Cited by 367SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections StudiesCOVID-19 Clinical Research Studies

Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine–elicited human sera

Open access
Muik, Alexander, Lui, Bonny Gaby, Wallisch, Ann-Kathrin, Bacher, Maren, Mühl, Julia, Reinholz, Jonas, Ozhelvaci, Orkun, Beckmann, Nina +9 more·2022·Science

Published version of a preprint

Abstract

The globally circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern Omicron (B.1.1.529) has a large number of mutations, especially in the spike protein, indicating that recognition by neutralizing antibodies may be compromised. We tested Wuhan (Wuhan-Hu-1 reference strain), Beta (B.1.351), Delta (B.1.617.2), or Omicron pseudoviruses with sera of 51 participants who received two or three doses of the messenger RNA (mRNA)–based COVID-19 vaccine BNT162b2. After two doses, Omicron-neutralizing titers were reduced >22-fold compared with Wuhan-neutralizing titers. One month after the third vaccine dose, Omicron-neutralizing titers were increased 23-fold relative to their levels after two doses and were similar to levels of Wuhan-neutralizing titers after two doses. The requirement of a third vaccine dose to effectively neutralize Omicron was confirmed with sera from a subset of participants using live SARS-CoV-2. These data suggest that three doses of the mRNA vaccine BNT162b2 may protect against Omicron-mediated COVID-19.

AI snapshot

Written from the paper’s full text.

TL;DR

Two doses of BNT162b2 elicited substantially reduced neutralizing activity against SARS-CoV-2 Omicron, while a third dose boosted Omicron-neutralizing titers to levels comparable to Wuhan-neutralizing titers after two doses in the pseudovirus assay. The data suggest that three BNT162b2 doses may protect against Omicron-mediated COVID-19.

Key findings

  • After two BNT162b2 doses, Omicron pseudovirus-neutralizing GMTs were 7 versus 160 for Wuhan, a 22.8-fold reduction; 20 of 32 sera had no detectable Omicron neutralization. Beta and Delta GMTs were 24 and 73, corresponding to 6.7- and 2.2-fold reductions versus Wuhan.
  • One month after a third dose, Omicron pseudovirus-neutralizing GMTs rose to 164, a 23.4-fold increase over post-dose-two levels and similar to Wuhan GMTs after two doses (160); 29 of 30 sera neutralized Omicron. Beta, Delta, and Wuhan GMTs after dose three were 279, 413, and 368.
  • In live SARS-CoV-2 assays, two doses gave Omicron GMTs of 6 versus 368 for Wuhan, a 61.3-fold reduction, with 17 of 25 sera showing no detectable Omicron neutralization. After a third dose, Omicron GMTs increased 17.6-fold to 106 and remained 3.4-fold lower than Wuhan GMTs after two doses; 27 of 28 sera neutralized live Omicron.
  • Among 244 HLA class I–restricted Wuhan S epitopes from IEDB, 85.3% (208) were unaffected at the amino acid sequence level in Omicron.

Methods

  • Pseudovirus-neutralization tests used VSV-SARS-CoV-2-S pseudoviruses bearing Wuhan, Omicron, Beta, or Delta S proteins with sera from 32 BNT162-01 participants 21 days after dose two and 30 BNT162-14/BNT162-17 participants 1 month after dose three; 11 participants were analyzed longitudinally.
  • Live SARS-CoV-2 neutralization tests used Wuhan and Omicron virus with sera from 32 and 25 participants after dose two, respectively, and 7 and 28 participants after dose three, respectively. Specimens were tested in duplicate and geometric mean 50% neutralizing titers were calculated.
  • T cell analysis assessed 244 HLA class I–restricted S epitopes reported in IEDB for conservation in Omicron.

Limitations

  • The paper states that serum panels came from different clinical trials with limited sample size, and the interval between second and third doses was not consistent across participants.
  • The paper states that future analyses are needed to evaluate antibody persistence, and notes that a longer interval (>42 days) between first and second doses may improve immunogenicity but was not evaluated here.
  • Evident from the text: the study reports neutralization titers, not clinical efficacy; live Omicron testing used smaller subsets than pseudovirus testing; and durability beyond 1 month after the third dose was not assessed.

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

Integrity signals

Registry

Crossref · 10.1126/science.abn7591

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 23 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    One month after the third BNT162b2 dose, live Omicron neutralizing GMTs were reduced 3.4-fold compared with Wuhan reference at 21 days after two doses (GMT 106 vs 368).

    “and were reduced 3.4-fold compared with those against the Wuhan reference at 21 days after two doses of BNT162b2 (GMT of 106 versus 368).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Sera from different clinical trials are comparable for neutralizing antibody analysis.
  • Findingown data

    Twenty-nine of 30 serum specimens after the third dose were capable of neutralizing Omicron pseudovirus.

    “Twenty-nine of 30 serum specimens were capable of neutralizing the Omicron pseudovirus (table S3).”
    Quote in the paperSubstantial claim
  • Findingown data

    After two doses of BNT162b2, geometric mean neutralization titers (GMTs) against Omicron pseudovirus were reduced 22.8-fold compared with Wuhan reference pseudovirus (GMT 7 vs 160).

    “After two doses of BNT162b2, geometric mean neutralization titers (GMTs) against Omicron pseudovirus were reduced 22.8-fold compared with those for the Wuhan reference pseudovirus (Fig. 1; GMT of 7 versus 160).”
    Quote in the paperSubstantial claim
  • Findingown data

    One month after the third BNT162b2 dose, neutralizing GMTs against Omicron pseudovirus increased 23.4-fold relative to their levels 21 days after the second dose (GMT 164 vs 7).

    “One month after the third BNT162b2 dose, neutralizing GMTs against the Omicron variant pseudovirus increased 23.4-fold relative to their levels 21 days after the second dose (GMT of 164 versus 7)”
    Quote in the paperSubstantial claim
  • Findingown data

    Twenty of 32 immune serum specimens after two doses displayed no detectable neutralizing activity against Omicron pseudovirus.

    “Twenty of 32 immune serum specimens displayed no detectable neutralizing activity against Omicron (table S2).”
    Quote in the paperSubstantial claim
  • May combine two claims. 9
  • Classified as probably not a substantial claim. 7
  • May combine two claims.

    Findingown data

    The majority of sera after two doses neutralized Beta and Delta pseudoviruses with GMTs of 24 and 73, respectively, corresponding to 6.7- and 2.2-fold reductions compared with Wuhan pseudovirus.

    “By contrast, the majority of sera neutralized Beta and Delta pseudoviruses with GMTs of 24 and 73, respectively. This corresponds to 6.7- and 2.2-fold reductions in neutralization activity compared with the Wuhan pseudovirus”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    The third dose of BNT162b2 resulted in a significant increase in neutralizing titers against Wuhan pseudovirus (GMT 320) and a 25.8-fold increase in neutralizing titers against Omicron 1 month after dose three compared with 21 days after dose two (GMT 181 vs 7).

    “the third dose of BNT162b2 resulted in a significant increase in neutralizing titers against the Wuhan pseudovirus (GMT of 320) and a 25.8-fold increase in neutralizing titers against Omicron 1 month after dose three compared with 21 days after dose two (GMT of 181 versus 7).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    Before receiving the third dose (median 256 days after dose two), neutralizing titers against Wuhan pseudovirus were considerably reduced (GMT 13), whereas Omicron-specific titers were below the limit of detection.

    “Before receiving the third dose of BNT162b2 (at a median 256 days after dose two), neutralizing titers against the Wuhan pseudovirus were considerably reduced (GMT of 13), whereas the Omicron-specific titers were below the limit of detection.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    The third dose of BNT162b2 increased neutralizing activity against Beta, Delta, and Wuhan pseudoviruses, with GMTs of 279, 413, and 368, respectively.

    “The third dose of BNT162b2 also increased neutralizing activity against Beta, Delta, and Wuhan pseudoviruses, with GMTs of 279, 413, and 368, respectively.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim.

    Premisecitation

    The receptor binding domain and N-terminal domain are immunodominant targets of neutralizing antibodies elicited by COVID-19 vaccines or SARS-CoV-2 infection.

    “both being immunodominant targets of neutralizing antibodies elicited by COVID-19 vaccines or by SARS-CoV-2 infection (5, 6).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] L. Premkumar, B. Segovia-Chumbez, R. Jadi, D. R. Martinez, R. Raut, A. Markmann, C. Cornaby, L. Bartelt, S. Weiss, Y. Park, C. E. Edwards, E. Weimer, E. M. Scherer, N. Rouphael, S. Edupuganti, D. Weiskopf, L. V. Tse, Y. J. Hou, D. Margolis, A. Sette, M. H. Collins, J. Schmitz, R. S. Baric, A. M. de Silva, The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients. Sci. Immunol. 5, eabc8413 (2020). 10.1126/sciimmunol.abc8413 32527802 PMC7292505 source

      Not checked in the free run.

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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BNT162b2 elicits strong antibody responses that effectively neutralize the parental strain and diverse SARS-CoV-2 VOCs.

    “and to elicit strong antibody responses, effectively neutralizing the parental strain as well as diverse SARS-CoV-2 VOCs (13–15).”
    Quote in the paperSubstantial claim0 of 3 sources checked
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      Not checked in the free run.

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      Not checked in the free run.

    • cites [15] Y. Liu, J. Liu, H. Xia, X. Zhang, C. R. Fontes-Garfias, K. A. Swanson, H. Cai, R. Sarkar, W. Chen, M. Cutler, D. Cooper, S. C. Weaver, A. Muik, U. Sahin, K. U. Jansen, X. Xie, P. R. Dormitzer, P.-Y. Shi, Neutralizing Activity of BNT162b2-Elicited Serum. N. Engl. J. Med. 384, 1466– 1468 (2021). 10.1056/NEJMc2102017 33684280 PMC7944950 source

      Not checked in the free run.

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

    Premisecitation

    Two 30-μg doses of BNT162b2 had 95% efficacy in a phase 3 trial.

    “Administration of two 30-μg doses of BNT162b2 was shown to have 95% efficacy in a phase 3 trial (12)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] F. P. Polack, S. J. Thomas, N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart, J. L. Perez, G. Pérez Marc, E. D. Moreira, C. Zerbini, R. Bailey, K. A. Swanson, S. Roychoudhury, K. Koury, P. Li, W. V. Kalina, D. Cooper, R. W. Frenck Jr., L. L. Hammitt, Ö. Türeci, H. Nell, A. Schaefer, S. Ünal, D. B. Tresnan, S. Mather, P. R. Dormitzer, U. Şahin, K. U. Jansen, W. C. Gruber; C4591001 Clinical Trial Group, Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N. Engl. J. Med. 383, 2603– 2615 (2020). 10.1056/NEJMoa2034577 33301246 PMC7745181 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fifteen mutations are located in the receptor binding domain and eight mutated sites in the N-terminal domain of the Omicron spike protein.

    “Fifteen mutations are located in the receptor binding domain and another eight mutated sites are found in the N-terminal domain”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] WHO Headquarters, WHO Health Emergencies Programme, “Enhancing Readiness for Omicron (B.1.1.529): Technical Brief and Priority Actions for Member States” (2021); www.who.int/publications/m/item/enhancing-readiness-for-omicron-(b.1.1.529)-technical-brief-and-priority-actions-for-member-states.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some amino acid changes shared with Alpha, Beta, Gamma, or Delta VOCs lead to increased transmissibility and partial escape from vaccine-induced humoral immunity.

    “Some amino acid changes [Δ69/70, T95I, G142D, Δ145, K417N, T478K, N501Y, and P681H (T, Thr; I, Ile; G, Gly; D, Asp; K, Lys; N, Asn; Y, Tyr; P, Pro; H, His)] are shared mutations also found in the Alpha, Beta (B.1.351), Gamma (P.1), or Delta VOCs and were described to lead to increased transmissibility, as well as to a typically mild partial escape from vaccine-induced humoral immunity (7–10).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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      Not checked in the free run.

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      Not checked in the free run.

    • cites [9] Q. Wang, M. S. Nair, S. Anang, S. Zhang, H. Nguyen, Y. Huang, L. Liu, D. D. Ho, J. G. Sodroski, Functional differences among the spike glycoproteins of multiple emerging severe acute respiratory syndrome coronavirus 2 variants of concern. iScience 24, 103393 (2021). 10.1016/j.isci.2021.103393 34746689 PMC8559451 source

      Not checked in the free run.

    • cites [10] A. J. Greaney, T. N. Starr, P. Gilchuk, S. J. Zost, E. Binshtein, A. N. Loes, S. K. Hilton, J. Huddleston, R. Eguia, K. H. D. Crawford, A. S. Dingens, R. S. Nargi, R. E. Sutton, N. Suryadevara, P. W. Rothlauf, Z. Liu, S. P. J. Whelan, R. H. Carnahan, J. E. Crowe Jr., J. D. Bloom, 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). 10.1016/j.chom.2020.11.007 33259788 PMC7676316 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Omicron is a highly divergent variant and harbors a previously unseen number of mutations in its spike glycoprotein.

    “Omicron is a highly divergent variant and harbors a previously unseen number of mutations in its spike (S) glycoprotein (4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] WHO Headquarters, WHO Health Emergencies Programme, “Enhancing Readiness for Omicron (B.1.1.529): Technical Brief and Priority Actions for Member States” (2021); www.who.int/publications/m/item/enhancing-readiness-for-omicron-(b.1.1.529)-technical-brief-and-priority-actions-for-member-states.

      Not checked in the free run.

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

    Premisecitation

    Beta is a benchmark for partially reduced neutralization without major impact on effectiveness.

    “Beta [as a benchmark for partially reduced neutralization (7) without major impact on effectiveness (19, 20)]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] P. Wang, M. S. Nair, L. Liu, S. Iketani, Y. Luo, Y. Guo, M. Wang, J. Yu, B. Zhang, P. D. Kwong, B. S. Graham, J. R. Mascola, J. Y. Chang, M. T. Yin, M. Sobieszczyk, C. A. Kyratsous, L. Shapiro, Z. Sheng, Y. Huang, D. D. Ho, Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593, 130– 135 (2021). 10.1038/s41586-021-03398-2 33684923 source

      Not checked in the free run.

    • cites [19] L. J. Abu-Raddad, H. Chemaitelly, A. A. Butt; National Study Group for COVID-19 Vaccination, 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). 10.1056/NEJMc2104974 33951357 PMC8117967 source

      Not checked in the free run.

    • cites [20] O. Mor, N. S. Zuckerman, I. Hazan, R. Fluss, N. Ash, N. Ginish, E. Mendelson, S. Alroy-Preis, L. Freedman, A. Huppert, BNT162b2 vaccine effectiveness was marginally affected by the SARS-CoV-2 beta variant in fully vaccinated individuals. J. Clin. Epidemiol. 142, 38– 44 (2022). 10.1016/j.jclinepi.2021.10.011 34715314 PMC8553421 source

      Not checked in the free run.

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

    Study design and conductnone given

    The analysis evaluated and compared serum panels from different clinical trials with a limited sample size.

    “In the analysis presented here, we have evaluated and compared serum panels from different clinical trials with a limited sample size.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Each specimen was tested in duplicate.

    “Each specimen was tested in duplicate, and geometric mean 50% pseudovirus-neutralizing titers (GMTs) were plotted.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The time elapsed between the second and third doses was not consistent across participants.

    “but the time elapsed between the second and third doses was not consistent across participants.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    T cell responses play a vital role as a second layer of defense, in particular in the prevention of severe COVID-19.

    “T cell responses play a vital role as a second layer of defense, in particular in the prevention of severe COVID-19 (26).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] A. Bertoletti, N. Le Bert, M. Qui, A. T. Tan, SARS-CoV-2-specific T cells in infection and vaccination. Cell. Mol. Immunol. 18, 2307– 2312 (2021). 10.1038/s41423-021-00743-3 34471260 PMC8408362 source

      Not checked in the free run.

15 of 15
  • The paper relies on this without support.

    Class I epitopes that are unchanged at the amino acid sequence level remain recognized by vaccine-elicited CD8+ T cells.

    “Despite the multitude of mutations in the Omicron S protein, 85.3% (n = 208) of the described class I epitopes were not affected on the amino acid sequence level, indicating that the targets of most T cell responses elicited by BNT162b2 may still be conserved in the Omicron variant (fig. S3).”
    “our analyses suggest that CD8+ T cell recognition of Omicron S glycoprotein epitopes is largely preserved.”
  • The paper relies on this without support.

    Sera from different clinical trials are comparable for neutralizing antibody analysis.

    “we have evaluated and compared serum panels from different clinical trials with a limited sample size.”
2 of 2

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?

  • Neutralization titers after two doses of BNT162b2 were 160, 7, 24, and 73 GMTs for wild-type SARS-CoV-2, Omicron, Beta, and Delta variants, respectively.

    “neutralization titers induced after two doses of BNT162b2 were 160, 7, 24, and 73 GMTs for wild-type SARS-CoV-2, Omicron, Beta, and Delta variants, respectively”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [406]

  • After one month following a booster vaccination, neutralization titers improved to 368, 164, 279, and 413 GMTs for wild-type, Omicron, Beta, and Delta, respectively.

    “but improved to 368, 164, 279, and 413 GMTs, after one month following a booster vaccination.”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [406]

  • 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 [113]

  • Comparable trends were observed in live virus neutralization testing.

    “Comparable trends were observed in live virus neutralization testing.”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [406]

  • Booster with BNT162b2 may enhance neutralization of the Omicron variant.

    “Thus vaccine booster with BNT162b2 may enhance neutralization of the Omicron variant.406”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [406]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Live-virus fold reduction does not match the reported GMTs

    Minor

    The reported GMTs give 368 ÷ 106 = 3.47, which rounds to a 3.5-fold reduction, not 3.4-fold. Rounding the GMTs to whole numbers cannot account for the difference.

    Reported 3.4 · recomputed 3.471698

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. https://doi.org/10.1101/2021.12.08.21267417.10.1101/2021.12.08.21267417 2021.12.08.21267417 · DOI · Paper page

Cited by

Sorted by citations

Authors
Muik, A., Lui, B. G., Wallisch, A.-K., Bacher, M., Mühl, J., Reinholz, J., Ozhelvaci, O., Beckmann, N., Güimil Garcia, R. D. L. C., Poran, A., Shpyro, S., Finlayson, A., Cai, H., Yang, Q., Swanson, K. A., Türeci, Ö., & Şahin, U.
Affiliations
  • BioNTech (Germany) (DE)
  • BioNTech, An der Goldgrube 12, 55131 Mainz, Germany.
  • BioNTech (United States) (US)
  • Pfizer (United States) (US)
  • Johannes Gutenberg University Mainz (DE)
Corresponding author
Şahin, Uğur
Venue
Science
Published
2022-02-11
Volume
375
Issue
6581
Pages
678-680
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W4205283268
Cited by
367
References
29
Citations by year
2026: 11 · 2025: 21 · 2024: 40 · 2023: 103 · 2022: 190 · 2021: 1
FWCI
43.20
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science (publishedVersion, cc-by)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Pfizer
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
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
Omicron variant, BNT162b2 mRNA vaccine, neutralizing antibodies, third vaccine dose, spike protein mutations, COVID-19 protection, pseudovirus neutralization
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, BNT162 Vaccine, Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Viral, Humans, Immunization Schedule, Immunization, Secondary, Middle Aged, Mutation, Neutralization Tests, T-Lymphocytes, Vaccination, Young Adult, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus

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