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Cited by 1,027SARS-CoV-2 and COVID-19 ResearchPharmacovigilance and Adverse Drug ReactionsCOVID-19 Clinical Research Studies

Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting

Open access
Barda, Noam, Dagan, Noa, Ben-Shlomo, Yatir, Kepten, Eldad, Waxman, Jacob, Ohana, Reut, Hernán, Miguel A., Lipsitch, Marc +4 more·2021·New England Journal of Medicine
DOI 10.1056/nejmoa2110475PMC PMC8427535
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Abstract

BACKGROUND: Preapproval trials showed that messenger RNA (mRNA)-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations. An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed. METHODS: We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine. For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables. Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan-Meier estimator. To place these results in context, we performed a similar analysis involving SARS-CoV-2-infected persons matched to uninfected persons. The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses. RESULTS: In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia. CONCLUSIONS: In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).

AI snapshot

Written from the paper’s full text.

TL;DR

In a nationwide Israeli matched-cohort emulation, BNT162b2 vaccination was not associated with elevated risk of most adverse events but was associated with excess myocarditis, lymphadenopathy, appendicitis, and herpes zoster over 42 days. SARS-CoV-2 infection was associated with substantially higher risks of myocarditis and multiple other serious adverse events.

Key findings

  • In the vaccination analysis, vaccinated and control groups each included a mean of 884,828 persons. Vaccination was associated with increased risk of myocarditis (risk ratio, 3.24; 95% CI, 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000; 95% CI, 8.2 to 24.2).
  • Vaccination was substantially protective against adverse events such as anemia, acute kidney injury, intracranial hemorrhage, and lymphopenia.
  • In the SARS-CoV-2 infection analysis, cohorts comprised a mean of 173,106 infected persons. Infection substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000; 95% CI, 5.6 to 15.8), acute kidney injury (risk ratio, 14.83; 95% CI, 9.24 to 28.75; risk difference, 125.4 events per 100,000), pulmonary embolism (risk ratio, 12.14; 95% CI, 6.89 to 29.20; risk difference, 61.7 events per 100,000), and other serious events including pericarditis, arrhythmia, deep-vein thrombosis, myocardial infarction, intracranial hemorrhage, and thrombocytopenia.
  • Among 21 vaccinated persons with myocarditis, median age was 25 years (interquartile range, 20 to 34) and 90.9% were male. Bell’s palsy risk ratio after vaccination was 1.32 (95% CI, 0.92 to 1.86).

Methods

  • Observational emulation of a target trial using Clalit Health Services data in Israel from December 20, 2020, to May 24, 2021. Eligible persons were 16 years or older, continuous members for one year, without previous SARS-CoV-2 infection, and without health care contact in the previous 7 days; persons with a previous diagnosis of each studied adverse event were excluded, as were long-term care residents, homebound persons, health care workers, and those missing body-mass index or residential-area data.
  • Each day, vaccinated persons were exactly matched to unvaccinated controls on sociodemographic and clinical variables including age, sex, residence, socioeconomic status, population sector, number of chronic conditions, outpatient diagnoses, and pregnancy. Follow-up was 42 days; matched pairs were censored when the control was vaccinated or either member was diagnosed with SARS-CoV-2 infection. A separate SARS-CoV-2 infection analysis matched infected persons to uninfected controls from March 1, 2020.
  • Risks at 42 days were estimated with Kaplan–Meier curves and compared using risk ratios and risk differences per 100,000 persons; confidence intervals used nonparametric percentile bootstrap with 500 repetitions. No adjustment for multiple comparisons was performed; analyses used R version 4.0.4.

Limitations

  • Stated: persons were not randomly assigned, so baseline confounding and selection bias at censoring may remain, especially because a single set of confounders was used across many disparate adverse events. Matching changed the study population composition (e.g., median age 38 years vs. 43 years in the eligible cohort), and certain populations were excluded, affecting generalizability.
  • Stated: diagnoses from out-of-network hospitals could be missed; increased clinical awareness or care-seeking after vaccination or infection could spuriously increase adverse-event incidence; and only new incidence was studied, not additional risk among persons with a history of each event.
  • Evident from the text: the vaccination and SARS-CoV-2 infection analyses used different cohorts and should not be directly compared; no multiple-comparison adjustment was made; and the per-protocol-like censoring approach may not fully address time-varying confounding.

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

Integrity signals

Registry

Crossref · 10.1056/nejmoa2110475

Cites

24 of 24 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 26 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the vaccination analysis, vaccination was associated with an elevated risk of lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3).

    “lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3)”
    • Also stated in: § Vaccination Analysis · plain
      “lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.
  • Findingown data

    SARS-CoV-2 infection was associated with a substantially increased risk of arrhythmia (risk ratio, 3.83; 95% CI, 3.07 to 4.95; risk difference, 166.1 events per 100,000 persons; 95% CI, 139.6 to 193.2).

    “arrhythmia (risk ratio, 3.83; 95% CI, 3.07 to 4.95; risk difference, 166.1 events per 100,000 persons; 95% CI, 139.6 to 193.2)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.
  • Findingown data

    SARS-CoV-2 infection was associated with a substantially increased risk of acute kidney injury (risk ratio, 14.83; 95% CI, 9.24 to 28.75; risk difference, 125.4 events per 100,000 persons; 95% CI, 107.0 to 142.6).

    “acute kidney injury (risk ratio, 14.83; 95% CI, 9.24 to 28.75; risk difference, 125.4 events per 100,000 persons; 95% CI, 107.0 to 142.6)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.
  • Findingown data

    SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8).

    “SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8)”
    • Also stated in: § Results · plain
      “myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.
  • Findingown data

    SARS-CoV-2 infection was associated with a substantially increased risk of pericarditis (risk ratio, 5.39; 95% CI, 2.22 to 23.58; risk difference, 10.9 events per 100,000 persons; 95% CI, 4.9 to 16.9).

    “pericarditis (risk ratio, 5.39; 95% CI, 2.22 to 23.58; risk difference, 10.9 events per 100,000 persons; 95% CI, 4.9 to 16.9)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.
  • May combine two claims. 12
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    Among the 21 persons with myocarditis in the vaccinated group, the median age was 25 years (interquartile range, 20 to 34), and 90.9% were male.

    “Among the 21 persons with myocarditis in the vaccinated group, the median age was 25 years (interquartile range, 20 to 34), and 90.9% were male.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.

  • May combine two claims.

    Findingown data

    SARS-CoV-2 infection was not estimated to have a meaningful effect on the incidence of lymphadenopathy, herpes zoster infection, or appendicitis.

    “SARS-CoV-2 infection was not estimated to have a meaningful effect on the incidence of lymphadenopathy, herpes zoster infection, or appendicitis”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.

  • The quote only partly states this claim.

    Findingown data

    SARS-CoV-2 infection was associated with a substantially increased risk of thrombocytopenia.

    “including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.

  • May combine two claims.

    Findingown data

    The effect estimate for Bell's palsy was consistent with a potentially mild increase in risk after vaccination, with a risk ratio of 1.32 (95% CI, 0.92 to 1.86); the absolute effect was small, with up to 8 excess events per 100,000 persons being highly compatible with the data.

    “In the current study, the effect estimate was consistent with a potentially mild increase in the risk of Bell’s palsy after vaccination, with a risk ratio of 1.32 (95% CI, 0.92 to 1.86). The absolute effect was small, with up to 8 excess events per 100,000 persons being highly compatible with our data according to the 95% confidence interval.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.

  • May combine two claims.

    Interpretationown data

    SARS-CoV-2 infection is itself a very strong risk factor for myocarditis, and it also substantially increases the risk of multiple other serious adverse events.

    “our results indicate that SARS-CoV-2 infection is itself a very strong risk factor for myocarditis, and it also substantially increases the risk of multiple other serious adverse events.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The set of matched baseline variables adequately controls confounding for the estimated effects of vaccination and SARS-CoV-2 infection.
    • Rests on an assumption: Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.
    • Rests on an assumption: Censoring at vaccination of the control member or at SARS-CoV-2 infection of either member is non-informative.
    • The authors state this as an assumption: A total of 42 days of follow-up is sufficient for identifying medium-term adverse events without diluting the incidence of short-term adverse events.
    • Rests on an assumption: The matching process attains exchangeability between the study groups.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Vaccinated persons were individually matched to unvaccinated persons according to sociodemographic and clinical variables.

    “we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables”
    • Also stated in: § Study Design and Oversight · plain
      “vaccinated persons and unvaccinated controls were exactly matched on a set of baseline variables that were deemed to be potential confounders according to domain expertise”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Phase 3 trials may have inherent limitations in assessing vaccine safety because of a small number of participants and a healthier-than-average sample population, and are often underpowered to identify less common adverse events.

    “However, phase 3 trials may have inherent limitations in assessing vaccine safety because of a small number of participants and a healthier-than-average sample population. Hence, they are often underpowered to identify less common adverse events.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Increased clinical awareness after vaccination or SARS-CoV-2 infection could result in a spuriously increased incidence of adverse events in the vaccinated or infected groups.

    “Fourth, it is possible that persons are more likely to increase their levels of clinical awareness, concern, or both after vaccination or SARS-CoV-2 infection, and thus they may be more likely to report or seek medical care for their symptoms, resulting in a spuriously increased incidence of the various adverse events in the vaccinated or infected groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Clalit Health Services insures approximately 52% of the population of Israel and the CHS-insured population is approximately representative of the Israeli population at large.

    “CHS insures approximately 52% of the population of Israel (>4.7 million of 9.0 million persons), and the CHS-insured population is approximately representative of the Israeli population at large.17”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Cohen R, Rabin H. National Insurance Institute of Israel. Membership in sick funds 2016. August 2017. (In Hebrew) (https://www.btl.gov.il/Publications/survey/Documents/seker289/seker_289.pdf).

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Phase 3 clinical trials showed that several Covid-19 vaccines were efficacious and had an acceptable safety profile.

    “Phase 3 clinical trials showed that several Covid-19 vaccines were efficacious and had an acceptable safety profile.2-4”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020; 383: 2603- 2615. 33301246 PMC7745181 source

      Not checked in the free run.

    • cites [3] Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021; 384: 403- 416. 33378609 PMC7787219 source

      Not checked in the free run.

    • cites [4] Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021; 397: 99- 111. 33306989 PMC7723445 source

      Not checked in the free run.

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

    Study design and conductnone given

    No adjustment for multiple comparisons was performed, as is standard practice for studies of safety outcomes.

    “As is standard practice for studies of safety outcomes, no adjustment for multiple comparisons was performed.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Data on a matched pair were censored if and when the control member was vaccinated or either member received a diagnosis of SARS-CoV-2 infection.

    “we censored data on the matched pair if and when the control member was vaccinated”
    • Also stated in: § Statistical Analysis · plain
      “we also censored data on the matched pair if and when either member received a diagnosis of SARS-CoV-2 infection”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Persons in the study were not randomly assigned according to exposures, which may have introduced confounding at baseline and selection bias at censoring.

    “First, persons in the study were not randomly assigned according to exposures (vaccinations and SARS-CoV-2 infections); this may have introduced confounding at baseline and selection bias at censoring, especially since a single set of confounders was used for adjustment in the assessment of many disparate adverse events.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductnone given

    A total of 42 days of follow-up was deemed sufficient for identifying medium-term adverse events without diluting the incidence of short-term adverse events.

    “A total of 42 days was deemed to be sufficient for identifying medium-term adverse events, without being so long as to dilute the incidence of short-term adverse events.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Because the cohorts used to study vaccine and infection effects were different in composition, care should be taken when comparing the resulting risk estimates.

    “Because the cohorts that we used to study the vaccine and infection effects were different in composition, care should be taken when comparing the resulting risk estimates.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Herpes zoster infection is one of the potential causes of facial-nerve palsy.

    “Herpes zoster infection, the incidence of which we found to be increased after vaccination, is one of the potential causes of facial-nerve palsy.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Peitersen E. Bell’s palsy: the spontaneous course of 2,500 peripheral facial nerve palsies of different etiologies. Acta Otolaryngol Suppl 2002; 549: 4- 30. 12482166 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Multiple cases of myocarditis after Covid-19 vaccination have recently been reported in the literature.

    “multiple cases of myocarditis after Covid-19 vaccination have recently been reported in the literature,21-25”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [21] Ammirati E, Cavalotti C, Milazzo A, et al. Temporal relation between second dose BNT162b2 mRNA Covid-19 vaccine and cardiac involvement in a patient with previous SARS-COV-2 infection. Int J Cardiol Heart Vasc 2021; 34: 100774- 100774. 33821210 PMC8011690 source

      Not checked in the free run.

    • cites [22] Abu Mouch S, Roguin A, Hellou E, et al. Myocarditis following COVID-19 mRNA vaccination. Vaccine 2021; 39: 3790- 3793. 34092429 PMC8162819 source

      Not checked in the free run.

    • cites [23] Marshall M, Ferguson ID, Lewis P, et al. Symptomatic acute myocarditis in seven adolescents following Pfizer-BioNTech COVID-19 vaccination. Pediatrics 2021 June 4 (Epub ahead of print). 34088762 source

      Not checked in the free run.

    • cites [24] Albert E, Aurigemma G, Saucedo J, Gerson DS. Myocarditis following COVID-19 vaccination. Radiol Case Rep 2021; 16: 2142- 2145. 34025885 PMC8130498 source

      Not checked in the free run.

    • cites [25] Bautista García J, Peña Ortega P, Bonilla Fernández JA, Cárdenes León A, Ramírez Burgos L, Caballero Dorta E. Acute myocarditis after administration of the BNT162b2 vaccine against COVID-19. Rev Esp Cardiol (Engl Ed) 2021 April 27 (Epub ahead of print). PMC8075838 33994339 source

      Not checked in the free run.

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

    Premisecitation

    Thromboembolic events primarily affect young women and have been linked with the ChAdOx1 nCoV-19 and Ad26.COV2.S Covid-19 vaccines, both of which are adenoviral vector vaccines.

    “These adverse events, which primarily affect young women, have been linked with the ChAdOx1 nCoV-1932 and Ad26.COV2.S (Johnson & Johnson–Janssen) Covid-19 vaccines,33 both of which are adenoviral vector vaccines.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021; 384: 2092- 2101. 33835769 PMC8095372 source

      Not checked in the free run.

    • cites [33] Centers for Disease Control and Prevention, Health Alert Network. Emergency preparedness and response: cases of cerebral venous sinus thrombosis with thrombocytopenia after receipt of the Johnson & Johnson COVID-19 vaccine. April 13, 2021 (https://emergency.cdc.gov/han/2021/han00442.asp).

      Not checked in the free run.

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

    Premisecitation

    Both the Israeli Ministry of Health and the CDC have investigated the association between Covid-19 vaccination and myocarditis.

    “both the Israeli Ministry of Health26 and the CDC have investigated this association.27”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Surveillance of myocarditis (inflammation of the heart muscle) cases between December 2020 and May 2021 (including). Press release of the Israeli Ministry of Health, February 6, 2021 (https://www.gov.il/en/departments/news/01062021-03).

      Not checked in the free run.

    • cites [27] Centers for Disease Control and Prevention. Myocarditis and pericarditis following mRNA COVID-19 vaccination. June 23, 2021 (https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/myocarditis.html).

      Not checked in the free run.

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

    Premisecitation

    Ozonoff et al. suggested a possible association between the BNT162b2 and mRNA-1273 vaccines and Bell's palsy and estimated a rate ratio of approximately 7.0.

    “Ozonoff et al.28 suggested a possible association between these vaccines and Bell’s palsy and estimated a rate ratio of approximately 7.0.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Ozonoff A, Nanishi E, Levy O. Bell’s palsy and SARS-CoV-2 vaccines. Lancet Infect Dis 2021; 21: 450- 452. 33639103 PMC7906673 source

      Not checked in the free run.

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

    Premisecitation

    The Food and Drug Administration briefing on the BNT162b2 and mRNA-1273 vaccines in December 2020 considered the incidence of Bell's palsy to be similar to the background incidence.

    “the Food and Drug Administration briefing on these vaccines in December 2020; that briefing considered the incidence of Bell’s palsy to be similar to the background incidence.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Food and Drug Administration. Vaccines and Related Biological Products Advisory Committee: December 10, 2020 meeting announcement. December 2020 (https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-december-10-2020-meeting-announcement).

      Not checked in the free run.

21 of 21

  • The paper relies on this without support.

    The set of matched baseline variables adequately controls confounding for the estimated effects of vaccination and SARS-CoV-2 infection.

    “In an attempt to emulate randomized assignment, vaccinated persons and unvaccinated controls were exactly matched on a set of baseline variables that were deemed to be potential confounders according to domain expertise”
    “this may have introduced confounding at baseline and selection bias at censoring”

  • The paper relies on this without support.

    Adverse events defined by diagnostic codes and short free-text phrases in the CHS database accurately identify the events.

    “Adverse events were defined according to diagnostic codes and short free-text phrases that accompany diagnoses in the CHS database.”

  • The paper relies on this without support.

    Censoring at vaccination of the control member or at SARS-CoV-2 infection of either member is non-informative.

    “we censored data on the matched pair if and when the control member was vaccinated”

  • The authors state this as an assumption.

    A total of 42 days of follow-up is sufficient for identifying medium-term adverse events without diluting the incidence of short-term adverse events.

    “A total of 42 days was deemed to be sufficient for identifying medium-term adverse events, without being so long as to dilute the incidence of short-term adverse events.”

  • The paper relies on this without support.

    The matching process attains exchangeability between the study groups.

    “the matching process that was necessary to attain exchangeability between the study groups”
5 of 5

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?

  • A cohort study reported a rate ratio of 0.84 (95% CI 0.54-1.27) for hemorrhagic stroke following Pfizer vaccine.

    “Among self-controlled case series, one reported a rate ratio of 1.38 (95 % CI 1.12-1.71) for hemorrhagic stroke following Pfizer vaccine, [26] another reported 0.97 (95 % CI 0.81-1.15), [27] while a cohort study[28] reported 0.84 (95 % CI 0.54-1.27).”

    From Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults (2022) · cites this paper as [28]

    The Discussion (page unavailable) describes a vaccination cohort and says BNT162b2 appeared protective against intracranial hemorrhage. It does not report hemorrhagic stroke specifically or the claimed ratio of 0.84 (95% CI, 0.54–1.27); the 6.89 ratio in the Results concerns intracranial hemorrhage after SARS-CoV-2 infection, not vaccination. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • The BNT162b2 vaccine was associated with increased risk of myocarditis in Israeli participants, reaching a rate of approximately 3 events per 100,000 persons.

    “However, the vaccine was associated with increased risk of myocarditis in Israeli participants, reaching a rate of approximately 3 events per 100,000 persons.398–400”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [398]

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Myocarditis sex percentage is impossible for 21 people

    Minor

    With 21 people, the number who were male must be a whole number. Neither 19 of 21 (90.5%) nor 20 of 21 (95.2%) rounds to the reported 90.9%.

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Surveillance of myocarditis (inflammation of the heart muscle) cases between December 2020 and May 2021 (including). Press release of the Israeli Ministry of Health February 6 2021 (https://www.gov.il/en/departments/news/01062021-03).

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Authors
Barda, N., Dagan, N., Ben-Shlomo, Y., Kepten, E., Waxman, J., Ohana, R., Hernán, M. A., Lipsitch, M., Kohane, I., Netzer, D., Reis, B. Y., & Balicer, R. D.
Affiliations
  • Ben-Gurion University of the Negev (IL)
  • From the Clalit Research Institute, Innovation Division (N.B., N.D., Y.B.-S., E.K., J.W., R.O., R.D.B.), and the Community Medical Services Division (D.N.), Clalit Health Services, Tel Aviv, and Software and Information Systems Engineering (N.B., N.D.) and the School of Public Health, Faculty of Health Sciences (R.D.B.), Ben-Gurion University of the Negev, Be’er Sheva — both in Israel; the Department of Biomedical Informatics (N.B., N.D., I.K.), and the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute (N.B., N.D., I.K., B.Y.R., R.D.B.), Harvard Medical School (B.Y.R.), the Departments of Epidemiology and Biostatistics (M.A.H.), CAUSALab (M.A.H.), and the Center for Communicable Disease Dynamics, Departments of Epidemiology and Immunology and Infectious Diseases (M.L.), Harvard T.H. Chan School of Public Health, and the Predictive Medicine Group, Computational Health Informatics Program, Boston Children’s Hospital (B.Y.R.) — all in B...
Corresponding author
Balicer, Ran D.
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2021-09-16
Volume
385
Issue
12
Pages
1078-1090
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa2110475
PMC
PMC8427535
OpenAlex
W3195586393
Semantic Scholar
e31b0a4dbace49b879831cae582dd9caa8829cf5
Cited by
1,027
References
24
Citations by year
2026: 58 · 2025: 94 · 2024: 109 · 2023: 220 · 2022: 440 · 2021: 101 · 2020: 3
FWCI
68.82
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Morris–Singer Foundation
  • The Ivan and Francesca Berkowitz Family Precision Medicine Clinic at Clalit Research Institute
  • Ivan and Francesca Berkowitz Family Living Laboratory at Harvard Medical School
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
BNT162b2, mRNA vaccines, COVID-19 vaccine safety, myocarditis, lymphadenopathy, appendicitis, herpes zoster, COVID-19 pandemic, adverse events, matched cohort, Israel, relative risk, risk difference, SARS-CoV-2 infection risk
MeSH terms
Lymphadenopathy, COVID-19, COVID-19 Vaccines, BNT162 Vaccine, Adolescent, Adult, Aged, Aged, 80 and over, Appendicitis, Cardiovascular Diseases, Female, Herpes Zoster, Humans, Israel, Male, Middle Aged, Myocarditis, Risk, Risk Factors, Kaplan-Meier Estimate, Young Adult

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