97] Chen, X. et al. Neutralizing antibodies against SARS-CoV-2 variants induced by natural infection or vaccination: a systematic review and pooled meta-analysis. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciab646 (2021). This paper presents a systematic review and meta-analysis of in vitro neutralization studies of SARS-CoV-2 variants by convalescent and vaccinee plasma. source

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    • cites [102] Supasa, P. et al. Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera. Cell 184, 2201–2211 (2021). source

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    • cites [121] Wang, P. et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593, 130–135 (2021). This paper presents a comprehensive analysis of the effects of Alpha and Beta variant mutations on antibody neutralization. source

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    Interpretationcitation
    § Secondary attack rate

    The Alpha variant is rarely associated with reduced susceptibility to convalescent plasma, consistent with it not being associated with an increased risk of reinfection.

    “The fact that the Alpha variant is rarely associated with reduced susceptibility to convalescent plasma is consistent with it not being associated with an increased risk of reinfection 207 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [207] Graham, M. S. et al. Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study. Lancet Public Health 6, e335–e345 (2021). source

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    Premisenone given
    § Abstract

    The four SARS-CoV-2 variants of concern are associated with increased transmissibility, increased risk of reinfection and/or reduced vaccine efficacy.

    “associated with increased transmissibility, increased risk of reinfection and/or reduced vaccine efficacy”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Beta variant (B.1.351)

    The Beta variant is associated with reduced susceptibility to many mAbs because E484K interferes with binding of several RBM class 1 and 2 mAbs and K417N interferes with the binding of several RBM class 1 mAbs.

    “The Beta variant is associated with reduced susceptibility to many mAbs because E484K interferes with binding of several RBM class 1 and 2 mAbs and K417N interferes with the binding of several RBM class 1 mAbs 104,117,121,163,217 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] Zhou, D. et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine induced sera. Cell 184, 2348–2361 (2021). source

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    • cites [117] Chen, R. E. et al. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat. Med. 27, 717–726 (2021). source

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    • cites [121] Wang, P. et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593, 130–135 (2021). This paper presents a comprehensive analysis of the effects of Alpha and Beta variant mutations on antibody neutralization. source

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    Premisecitation
    § E484K

    E484K has resulted in 3-fold to 10-fold reduced susceptibility to about 30% and >10-fold reduced susceptibility to about 10% of convalescent plasma samples.

    “E484K has resulted in 3-fold to 10-fold reduced susceptibility to about 30% and >10-fold reduced susceptibility to about 10% of convalescent plasma samples”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [121] Wang, P. et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593, 130–135 (2021). This paper presents a comprehensive analysis of the effects of Alpha and Beta variant mutations on antibody neutralization. source

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    • cites [130] 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.e9 (2021). source

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    • cites [160] Liu, Z. et al. Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. Cell Host Microbe 29, 477–488.e4 (2021). source

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    Premisecitation
    § Secondary attack rate

    The Alpha variant contains non-spike mutations including nsp6:Δ106-108 and nucleocapsid mutations D3L, R203K and G204R, which may increase transmission by antagonizing innate immunity.

    “The Alpha variant also contains several non-spike mutations including nsp6:Δ106-108 and the nucleocapsid mutations D3L, R203K and G204R, which may increase transmission by antagonizing innate immunity 25,[185][186][187] .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] Martin, D. P. et al. The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape. Preprint at medRxiv https://doi.org/10.1101/2021.02.23.21252268 (2021). source

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    • cites [185] Thorne, L. G. et al. Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant. Preprint at bioRxiv https://doi.org/10.1101/2021.06.06.446826 (2021). This systems biology study shows that in contrast to earlier SARS-CoV-2 variants, the alpha variant may owe its increased transmissibility and virulence to its antagonism of cellular innate immunity. source

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    • cites [186] Jiang, H. et al. SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70. Cell Mol. Immunol. 17, 998–1000 (2020). source

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    Premisecitation
    § N501Y

    N501Y increases ACE2 affinity and increases virus replication in human upper-airway cells and in the upper respiratory tracts of hamsters.

    “N501Y increases ACE2 affinity 128,146,147 and increases virus replication in human upper-airway cells and in the upper respiratory tracts of hamsters 127”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [128] Starr, T. N. et al. Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. Cell 182, 1295–1310.e20 (2020). source

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    • cites [146] Zhu, X. et al. Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies. PLoS Biol. 19, e3001237 (2021).

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    • cites [127] Liu, Y. et al. The N501Y spike substitution enhances SARS-CoV-2 transmission. Preprint at bioRxiv https://doi.org/10.1101/2021.03.08.434499 (2021). source

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    Premisecitation
    § Beta variant (B.1.351)

    In the previously cited Qatar cohort study, the efficacy of BNT162b against the Beta variant was estimated to be 72%, which was 15% lower than that for the Alpha variant.

    “In the previously cited Qatar cohort study, the efficacy of BNT162b against the Beta variant was estimated to be 72%, which was 15% lower than that for the Alpha variant 211 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Abu-Raddad, L. J., Chemaitelly, H. & Butt, A. A. Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants. N. Engl. J. Med. 385, 187-189 (2021). source

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    Interpretationcitation
    § Delta variant (B.1.617.2)

    Even though E484Q is more likely than T478K to evade antibody neutralization, only the Delta variant has demonstrated increased transmissibility, spreading to 54 countries and rapidly replacing the Alpha variant in the UK and the USA.

    “Even though E484Q is more likely than T478K to evade antibody neutralization 48,100,165 , only the Delta variant has demonstrated increased transmissibility, spreading to 54 countries and rapidly replacing the Alpha variant in the UK 32,35 and the USA 33 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48] Weisblum, Y. et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. eLife 9, e61312 (2020). source

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    • cites [100] Liu, C. et al. Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum. Cell 184, 4220–4336 (2021). source

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    • cites [165] Ferreira, I. et al. SARS-CoV-2 B.1.617 mutations L452 and E484Q are not synergistic for antibody evasion. J. Infect. Dis. https://doi.org/10.1093/infdis/jiab368 (2021). source

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    Premisecitation
    § Beta variant (B.1.351)

    Of 34 convalescent plasma samples from persons infected with the Alpha variant, 59% had 3-fold to 10-fold reduced neutralizing activity and 18% had >10-fold reduced neutralizing activity to the Beta variant.

    “Of 34 convalescent plasma samples from persons infected with the Alpha variant, 59% had 3-fold to 10-fold reduced neutralizing activity and 18% had >10-fold reduced neutralizing activity to the Beta variant 99,104,221 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [99] Faulkner, N. et al. Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains. Elife 10, e69317 (2021). source

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    • cites [104] Zhou, D. et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine induced sera. Cell 184, 2348–2361 (2021). source

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    • cites [221] McCallum, M. et al. SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern. Science 373, 648–654 (2021). source

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    Premisecitation
    § Gamma variant (P.1)

    The Gamma variant contains five NTD mutations, of which L18F has been shown to interfere with the binding of NTD-targeting neutralizing antibodies.

    “It also contains five NTD mutations, of which L18F has been shown to interfere with the binding of NTD-targeting neutralizing antibodies 51 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] McCallum, M. et al. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell 184, 2332–2347.e16 (2021). source

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    Premisecitation
    § Gamma variant (P.1)

    By June 2021, the Gamma variant accounted for a high proportion of infections in several South American and Caribbean countries and 10% of US infections.

    “By June 2021, the Gamma variant accounted for a high proportion of infections in several South American and Caribbean countries 196 and 10% of US infections 33 .”
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    • cites [196] Mullen, J. L. et al. Outbreak.info https://outbreak.info/citation (2020).

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    • cites [33] Bolze, A. et al. Rapid displacement of SARS-CoV-2 variant B.1.1.7 by B.1.617.2 and P.1 in the United States. Preprint at medRxiv https://doi.org/10.1101/2021.06.20.21259195 (2021). source

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    Premisecitation
    § Gamma variant (P.1)

    The Gamma variant was estimated to result in virus levels 3-4 times higher than earlier variants and to be responsible for an estimated 1.1-fold to 1.8-fold higher mortality.

    “It was estimated to result in virus levels 3-4 times higher than earlier variants and to be responsible for an estimated 1.1-fold to 1.8-fold higher mortality 19 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Faria, N. R. et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science 372, 815–821 (2021). This paper presents an analysis showing that the Gamma variant is about twofold more transmissible than previous variants in Manaus, Brazil, and that it poses an increased risk of reinfection compared with previous variants. source

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    Premisecitation
    § Beta variant (B.1.351)

    Of the five FDA EUA-approved mAbs, bamlanivimab, etesevimab and casirivimab are largely inactive against B.1.351 whereas imdevimab and sotrovimab, which bind to the RBD core, retain neutralizing activity.

    “Of the five FDA EUA-approved mAbs, bamlanivimab, etesevimab and casirivimab are largely inactive against B.1.351whereas imdevimab and sotrovimab, which bind to the RBD core, retain neutralizing activity 104,109,117,175,204 (TABLe 1).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] Zhou, D. et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine induced sera. Cell 184, 2348–2361 (2021). source

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    • cites [109] Copin, R. et al. The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies. Cell 184, 3949–3961 (2021). source

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    • cites [117] Chen, R. E. et al. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat. Med. 27, 717–726 (2021). source

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    Interpretationcitation
    § Gamma variant (P.1)

    As the Gamma variant was associated with a surge of infections in a region of Brazil estimated to have achieved a high infection rate, it is suspected of being able to infect and cause illness in persons previously infected with other variants.

    “As the Gamma variant was associated with a surge of infections in a region of Brazil estimated to have achieved a high infection rate, it is suspected of being able to infect and cause illness in persons previously infected with other variants 19,29,30 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Faria, N. R. et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science 372, 815–821 (2021). This paper presents an analysis showing that the Gamma variant is about twofold more transmissible than previous variants in Manaus, Brazil, and that it poses an increased risk of reinfection compared with previous variants. source

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    • cites [29] Buss, L. F. et al. Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic. Science 371, 288–292 (2021). source

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    • cites [30] Sabino, E. C. et al. Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. Lancet 397, 452–455 (2021). source

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    Premisecitation
    § Variants of interest

    Of convalescent plasma samples, about 40% display 3-fold to 10-fold and 10% display >10-fold reduced Iota variant neutralizing activity.

    “Of convalescent plasma samples, about 40% display 3-fold to 10-fold and 10% display >10-fold reduced Iota variant neutralizing activity 166,235 .”
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    • cites [166] Zhang, L. et al. Comparison of 10 emerging SARS-CoV-2 variants: infectivity, animal tropism, and antibody neutralization. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-492659/v1 (2021). source

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    • cites [235] Zhou, H. et al. B.1.526 SARS-CoV-2 variants identified in new york city are neutralized by vaccine-elicited and therapeutic monoclonal antibodies. mBio https://doi.org/10.1128/mBio.01386-21 (2021). source

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    Interpretationreasoning
    § Conclusions and implications for COVID-19

    Although SARS-CoV-2 variants differ in their transmission rates, disease severity and risk of reinfection, there is no evidence that they are differentially affected by non-pharmaceutical public health measures such as social distancing and the use of personal protective equipment, or that they will respond differently to most antiviral therapies.

    “Although SARS-CoV-2 variants differ in their transmission rates, disease severity and risk of reinfection, there is no evidence that they are differentially affected by non-pharmaceutical public health measures such as social distancing and the use of personal protective equipment, or that they will respond differently to most antiviral therapies.”
    Quote in the paperSubstantial claim

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    Interpretationcitation
    § Conclusions and implications for COVID-19

    The mRNA vaccines appear to often elicit memory B cells that undergo somatic hypermutation, which should broaden the response to viruses with variant spike proteins.

    “In addition, the mRNA vaccines appear to often elicit memory B cells that undergo somatic hypermutation, which should broaden the response to viruses with variant spike proteins 239,240 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [239] Wang, Z. et al. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection. Nature 595, 426–431 (2021). source

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    • cites [240] Turner, J. S. et al. SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Nature https://doi.org/10.1038/s41586-021-03738-2 (2021). source

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    Premisecitation
    § Variants of interest

    The Zeta variant was common in Brazil in late 2020 and early 2021, but appears to be decreasing in prevalence.

    “The Zeta variant was common in Brazil in late 2020 and early 2021 (ref. 157 ), but appears to be decreasing in prevalence.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Ferrareze, P. A. G. et al. E484K as an innovative phylogenetic event for viral evolution: genomic analysis of the E484K spike mutation in SARS-CoV-2 lineages from Brazil. Infect. Genet. Evol. 93, 104941 (2021). source

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    Interpretationreasoning
    § Conclusions and implications for COVID-19

    The two most recently approved mAb preparations, casirivimab/imdevimab and sotrovimab, retain activity against all VOCs and VOIs, in part because imdevimab and sotrovimab target the RBD core whereas the most prevalent immune escape mutations are in the RBD RBM.

    “The two most recently approved mAb preparations, casirivimab/imdevimab and sotrovimab, retain activity against all VOCs and VOIs, in part because imdevimab and sotrovimab target the RBD core whereas the most prevalent immune escape mutations are in the RBD RBM.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § Variants of interest

    The Theta variant was first reported in March 2021 in the Philippines and contains 13 lineage-defining mutations including N501Y, E484K, P681H and the NTD deletion at positions 141-143.

    “The Theta variant was first reported in March 2021 in the Philippines.It contains 13 lineage-defining mutations including N501Y, E484K, P681H and the NTD deletion at positions 141-143 (refs 155,156 ).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Bascos, N. A. D., Mirano-Bascos, D. & Saloma, C. P. Structural analysis of spike protein mutations in an emergent SARS-CoV-2 variant from the Philippines. Preprint at bioRxiv https://doi.org/10.1101/2021.03.06.434059 (2021). source

      Not checked in the free run.

    • cites [156] Tablizo, F. A. et al. Genome sequencing and analysis of an emergent SARS-CoV-2 variant characterized by multiple spike protein mutations detected from the Central Visayas Region of the Philippines. Preprint at bioRxiv https://doi.org/10.1101/2021.03.03.21252812 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Variants of interest

    Of plasma samples from recipients of an mRNA vaccine, approximately 55% had 3-fold to 10-fold and 5% had >10-fold reduced neutralizing activity against the Kappa variant.

    “Of plasma samples from recipients of an mRNA vaccine, approximately 55% had 3-fold to 10-fold and 5% had >10-fold reduced neutralizing activity 100,118,122,234 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [100] Liu, C. et al. Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum. Cell 184, 4220–4336 (2021). source

      Not checked in the free run.

    • cites [118] Liu, J. et al. BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants. Nature 596, 273–275 (2021). source

      Not checked in the free run.

    • cites [122] Edara, V. V. et al. Infection and Vaccine-Induced Neutralizing-Antibody Responses to the SARS-CoV-2 B.1.617 Variants. N. Engl. J. Med. 385, 664–666 (2021) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Variants of interest

    The Iota variant was first identified in New York state; in June 2021, it had a prevalence of 5-10% in the USA but remained rare outside the USA.

    “The Iota variant was first identified in New York state.In June 2021, it had a prevalence of 5-10% in the USA but remained rare outside the USA 154 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Annavajhala, M. K. et al. A novel SARS-CoV-2 variant of concern, B.1.526, identified in New York. Preprint at bioRxiv https://doi.org/10.1101/2021.02.23.21252259 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Conclusions and implications for COVID-19

    The Beta and Gamma variants are each associated with increased transmissibility because of their ability to evade humoral immunity and cause reinfections.

    “The Beta and Gamma variants are each associated with increased transmissibility because of their ability to evade humoral immunity and cause reinfections.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Test-negative case-control study

    AY.1 and AY.2 are recently reported sub-lineages of the Delta variant that have developed additional mutations including the RBD mutation K417N.

    “AY.1 and AY.2 are recently reported sub-lineages of the Delta variant that have developed additional mutations including the RBD mutation K417N (ref. 196 ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Mullen, J. L. et al. Outbreak.info https://outbreak.info/citation (2020).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Variants of interest

    Of convalescent plasma samples, about 40% had 3-fold to 10-fold and 15% had >10-fold reduced neutralizing activity against the Kappa variant.

    “Of convalescent plasma samples, about 40% had 3-fold to 10-fold and 15% had >10-fold reduced neutralizing activity 100,122,234 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [100] Liu, C. et al. Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum. Cell 184, 4220–4336 (2021). source

      Not checked in the free run.

    • cites [122] Edara, V. V. et al. Infection and Vaccine-Induced Neutralizing-Antibody Responses to the SARS-CoV-2 B.1.617 Variants. N. Engl. J. Med. 385, 664–666 (2021) source

      Not checked in the free run.

    • cites [234] Hoffmann, M. et al. SARS-CoV-2 variant B.1.617 is resistant to bamlanivimab and evades antibodies induced by infection and vaccination. Cell Rep. 36, 109415 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Variants of interest

    The Lambda variant is highly prevalent in several South American countries and is associated with reduced susceptibility to the locally used CoronaVac vaccine.

    “It is highly prevalent in several South American countries and is associated with reduced susceptibility to the locally used CoronaVac vaccine 238 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [238] Acevedo, M. L. et al. Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda. Preprint at medRxiv https://doi.org/10.1101/2021.06.28.21259673 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Test-negative case-control study

    In case-control studies from the UK, the BNT162b vaccine was approximately 85% effective for the Delta variant whereas the AZD1222 vaccine was approximately 60% effective.

    “In case-control studies from the UK, the BNT162b vaccine was approximately 85% effective for the Delta variant whereas the AZD1222 vaccine was approximately 60% effective 232,233 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [232] Bernal, J. L. et al. Effectiveness of COVID-19 vaccines against the B.1.617.2 variant. N. Engl. J. Med. 385, 585–594 (2021). source

      Not checked in the free run.

    • cites [233] Sheikh, A., McMenamin, J., Taylor, B. & Robertson, C. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet 397, 2461–2462 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Variants of interest

    The Epsilon variant was estimated to be about 20% more transmissible than co-circulating lineages and to be associated with twofold higher upper-airway virus levels.

    “It was estimated to be about 20% more transmissible than co-circulating lineages and to be associated with twofold higher upper-airway virus levels 123,192 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [123] Deng, X. et al. Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant. Cell 184, 3426–3437.e8 (2021). source

      Not checked in the free run.

    • cites [192] Peng, J. et al. Estimation of secondary household attack rates for emergent spike L452R SARS-CoV-2 variants detected by genomic surveillance at a community-based testing site in San Francisco. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciab283 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Conclusions and implications for COVID-19

    The levels of neutralizing mAbs elicited by the mRNA vaccines has been high and in most persons are likely to be maintained for many months above the levels required for protection against even the most resistant circulating variants.

    “The levels of neutralizing mAbs elicited by the mRNA vaccines has been high and in most persons are likely to be maintained for many months above the levels required for protection against even the most resistant circulating variants 164,239,240 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [164] Greaney, A. J. et al. Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection. Sci. Transl Med. 13, eabi9915 (2021). source

      Not checked in the free run.

    • cites [239] Wang, Z. et al. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection. Nature 595, 426–431 (2021). source

      Not checked in the free run.

    • cites [240] Turner, J. S. et al. SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Nature https://doi.org/10.1038/s41586-021-03738-2 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Variants of interest

    The Eta variant is present at low levels in many countries, with Nigeria having the highest proportion of infections.

    “The Eta variant is present at low levels in many countries, with Nigeria having the highest proportion of infections 236 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [236] Ozer, E. A. et al. High prevalence of SARS-CoV-2 B.1.1.7 (UK variant) and the novel B.1.525 lineage in Oyo State, Nigeria. Preprint at medRxiv https://doi.org/10.1101/2021.04.09.21255206 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Delta variant (B.1.617.2)

    The Delta variant results in approximately 3-fold to 10-fold reduced susceptibility to 45% and >10-fold reduced susceptibility to 5% of convalescent plasma samples.

    “It results in approximately 3-fold to 10-fold reduced susceptibility to 45% and >10-fold reduced susceptibility to 5% of convalescent plasma samples 100,118,214,215,231 (fIg.5).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [100] Liu, C. et al. Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum. Cell 184, 4220–4336 (2021). source

      Not checked in the free run.

    • cites [118] Liu, J. et al. BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants. Nature 596, 273–275 (2021). source

      Not checked in the free run.

    • cites [214] Planas, D. et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature 596, 276–280 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Conclusions and implications for COVID-19

    The Alpha and Delta variants are each associated with increased transmissibility and greater disease severity because of immune evasion, and potentially because of higher virus levels resulting from the antagonism of innate immunity.

    “The Alpha and Delta variants are each associated with increased transmissibility and greater disease severity because of immune evasion, and potentially because of higher virus levels resulting from the antagonism of innate immunity.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § References

    The level of neutralizing antibodies elicited by a vaccine is strongly correlated with its efficacy.

    “This paper presents a meta-analysis showing that the level of neutralizing antibodies elicited by a vaccine is strongly correlated with its efficacy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Khoury, D. S. et al.

      Not checked in the free run.

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

    Premisecitation
    § References

    The beta variant was frequently responsible for reinfections in South Africa.

    “This post-hoc analysis of a clinical trial shows that the beta variant was frequently responsible for reinfections in South Africa.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shinde, V. et al.

      Not checked in the free run.

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

    Premisecitation
    § References

    SARS-CoV-2 neutralizing monoclonal antibody Fc-effector functions are likely important for protection in an animal model.

    “This study demonstrates the likely importance of SARS-CoV-2 neutralizing mAb Fc-effector functions in an animal model.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schäfer, A. et al.

      Not checked in the free run.

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

    Premisecitation
    § References

    AZD1222 appeared ineffective at preventing infection with the beta variant.

    “This post-hoc analysis of a clinical trial shows that AZD1222 appeared ineffective at preventing infection with the beta variant.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Madhi, S. A. et al.

      Not checked in the free run.

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

    Premisecitation
    § References

    Plasma from persons infected with the beta variant can usually neutralize pre-variant viruses.

    “This experimental study shows that the plasma from persons infected with the beta variant can usually neutralize pre-variant viruses.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Moyo-Gwete, T. et al.

      Not checked in the free run.

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

    Premisecitation
    § References

    In contrast to earlier SARS-CoV-2 variants, the alpha variant may owe its increased transmissibility and virulence to its antagonism of cellular innate immunity.

    “This systems biology study shows that in contrast to earlier SARS-CoV-2 variants, the alpha variant may owe its increased transmissibility and virulence to its antagonism of cellular innate immunity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Thorne, L. G. et al.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § References

    A high proportion of neutralizing antibodies elicited by SARS-CoV-2 infection bind poorly to epitopes containing the spike RBD mutation E484K.

    “This paper demonstrates that a high proportion of neutralizing antibodies elicited by SARS-CoV-2 infection will bind poorly to epitopes containing the spike RBD mutation E484K.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Greaney, A. J. et al.

      Not checked in the free run.

40 of 40

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Cites

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Research works printed but not linked: 1

  1. Edara, V. V., Hudson, W. H., Xie, X., Ahmed, R. & Suthar, M. S. Neutralizing antibodies against SARS-CoV-2 variants after infection and vaccination. JAMA 325, 1896–1898 (2021). · DOI · Paper page

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Sorted by citations

Authors
Tao, K., Tzou, P. L., Nouhin, J., Gupta, R. K., de Oliveira, T., Kosakovsky Pond, S. L., Fera, D., & Shafer, R. W.
Affiliations
  • Stanford Medicine (US)
  • University of Cambridge (GB)
  • Swarthmore College (US)
Corresponding author
Shafer, Robert W.
ORCID
Venue
Nature Reviews Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-09-17
Volume
22
Issue
12
Pages
757-773
ISSN
  • 1471-0056 (ISSN-L)
  • 1471-0064
DOI
10.1038/s41576-021-00408-x
PMC
PMC8447121
OpenAlex
W3199849883
Cited by
1,009
References
281
Citations by year
2026: 43 · 2025: 90 · 2024: 170 · 2023: 251 · 2022: 415 · 2021: 38 · 2020: 1
FWCI
25.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Works - Scholarship, Research, & Creative Expression (Swarthmore College) (submittedVersion)
Funders
  • University of Washington
  • National Institute of Allergy and Infectious Diseases (R24AI136618)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Physical Sciences › Mathematics › Modeling and Simulation › COVID-19 epidemiological studies
Keywords
SARS-CoV-2, COVID-19 variants of concern, spike protein mutations, Alpha variant, Beta variant, Gamma variant, Delta variant, virus transmission, reinfection risk, neutralizing antibodies, vaccine effectiveness, herd immunity, viral replication fitness
MeSH terms
COVID-19, SARS-CoV-2, Epitopes, Biological Evolution, Humans, Mutation, Spike Glycoprotein, Coronavirus

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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.

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