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Cited by 1,045SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections Studiesvaccines and immunoinformatics approaches

mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant

Open access
Garcia-Beltran, Wilfredo F., St. Denis, Kerri J., Hoelzemer, Angelique, Lam, Evan C., Nitido, Adam D., Sheehan, Maegan L., Berrios, Cristhian, Ofoman, Onosereme +10 more·2022·Cell
DOI 10.1016/j.cell.2021.12.033PMC PMC8687472

Published version of a preprint

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Abstract

Recent surveillance has revealed the emergence of the SARS-CoV-2 Omicron variant (BA.1/B.1.1.529) harboring up to 36 mutations in spike protein, the target of vaccine-induced neutralizing antibodies. Given its potential to escape vaccine-induced humoral immunity, we measured neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40 Ad26.COV2.S vaccine recipients against wild type, Delta, and Omicron SARS-CoV-2 pseudoviruses. We included individuals that were vaccinated recently (<3 months), distantly (6-12 months), or recently boosted, and accounted for prior SARS-CoV-2 infection. Remarkably, neutralization of Omicron was undetectable in most vaccinated individuals. However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron only 4-6-fold lower than wild type, suggesting that boosters enhance the cross-reactivity of neutralizing antibody responses. In addition, we find Omicron pseudovirus is significantly more infectious than any other variant tested. Overall, this study highlights the importance of boosters to broaden neutralizing antibody responses against highly divergent SARS-CoV-2 variants.

AI snapshot

Written from the paper’s full text.

TL;DR

Sera from 239 recipients of mRNA-1273, BNT162b2, or Ad26.COV2.S showed substantial escape of SARS-CoV-2 Omicron pseudovirus from primary vaccine-induced neutralization, but mRNA boosters restored potent cross-neutralizing activity. Omicron pseudovirus also entered cells via ACE2 and was about 4-fold more infectious than wild type and 2-fold more infectious than Delta in vitro.

Key findings

  • Omicron neutralization was undetectable in most vaccinated individuals after primary series; among recently vaccinated mRNA recipients, GMNT decreased 43-fold for mRNA-1273 and 122-fold for BNT162b versus wild type, with complete loss in >50% of individuals.
  • Recently boosted mRNA vaccine recipients showed potent Omicron neutralization only 4–6-fold lower than wild type: GMNT decrease was 6-fold for mRNA-1273, 4-fold for BNT162b, and 13-fold for Ad26.COV2.S.
  • Boosters increased Omicron cross-neutralization versus two-dose primary series: GMNT increase of 19-fold for mRNA-1273 and 27-fold for BNT162b; wild type neutralization correlated strongly with Omicron cross-neutralization in boosted individuals (R² = 0.56, slope = 0.94, p < 0.0001) but not in primary-series individuals (R² = 0.03, slope = 0.05, p = 0.16).
  • Omicron pseudovirus remained ACE2-dependent and was 4-fold more infectious than wild type and 2-fold more infectious than Delta; anti-spike antibody levels predicted neutralization with ROC AUC 0.97 for wild type, 0.91 for Delta, and 0.84 for Omicron.

Methods

  • Cross-sectional cohort of 239 COVID-19 vaccinees (88 mRNA-1273, 111 BNT162b, 40 Ad26.COV2.S) who were healthcare workers and/or community dwellers in Boston or Chelsea, Massachusetts; median age 38 years (range 18–78), 63% female.
  • Subgroups included infection-naive recent primary vaccination (<3 months), distant primary vaccination (6–12 months), distant vaccination plus prior SARS-CoV-2 infection, and infection-naive mRNA booster vaccination within the last 3 months.
  • Sera were tested in a high-throughput luminescence-based pseudovirus neutralization assay against wild type, Delta, and Omicron SARS-CoV-2 pseudoviruses; pNT50 values were converted to WHO IU/mL. Anti-spike and anti-nucleocapsid antibodies were measured with Roche Elecsys assays, and infectivity was assessed in 293T-ACE2 versus parental 293T cells.

Limitations

  • The paper states that Omicron spike mutations may cause Omicron pseudovirus to behave differently from previously tested variants, although prior reports showed similar neutralization loss with intact Omicron coronavirus.
  • The paper states that natural respiratory tract target cells may express alternative receptors or attachment factors not modeled in 293T-ACE2 cells, and that the cross-sectional design limits estimation of changes in neutralization titers over time within individuals.
  • The paper states that it did not assess other antibody-mediated functions such as complement deposition, antibody-dependent cellular cytotoxicity, or antibody-dependent cellular phagocytosis, nor vaccine-elicited T cell and NK cell responses; the text also notes the Omicron spike used lacked R346K and that prior infection could not be distinguished from asymptomatic breakthrough infection.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2021.12.033

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 24 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Wild type neutralization of boosted individuals correlated strongly with Delta (R2 = 0.68; slope = 1.00; p < 0.0001) and Omicron (R2 = 0.56; slope = 0.94; p < 0.0001) variant cross-neutralization.

    “In contrast, wild type neutralization of boosted individuals correlated strongly with Delta (R2 = 0.68; slope = 1.00; p < 0.0001) and Omicron (R2 = 0.56; slope = 0.94; p < 0.0001) variant cross-neutralization.”
    Quote in the paperSubstantial claim
  • Findingown data

    Prior history of infection was associated with high levels of wild type neutralization titers even in distantly vaccinated individuals, particularly in Ad26.COV2.S vaccinees (GMNT 904 IU/mL for mRNA-1273; 947 IU/mL for BNT162b; and 603 IU/mL for Ad26.COV2.S).

    “Prior history of infection was associated with high levels of wild type neutralization titers even in distantly vaccinated individuals, particularly in Ad26.COV2.S vaccinees (GMNT 904 IU/mL for mRNA-1273; 947 IU/mL for BNT162b; and 603 IU/mL for Ad26.COV2.S)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Omicron neutralization was dramatically decreased among all subgroups.

    “In contrast, Omicron neutralization was dramatically decreased among all subgroups, including recently vaccinated mRNA-1273 and BNT162b recipients”
    Quote in the paperSubstantial claim
  • Findingcitation

    Recently vaccinated mRNA-1273 or BNT162b recipients achieved substantially higher wild type neutralization titers than Ad26.COV2.S vaccinees (GMNT 1,362 IU/mL for mRNA-1273, 2,402 IU/mL for BNT162b, and 42 IU/mL for Ad26.COV2.S).

    “In line with previous studies (Naranbhai et al., 2021a, 2021b), individuals that were recently vaccinated with mRNA-1273 or BNT162b achieved substantially higher wild type neutralization titers than Ad26.COV2.S vaccinees, with geometric mean neutralization titers (GMNT) of 1,362 IU/mL for mRNA-1273, 2,402 IU/mL for BNT162b, and 42 IU/mL for Ad26.COV2.S”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Naranbhai et al., 2021a

      Not checked in the free run.

    • cites Naranbhai et al., 2021b

      Not checked in the free run.

  • Findingown data

    Omicron pseudovirus remains dependent on ACE2 for host cell entry.

    “None of the pseudoviruses tested infected 293T cells in the absence of ACE2 protein, confirming that like other SARS-CoV-2 strains, Omicron remains dependent on ACE2 for host cell entry”
    Quote in the paperNot a substantial claim
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Gamma variant exhibited similar infectivity to wild type, Beta was less infectious, and Delta was nearly 2-fold more infectious.

    “Comparison of the linear regressions of each pseudovirus to wild type over the entire range revealed that, whereas Gamma variant exhibited similar infectivity to wild type, Beta was less infectious, and Delta was nearly 2-fold more infectious.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Delta neutralization became undetectable in most individuals vaccinated >6 months before blood draw, but was detectable and only modestly decreased in recently vaccinated, previously infected, and recently boosted vaccinees.

    “While Delta neutralization became undetectable in most individuals vaccinated >6 months before blood draw, Delta neutralization was detectable and only modestly decreased in recently vaccinated, previously infected, and recently boosted vaccinees”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wild type neutralization titers from individuals who received their primary series correlated weakly to Delta variant cross-neutralization (R2 = 0.35; slope = 0.44; p < 0.0001), and did not correlate with Omicron variant cross-neutralization (R2 = 0.03; slope = 0.05; p = 0.16).

    “Interestingly, we found that wild type neutralization titers from individuals who received their primary series correlated weakly to Delta variant cross-neutralization (R2 = 0.35; slope = 0.44; p < 0.0001), and did not correlate with Omicron variant cross-neutralization (R2 = 0.03; slope = 0.05; p = 0.16).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Previously infected vaccinees had a substantial decrease in Omicron neutralization titer (GMNT decrease of 9-fold for mRNA-1273, 12-fold for BNT162b, and 17-fold for Ad26.COV2.S), but most retained detectable neutralization.

    “Previously infected vaccinees also had a substantial decrease in Omicron neutralization titer (GMNT decrease of 9-fold for mRNA-1273, 12-fold for BNT162b, and 17-fold for Ad26.COV2.S), but most retained detectable neutralization”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Optimal cut-offs for anti-spike antibody levels predicting positive neutralization were 711 U/mL for wild type (88.4% Se, 96.7% Sp), 1,591 U/mL for Delta (88.4% Se, 83.8% Sp), and 10,300 U/mL for Omicron (67.2% Se, 90.6% Sp).

    “for wild type, optimal cut-off of 711 U/mL achieved 88.4% Se and 96.7% Sp; for Delta, optimal cut-off of 1,591 U/mL achieved 88.4% Se and 83.8% Sp; and for Omicron variant, optimal cut-off of 10,300 achieved 67.2% Se and 90.6% Sp”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Roche Elecsys anti-SARS-CoV-2 spike semi-quantitative immunoassay measures anti-spike antibody levels.

  • May combine two claims.

    Findingown data

    Recently vaccinated mRNA-1273 and BNT162b recipients demonstrated a complete loss of Omicron neutralization in >50% of individuals and GMNT decrease of 43-fold for mRNA-1273 and 122-fold for BNT162b.

    “which demonstrated a complete loss of neutralization in >50% of individuals and GMNT decrease of 43-fold for mRNA-1273 and 122-fold for BNT162b”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The difference in neutralization of Delta pseudoviruses between three-dose and two-dose vaccinees was similar for mRNA-1273 (GMNT increase of 3-fold) but increased in BNT162b vaccinees (GMNT increase of 9-fold).

    “The difference in neutralization of Delta pseudoviruses between three-dose and two-dose vaccinees was similar for mRNA-1273 (GMNT increase of 3-fold) but increased in BNT162b vaccinees (GMNT increase of 9-fold).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Omicron pseudovirus is more infectious than any other variant tested, being nearly 4-fold more infectious than wild-type and 2-fold more infectious than Delta pseudovirus.

    “In addition, we find Omicron pseudovirus is more infectious than any other variant tested.”
    • Also stated in: § Omicron retains ACE2 usage and exhibits higher infectivity than other SARS-CoV-2 variants in vitro · plain
      “Strikingly, Omicron was 4-fold more infectious than wild type and 2-fold more infectious than Delta.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ROC AUC for anti-spike antibody levels predicting positive neutralization was 0.97 for wild type, 0.91 for Delta, and 0.84 for Omicron.

    “Area under curve (AUC) for wild type was 0.97, Delta was 0.91, and Omicron was 0.84”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Roche Elecsys anti-SARS-CoV-2 spike semi-quantitative immunoassay measures anti-spike antibody levels.

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

    Findingnone given

    The Delta strain exhibited 2-fold increased pseudovirus infectivity relative to wild type.

    “In contrast, the now globally dominant Delta strain exhibited 2-fold increased pseudovirus infectivity relative to wild type, which may have contributed to its rapid spread.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Mutations within the RBD mediate escape from vaccine-induced neutralizing antibodies.

    “Studies of previous SARS-CoV-2 variants have demonstrated that mutations within the receptor binding domain (RBD) mediate escape from vaccine-induced neutralizing antibodies (Cele et al., 2021a; Garcia-Beltran et al., 2021a; Zhou et al., 2021)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cele et al., 2021a

      Not checked in the free run.

    • cites Garcia-Beltran et al., 2021a

      Not checked in the free run.

    • cites Zhou et al., 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutralizing antibody responses and vaccine effectiveness vary by vaccine agent, decrease with increased time post vaccination, and are negatively impacted by emerging variants.

    “However, it has now been shown that neutralizing antibody responses and vaccine effectiveness vary by vaccine agent, decrease with increased time post vaccination, and are negatively impacted by emerging variants (Bajema et al., 2021; Bar-On et al., 2021; Cromer et al., 2021; Khoury et al., 2021; Lopez Bernal et al., 2021; Naranbhai et al., 2021a; Tregoning et al., 2021).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bajema et al., 2021

      Not checked in the free run.

    • cites Bar-On et al., 2021

      Not checked in the free run.

    • cites Cromer et al., 2021

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Two-dose mRNA-based vaccines are effective at inducing neutralizing immunity to SARS-CoV-2 wild type and Delta variants but suboptimal for inducing neutralizing responses to the Omicron variant.

    “Taken together, our results indicate that two-dose mRNA-based vaccines are effective at inducing neutralizing immunity to SARS-CoV-2 wild type and Delta variants but suboptimal for inducing neutralizing responses to the Omicron variant.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Omicron pseudovirus with 34 mutations is representative of circulating Omicron.

  • May combine two claims.

    Interpretationown data

    Boosting increases the breadth of humoral immunity and cross-reactivity against highly mutated SARS-CoV-2 variants such as Omicron.

    “This indicates that in addition to inducing higher neutralization titers against wild type SARS-CoV-2, boosting increases the breadth of humoral immunity and cross-reactivity against highly mutated SARS-CoV-2 variants such as Omicron.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    SARS-CoV-2 Omicron variant evades vaccine-induced neutralizing immunity under current vaccine regimens and is more infectious than previous variants.

    “Together, our results highlight that SARS-CoV-2 Omicron variant evades vaccine-induced neutralizing immunity under current vaccine regimens and is more infectious than previous variants.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Omicron pseudovirus with 34 mutations is representative of circulating Omicron.

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

    Premisecitation

    Beta (B.1.351) and Gamma (P.1) harbor mutations in residues K417, E484, and N501 that potently diminish vaccine-induced neutralization.

    “For example, Beta (B.1.351) and Gamma (P.1) harbor mutations in residues K417, E484, and N501 that potently diminish vaccine-induced neutralization (Garcia-Beltran et al., 2021a)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Garcia-Beltran et al., 2021a

      Not checked in the free run.

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

    Study design and conductnone given

    Use of human samples was approved by Partners Institutional Review Board (protocol 2020P002274).

    “Use of human samples was approved by Partners Institutional Review Board (protocol 2020P002274).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The study accounted for prior SARS-CoV-2 infection.

    “We included individuals that were vaccinated recently (<3 months), distantly (6-12 months), or recently boosted, and accounted for prior SARS-CoV-2 infection.”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    Delta's increased pseudovirus infectivity may have contributed to its rapid spread.

    “In contrast, the now globally dominant Delta strain exhibited 2-fold increased pseudovirus infectivity relative to wild type, which may have contributed to its rapid spread.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study did not assess other antibody-mediated functions such as complement deposition, antibody-dependent cellular cytotoxicity, or antibody-dependent cellular phagocytosis.

    “Furthermore, we did not assess other antibody-mediated functions such as complement deposition, antibody-dependent cellular cytotoxicity, or antibody-dependent cellular phagocytosis, which may contribute to protection even in the absence of neutralizing antibodies.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    All plasmid DNA utilized in the study was verified by whole-plasmid deep sequencing to confirm the presence of only the intended mutations.

    “All resulting plasmid DNA utilized in the study was verified by whole-plasmid deep sequencing (Illumina) to confirm the presence of only the intended mutations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Recipients of Ad26.COV2.S vaccines may benefit from additional mRNA vaccine doses, with the potential to further raise titers and broaden their neutralizing activity.

    “Our results would suggest that these recipients of Ad26.COV2.S vaccines may benefit from additional mRNA vaccine doses with the potential to further raise titers and broaden their neutralizing activity.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Natural target cells in the respiratory tract may express alternative receptors or attachment factors that facilitate infection and are not adequately modeled in the study system.

    “In addition, while we confirmed that ACE2 expression is required for infection of 293T cells, natural target cells in the respiratory tract may express alternative receptors or attachment factors that facilitate infection and are not adequately modeled in our system.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Omicron breakthrough infections may result in attenuated disease severity in vaccinees due to cellular and innate immunity.

    “Of note, despite escape from humoral immunity, Omicron breakthrough infections may result in attenuated disease severity in vaccinees due to cellular and innate immunity.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Other antibody-mediated functions (complement deposition, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis) may contribute to protection even in the absence of neutralizing antibodies.

    “Furthermore, we did not assess other antibody-mediated functions such as complement deposition, antibody-dependent cellular cytotoxicity, or antibody-dependent cellular phagocytosis, which may contribute to protection even in the absence of neutralizing antibodies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Mutations in Omicron are structurally focused at the top of the spike, in regions accessible to antibodies, raising the likelihood of immune evasion.

    “These mutations are structurally focused at the top of the spike, in regions accessible to antibodies, raising the likelihood of immune evasion (Figure 1C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Omicron's escape from vaccine-induced immunity and increased infectivity raise the potential for increased transmissibility.

    “Taken together, we demonstrate that Omicron drastically escapes vaccine-induced immunity after primary vaccination series with mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech) or Ad26.COV2.S (Johnson & Johnson/Janssen) and exhibits increased infectivity in vitro, raising the potential for increased transmissibility.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Neutralizing antibody responses raised by mRNA COVID-19 vaccines decay with a half-life of 69-173 days.

    “Several reports have measured the decay of neutralizing antibody responses raised by mRNA COVID-19 vaccines with a half-life of 69-173 days (Doria-Rose et al., 2021; Levin et al., 2021).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Doria-Rose et al., 2021 source

      Not checked in the free run.

    • cites Levin et al., 2021 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    mRNA vaccine boosters appear to enable cross-neutralizing responses against Omicron, either by further affinity maturation of existing antibodies or targeting of new epitopes shared among variants.

    “Strikingly, however, mRNA vaccine boosters appear to enable cross-neutralizing responses against Omicron, either by further affinity maturation of existing antibodies or targeting of new epitopes shared among variants.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Omicron pseudovirus with 34 mutations is representative of circulating Omicron.

  • May combine two claims.

    Study design and conductreasoning

    The cohort was cross-sectional and not longitudinal, which limits the ability to estimate changes in neutralization titers over time across single individuals.

    “In addition, our cohort was cross-sectional and not longitudinal, which limits our ability to estimate changes in neutralization titers over time across single individuals.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    NT50 values were converted to WHO International Units using the Human SARS-CoV-2 Serology Standard calibrated to the WHO SARS-CoV-2 Serology International Standard (20/136).

    “NT50 values were converted to WHO International Units using the Human SARS-CoV-2 Serology Standard (Lot #COVID-NS01097) obtained from NCI-Frederick National Laboratory for cancer research which was calibrated to the WHO SARS-CoV-2 Serology International Standard (20/136).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Confirmation of ACE2 expression in 293T-ACE2 cells was done via flow cytometry.

    “Confirmation of ACE2 expression in 293T-ACE2 cells was done via flow cytometry.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Omicron variant, harboring substantially more mutations than prior variants, efficiently escapes humoral immunity induced by primary vaccination.

    “Consistent with this framework, we found that the Omicron variant, harboring substantially more mutations than prior variants, efficiently escapes humoral immunity induced by primary vaccination.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The response to vaccination is polyclonal.
    • Rests on an assumption: The Omicron pseudovirus with 34 mutations is representative of circulating Omicron.
33 of 33

  • The authors state this as an assumption.

    The Omicron variant would be significantly more resistant to neutralization by vaccinee sera.

    “Given the 15 mutations present in the RBD of Omicron, which overlap the three sites mutated in Gamma and Beta (K417, E484, N501), as well as prior work done to understand the potential for antibody escape (Schmidt et al., 2021), it was anticipated that this variant would be significantly more resistant to neutralization by vaccinee sera. To experimentally validate this assumption”

  • The authors state this as an assumption.

    The response to vaccination is polyclonal.

    “As stated in our previous study, given the assumption of a polyclonal response to vaccination, we would have initially anticipated that small numbers of variations in spike protein would have only modest effects on recognition by the immune system (Garcia-Beltran et al., 2021a).”

  • The paper relies on this without support.

    The Omicron pseudovirus with 34 mutations is representative of circulating Omicron.

    “we generated pseudovirus with Omicron spike incorporating 34 distinct mutations (including three deletions and one insertion) relative to the Wuhan spike. Importantly, our spike did not contain R346K, which has been observed at relatively low frequency (<10%) within the Omicron lineage”

  • The paper relies on this without support.

    The Roche Elecsys anti-SARS-CoV-2 spike semi-quantitative immunoassay measures anti-spike antibody levels.

    “we correlated the neutralization signal obtained by our high-throughput assay to measurements made by the Roche Elecsys® anti-SARS-CoV-2 spike semi-quantitative immunoassay in the clinical laboratory.”

  • The paper relies on this without support.

    Omicron is spreading rapidly globally.

    “In support of the rapid spread of Omicron globally, our studies suggest that Omicron spike may exhibit increased infectivity.”

  • The paper relies on this without support.

    Neutralization is the leading correlate of protection from infection.

    “However, neutralization remains the leading correlate of protection from infection, and this study demonstrates that receiving a third dose of an mRNA-based vaccine effectively yields a potent cross-neutralizing response against SARS-CoV-2 Omicron, likely through increasing breadth and cross-reactivity of neutralizing antibodies.”
6 of 6

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?

  • Owing to reduced efficacy of LNP-mRNA vaccines over time and the emergence of highly transmissible SARS-CoV-2 variants such as delta and omicron, the effects of booster vaccination are being examined.

    “Owing to the reduced efficacy of LNP-mRNA vaccines over time and the emergence of highly transmissible SARS-CoV-2 variants such as delta (B.1.617.2) and omicron (B.1.1.529),109,110 the effects of booster vaccination are being examined.”

    From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [110]

  • In multiple trials, neutralizing antibody titers after the second dose of mRNA-based vaccines were highly reduced for omicron compared with delta and especially compared with the wild-type variant, while the third dose significantly improved antibody neutralization titers.

    “In all cases, neutralizing antibody titers after the second dose of mRNA-based vaccines were highly reduced for omicron (B.1.1.529) compared with delta (B.1.617.2) and especially compared with the wild-type variant, while the third dose significantly improved antibody neutralization titers.110,112,113”

    From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [110]

  • Vaccines that elicited lower neutralizing titres are expected to fare worse against B.1.1.529.

    “Vaccines that elicited lower neutralizing titres 35,42 are expected to fare worse against B.1.1.529.”

    From Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2 (2022) · cites this paper as [35]

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Authors
Garcia-Beltran, W. F., St. Denis, K. J., Hoelzemer, A., Lam, E. C., Nitido, A. D., Sheehan, M. L., Berrios, C., Ofoman, O., Chang, C. C., Hauser, B. M., Feldman, J., Roederer, A. L., Gregory, D. J., Poznansky, M. C., Schmidt, A. G., Iafrate, A. J., Naranbhai, V., & Balazs, A. B.
Affiliations
  • Ragon Institute of MGH, MIT and Harvard (US)
  • Harvard University (US)
  • Massachusetts General Hospital (US)
  • Centre for the AIDS Programme of Research in South Africa (ZA)
Corresponding author
Balazs, Alejandro B.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2022-02
Volume
185
Issue
3
Pages
457-466.e4
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2021.12.033
PMC
PMC8687472
OpenAlex
W4225982774
Semantic Scholar
e9410571cb7af9dd15539ab83125e96984bce3c8
Cited by
1,045
References
46
Citations by year
2026: 21 · 2025: 54 · 2024: 110 · 2023: 225 · 2022: 621 · 2021: 14
FWCI
123.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • medRxiv (acceptedVersion, cc-by-nc)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc)
Funders
  • Deutsches Zentrum für Infektionsforschung (TTU01.709)
  • Massachusetts Consortium on Pathogen Readiness
  • National Institutes of Health (NIH-R01)
  • National Institute on Drug Abuse (DP2DA040254)
  • National Institute of General Medical Sciences (T32GM008313, T32GM007753)
  • National Institute of Allergy and Infectious Diseases (F30AI160908, R01AI146779, T32AI007245)
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
COVID-19 booster vaccination, mRNA vaccines, Omicron variant, neutralizing antibodies, spike protein mutations, cross-reactivity, mRNA-1273, BNT162b2, Ad26.COV2-S, Delta variant, pseudovirus infection, prior SARS-CoV-2 infection

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 2026-10-10.

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

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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