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Cited by 87SARS-CoV-2 and COVID-19 ResearchVaccine Coverage and HesitancyCOVID-19 epidemiological studies

Short term, relative effectiveness of four doses versus three doses of BNT162b2 vaccine in people aged 60 years and older in Israel: retrospective, test negative, case-control study

Open access
Gazit, Sivan, Saciuk, Yaki, Perez, Galit, Peretz, Asaf, Pitzer, Virginia E, Patalon, Tal·2022·BMJ
DOI 10.1136/bmj-2022-071113PMC PMC9127435

Published version of a preprint

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Abstract

Objective: To examine the relative effectiveness of a fourth dose of the Pfizer-BioNTech mRNA (BNT162b2) vaccine compared with three vaccine doses over the span of 10 weeks. Design: Retrospective, test negative, case-control study, with a matched analysis and an unmatched multiple tests analysis. Setting: Nationally centralised database of Maccabi Healthcare Services, an Israeli national health fund for 2.5 million people; from 10 January 2022 (seven days after the fourth dose was first given to eligible individuals) to 13 March 2022, an omicron dominant period in Israel. Participants: 97 499 Maccabi Healthcare Services members aged 60 years and older, who were eligible to receive a fourth vaccine dose and obtained at least one polymerase chain reaction (PCR) test during the study. Main outcome measures: Breakthrough SARS-CoV-2 infection, defined as a positive PCR test performed seven or more days after inoculation with the BNT162b2 vaccine; and breakthrough SARS-CoV-2 infection resulting in severe covid-19 disease, defined as hospital admission or death related to covid-19. Results: 27 876 participants received the fourth BNT162b2 vaccine dose and 69 623 received three doses only. Of 106 participants who died during the follow-up period, 77 had had their third doses only and 23 had had their fourth doses during the first three weeks after inoculation. In the first three weeks, a fourth dose provided additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, relative vaccine effectiveness against infection quickly decreased over time, peaking during the third week at 65.1% (95% confidence interval 63.0% to 67.1%) and falling to 22.0% (4.9% to 36.1%) by the end of the 10 week follow-up period. Unlike relative effectiveness against SARS-CoV-2 infection, the relative effectiveness of a fourth dose against severe covid-19 was maintained at a high level (>72%) throughout follow-up. However, severe disease was a relatively rare event, occurring in <1% of study participants who received four doses or three doses only. Conclusions: A fourth dose of the BNT162b2 vaccine appears to have provided additional protection against both SARS-CoV-2 infection and severe covid-19 disease relative to three vaccine doses. However, relative effectiveness of the fourth dose against infection appears to wane sooner than that of the third dose.

AI snapshot

Written from the paper’s full text.

TL;DR

In Israeli Maccabi Healthcare Services members aged ≥60 during an omicron-dominant period, a fourth BNT162b2 dose provided additional short-term protection against SARS-CoV-2 infection and severe covid-19 compared with three doses. Relative protection against infection waned quickly, while protection against severe disease remained high.

Key findings

  • Among 97,499 eligible members aged ≥60 with at least one PCR test, 27,876 received a fourth BNT162b2 dose and 69,623 received three doses only; 106 participants died, including 77 who had received three doses only and 23 who had received a fourth dose during the first three weeks after inoculation.
  • Relative vaccine effectiveness against SARS-CoV-2 infection peaked in the third week after the fourth dose at 65.1% (95% CI 63.0% to 67.1%) and fell to 22.0% (4.9% to 36.1%) by the end of the 10-week follow-up.
  • Relative vaccine effectiveness against severe covid-19 remained high throughout follow-up (>72%), reaching 86.5% (63.4% to 95%) during weeks 6-9, but severe disease was rare, occurring in <1% of participants who received four doses or three doses only.
  • In the unmatched multiple tests sensitivity analysis, estimates were similar for both outcomes, although the decline in protection against infection over time was slightly attenuated.

Methods

  • Retrospective, test-negative, case-control study using the centralised Maccabi Healthcare Services database from 10 January to 13 March 2022, an omicron-dominant period in Israel; participants were members aged ≥60 eligible for a fourth dose who had at least one PCR test, excluding those with prior positive PCR tests or possibly incomplete covid-19 history.
  • Primary matched analysis defined cases as positive PCR tests or severe covid-19 and controls as negative PCR tests, matching up to five controls per case on sex, age group (≥70 years), city, socioeconomic status, calendar week of first test, month of third dose, and living environment; conditional logistic regression adjusted for comorbidities and previous PCR test count, with relative vaccine effectiveness calculated as 100%×(1−odds ratio).
  • Outcomes were breakthrough infection, defined as a positive PCR test ≥7 days after vaccination, and breakthrough infection resulting in severe covid-19, defined as hospital admission ≤21 days from first positive PCR test or death related to covid-19; an unmatched multiple tests analysis using generalised estimating equations served as a sensitivity analysis.

Limitations

  • The paper states that only 10 weeks of data were available, so long-term vaccine effectiveness and waning of protection against severe covid-19 require longer follow-up.
  • The paper states that the omicron-dominant period limits assessment against other variants, the eligible population was aged ≥60 so findings cannot be inferred for younger people, and the relative vaccine effectiveness metric compares fourth versus third dose rather than absolute effectiveness versus unvaccinated individuals.
  • The paper also notes lack of pre-defined PCR testing protocols and possible healthcare-seeking behaviour bias, mitigated but not fully resolved by the test-negative design; evident from the text, severe disease was a rare event (<1%) with few late severe outcomes, making those estimates imprecise, and fourth dose recipients were more chronically ill overall despite adjustment.

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

Integrity signals

Registry

Crossref · 10.1136/bmj-2022-071113

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 38 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Having received the third dose after August 2021 was associated with slightly lower odds of SARS-CoV-2 infection.

    “Having received the third dose after August 2021 was associated with a slightly lower odds of infection, but was not significantly associated with the odds of hospital admission or death associated with covid-19; figure S5 shows the distribution of months between the third and fourth dose.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Having received the second dose more than nine months before the third dose was associated with significantly decreased odds of SARS-CoV-2 infection (odds ratio 0.14, 95% confidence interval 0.02 to 0.95), compared with having received the second dose between six and nine months before the third dose.

    “Finally, when examining the interval between the second and third vaccine dose, we found that having received the second dose more than nine months before the third one was associated with a significantly decreased odds of infection with SARS-CoV-2 (odds ratio 0.14, 95% confidence interval 0.02 to 0.95), compared with having received the second dose between six and nine months before the third”
    Quote in the paperNot a substantial claim
  • Findingown data

    Each 1% increase in the attack rate in city of residence was associated with a 10.12-fold increase in the odds of SARS-CoV-2 infection (95% confidence interval 4.17 to 24.58).

    “The attack rate analysis pointed to the importance of exposure, where each 1% increase in the attack rate in each city of residence was associated with a 10.12-fold (95% confidence interval 4.17 to 24.58) increase in the odds of SARS-CoV-2 infection.”
    Quote in the paperNot a substantial claim
  • Findingown data

    A total of 97,499 MHS members aged 60 years and older were eligible for the study and obtained at least one PCR test during the outcome period of 10 January to 13 March 2022.

    “A total of 97 499 MHS members aged 60 years and older were eligible for the study and obtained at least one PCR test during the outcome period of 10 January to 13 March 2022.”
    Quote in the paperSubstantial claim
  • Findingown data

    During that time period, 233,582 PCR tests were performed on 27,876 participants who received a fourth dose of the BNT162b2 vaccine and on 69,623 people who were eligible for a fourth dose but had not (yet) received one.

    “During that time period, 233 582 PCR tests were performed on 27 876 participants who received a fourth dose of the BNT162b2 vaccine and on 69 623 people who were eligible for a fourth dose but had not (yet) received one.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 27

  • May combine two claims.

    Findingown data

    27,876 participants received the fourth BNT162b2 vaccine dose and 69,623 received three doses only.

    “27 876 participants received the fourth BNT162b2 vaccine dose and 69 623 received three doses only.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The unmatched multiple tests analysis showed relative vaccine effectiveness similar to the primary analysis for both SARS-CoV-2 infection and severe covid-19, although the decline in these estimates against infection with time since inoculation was slightly attenuated.

    “Relative vaccine effectiveness was similar to the primary analysis for both SARS-CoV-2 infection and severe covid-19, although the decline in these estimates against infection with time since inoculation was slightly attenuated (table 2, table 3, and figs S1-S2).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Of those who had PCR tests, 572 (0.25%) participants were either admitted to hospital or died as a result of covid-19.

    “Of those who had PCR tests, 572 (0.25%) participants were either admitted to hospital or died as a result of covid-19.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The matched analysis included 30,731 cases and 60,054 matched controls.

    “The matched analysis included 30 731 cases and 60 054 matched controls (table 2);”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Relative effectiveness of a fourth dose against severe covid-19 was maintained at a high level (>72%) throughout follow-up, reaching 86.5% (95% CI 63.4% to 95%) during weeks 6-9.

    “Unlike relative effectiveness against SARS-CoV-2 infection, the relative effectiveness of a fourth dose against severe covid-19 was maintained at a high level (>72%) throughout follow-up.”
    • Also stated in: § Relative vaccine effectiveness against severe covid-19 disease · plain
      “Unlike relative effectiveness against SARS-CoV-2 infection, relative effectiveness of a fourth dose against severe covid-19 did not vary significantly as a function of time since vaccination, reaching 86.5% (95% confidence interval 63.4% to 95%) compared with a third dose during weeks 6-9 of the outcome period (table 3, fig 2).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Severe disease was a relatively rare event, occurring in <1% of study participants who received four doses or three doses only.

    “However, severe disease was a relatively rare event, occurring in <1% of study participants who received four doses or three doses only.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Most comorbidities were not significantly associated with the odds of SARS-CoV-2 infection, although chronic obstructive pulmonary disease and chronic kidney disease were associated with slightly lower odds of infection.

    “Most comorbidities were not significantly associated with the odds of infection, although chronic obstructive pulmonary disease and chronic kidney disease were associated with slightly lower odds of infection, possibly because of risk averse behaviour (tables S1-S2).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Only 52 individuals in the analysis had an interval of more than nine months between the second and third dose.

    “However, only 52 individuals in our analysis had an interval of more than nine months between the second and third dose (fig S5).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The unmatched multiple test analysis included 229,433 PCR tests, of which 35,101 (15.3%) were positive and 572 were admitted to hospital or died due to covid-19.

    “The unmatched multiple test analysis included 229 433 PCR tests, of which 35 101 (15.3%) were positive and 572 were admitted to hospital or died due to covid-19 (table 2 and table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Relative vaccine effectiveness of the fourth dose against SARS-CoV-2 infection peaked during the third week at 65.1% (95% CI 63.0% to 67.1%) and fell to 22.0% (4.9% to 36.1%) by the end of the 10 week follow-up period.

    “relative vaccine effectiveness against infection quickly decreased over time, peaking during the third week at 65.1% (95% confidence interval 63.0% to 67.1%) and falling to 22.0% (4.9% to 36.1%) by the end of the 10 week follow-up period.”
    Quote in the paperSubstantial claim

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

    Findingreasoning

    Fourth dose recipients were more unwell overall, possibly stemming from targeted vaccination campaigns and previous rollout policies.

    “Additionally, fourth dose recipients were more unwell overall, possibly stemming from targeted vaccination campaigns and previous rollout policies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The booster (third dose) was shown to largely restore short term effectiveness.

    “The booster was shown to largely restore short term effectiveness,6 7 8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 6 7 8

      Not checked in the free run.

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

    Premisecitation

    Older age groups are at higher risk, especially for severe disease.

    “because studies19 have indicated that older age groups are at higher risk, especially for severe disease”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] source

      Not checked in the free run.

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

    Premisecitation

    The seven day cut-off period was based on previous breakthrough infection definitions in vaccine effectiveness studies.

    “where the seven day cut-off period was based on previous breakthrough infection definitions in vaccine effectiveness studies.6 16”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 6 16

      Not checked in the free run.

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

    Premisecitation

    Sustained vaccine effectiveness against severe disease has been shown for previous doses also.

    “Sustained vaccine effectiveness against severe disease has been shown for previous doses also.20 34”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] source

      Not checked in the free run.

    • cites [34] source

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

    Study design and conductreasoning

    The analysis examined the interval between the second and third vaccine doses because the dosing interval was possibly associated with both the administration and effectiveness of later doses, namely, the fourth dose.

    “Finally, we also examined the interval between the second and third vaccine doses, because the dosing interval was possibly associated with both the administration and effectiveness of later doses, namely, the fourth dose.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Compared with the previously demonstrated waning pattern of relative vaccine effectiveness of three doses versus two doses in real world settings, the relative effectiveness of the fourth dose against infection appears to wane sooner, just as waning after the third dose was sooner than after the second dose.

    “Nonetheless, compared with the previously demonstrated waning pattern of the relative vaccine effectiveness of three doses versus two doses in real world settings (which begins around three months after inoculation), the relative effectiveness of the fourth dose against infection appears to wane sooner, just as waning after the third dose was sooner than after the second dose.11 26”
    • Also stated in: § Conclusions and policy implications · plain
      “Relative effectiveness of the fourth dose of the BNT162b2 vaccine compared with a third dose against SARS-CoV-2 infection wanes sooner than the relative effectiveness of previous doses”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] source

      Not checked in the free run.

    • cites [26] source

      Not checked in the free run.

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

    Study design and conductnone given

    Similar results were obtained with different analytical approaches.

    “Similar results were obtained with different analytical approaches.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The analysis also adjusted for a categorical variable consisting of the number of PCR tests each person undertook from the beginning of the pandemic to the start of the outcome period, as a proxy for healthcare seeking behaviour related to SARS-CoV-2.

    “We also adjusted for a categorical variable consisting of the number of PCR tests each person undertook from the beginning of the pandemic (March 2020) to the start of the outcome period, as a proxy for healthcare seeking behaviour related to SARS-CoV-2.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    An additional analysis restricted the severe covid-19 outcome to people who met the US National Institutes of Health's definition of severe disease, critical disease, or death due to covid-19.

    “In another additional analysis, the measured outcome for severe covid-19 included only people who met the US National Institutes of Health’s definition of severe disease (oxygen saturation <94% on room air, respiratory rate >30 breaths per minute, or lung infiltrates >50%), critical disease,25 or death due to covid-19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Clinical Spectrum of SARS-CoV-2 Infection. National Institutes of Health. 2021. https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/

      Not checked in the free run.

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

    Study design and conductcitation

    In the unmatched approach, a logistic regression model using generalised estimating equations was fit to the data to account for the possibility of repeated samples from the same participant.

    “In the unmatched approach, a logistic regression model using generalised estimating equations was fit to the data to account for the possibility of repeated samples from the same participant,24 assuming an unstructured correlation matrix.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] source

      Not checked in the free run.

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

    Premisecitation

    Recent studies have so far only investigated the second dose and have not evaluated responses to the omicron variant.

    “But even recent studies have so far only investigated the second dose and have not evaluated responses to the omicron variant.30 33”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] source

      Not checked in the free run.

    • cites [33] source

      Not checked in the free run.

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

    Interpretationnone given

    The effect of waning protection of sequential vaccine doses is difficult to differentiate from the real world circulation of variants.

    “However, the effect of waning protection of sequential vaccine doses is difficult to differentiate from the real world circulation of variants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Although findings point to a protective effect of a longer interval between the second and third doses, the distribution in the population is narrow overall, and the number of people with longer intervals is small.

    “Although our findings point to a protective effect of a longer interval between the second and third doses, owing to Israeli regulations, the distribution in the population is narrow overall, and the number of people with longer intervals is small; thus, these questions should be further researched in other countries.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    To deal with potential confounders, the analysis adjusted for underlying comorbidities, including obesity, cardiovascular diseases, diabetes, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, and immunosuppression conditions.

    “To deal with potential confounders, we adjusted for underlying comorbidities, including obesity, cardiovascular diseases, diabetes, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, and immunosuppression conditions.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    The unmatched multiple tests analysis adjusted for all of the covariates included in the matched approach as well as the previously matched parameters.

    “We used an unmatched logistic regression analysis, adjusting for all of the covariates included in the matched approach (that is, comorbidities and the number of previous PCR tests) as well as the previously matched parameters (biological sex, age group (<70 v ≥70 years), calendar week of testing, socioeconomic status, month of receipt of the third dose, and residence in a nursing home or assisted”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    An additional sensitivity analysis created an accumulative attack rate variable, which was later adjusted for in the unmatched multiple test analysis.

    “To examine how the time-varying risk of exposure might influence effectiveness, we conducted an additional sensitivity analysis in which we created an accumulative attack rate variable, which we later adjusted for in the unmatched multiple test analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In the first three weeks, a fourth dose provided additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine.

    “In the first three weeks, a fourth dose provided additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A growing number of studies suggest that an extended dosing interval amplifies both the humoral immune response and perhaps the cellular response, and is an effective global strategy given discrepancies between regions with high and low vaccination coverage.

    “Nonetheless, a growing number of studies suggest that an extended dosing interval amplifies both the humoral immune response30 and perhaps the cellular response,31 and is an effective global strategy given the discrepancies between regions with high and low vaccination coverage.32”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] source

      Not checked in the free run.

    • cites [31] source

      Not checked in the free run.

    • cites [32] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    A fourth dose of the BNT162b2 vaccine appears to have provided additional protection against both SARS-CoV-2 infection and severe covid-19 disease relative to three vaccine doses.

    “A fourth dose of the BNT162b2 vaccine appears to have provided additional protection against both SARS-CoV-2 infection and severe covid-19 disease relative to three vaccine doses.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: MHS covers 26.7% of the population and provides a representative sample of the Israeli population.
    • Rests on an assumption: The MHS database has a disengagement rate of less than 1% among its members, allowing for comprehensive longitudinal medical follow-up.

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

    Study design and conductreasoning

    Cases were matched to controls using 1:m matching, with up to five controls per case, based on seven factors: sex, age group, city of residence, socioeconomic status, calendar week of first test, month of receipt of the third dose, and a categorical variable for the living environment.

    “For our primary analysis, cases were matched to controls using 1:m matching, with up to five controls per case, based on seven factors: sex, age group (using a binary cut-off age of ≥70 years, because studies19 have indicated that older age groups are at higher risk, especially for severe disease), city of residence, socioeconomic status, calendar week of first test (to account for potential time-”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    In a test negative design, participants not tested are not eligible to be considered uninfected controls, thus reducing potential misclassification of SARS-CoV-2 infection status.

    “Firstly, those participants not tested are not eligible to be considered uninfected controls, thus reducing potential misclassification of SARS-CoV-2 infection status (which is more likely to occur in a cohort study), especially when the omicron variant was spreading rapidly and patients with no or mild symptoms might not be tested.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Previous studies have shown that improved healthcare seeking behaviour might be related both to improved vaccine uptake and to behaviours that could influence risk of SARS-CoV-2 infection or to more severe outcomes if infected.

    “Secondly, previous studies37 have shown that improved healthcare seeking behaviour might be related both to improved vaccine uptake as well as behaviours that could influence the risk of SARS-CoV-2 infection (eg, mask wearing, social distancing, and handwashing) or to more severe outcomes if infected (such as chronic disease management).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The relative nature between the fourth dose and three doses is inherent to the healthcare policy question of whether a second booster should be recommended for those eligible for the fourth dose.

    “This question is specific to those individuals who are eligible for the fourth dose—that is, those who have already received three vaccine doses. Therefore, the relative nature between the fourth dose and three doses is inherent to this healthcare policy question.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    The lack of pre-defined PCR testing protocols implemented in the study population presented a challenge and could lead to potential biases relating to healthcare seeking behaviour.

    “The lack of pre-defined PCR testing protocols implemented in the study population also presented a challenge. This limitation has been discussed extensively in previous covid-19 observational studies and could lead to potential biases relating to healthcare seeking behaviour.6 11 38 39”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] source

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    • cites [11] source

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    • cites [38] source

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

    Premisecitation

    Protection from previous doses against severe disease has been shown to wane more slowly than protection against infection.

    “Protection from previous doses against severe disease has been shown to wane more slowly than protection against infection.20 34”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] source

      Not checked in the free run.

    • cites [34] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The criterion for minimal eligibility in a test negative design is that a patient was tested, so this selection bias could create a scenario where we condition on the collider.

    “The criterion for minimal eligibility in a test negative design is the fact that a patient was tested, so this selection bias could create a scenario where we condition on the collider (testing is a common effect of both healthcare seeking behaviour and potentially of the severity of the SARS-CoV-2 manifestation, which prompts the patient to be tested, as seen in fig 3C).41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The period after fourth dose vaccination in Israel has been dominated by the omicron variant, which makes assessing the relative effectiveness of the fourth dose against other covid-19 variants difficult.

    “A second limitation stems from the varying dominance of different SARS-CoV-2 variants over time. The period after fourth dose vaccination in Israel has been dominated by the omicron variant, which makes assessing the relative effectiveness of the fourth dose against other covid-19 variants difficult—a well recognised limitation of real world analyses during this pandemic.6 36 37”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] source

      Not checked in the free run.

    • cites [36] source

      Not checked in the free run.

    • cites [37] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous covid-19 studies implementing a test negative design yielded comparable results to cohort studies on this population, while presenting diminished bias in short term outcomes of vaccine effectiveness.

    “Nonetheless, supporting this design were previous covid-19 studies implementing a test negative design that yielded comparable results to cohort studies on this population,6 11 while presenting diminished bias in the short term outcomes of vaccinee effectiveness.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] source

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    • cites [11] source

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

    Premisecitation

    Immunological memory (memory B and T cells) does not wane, and might be important for protection against severe disease.

    “By contrast, immunological memory (memory B and T cells) does not wane, and might be important for protection against severe disease.33”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To provide timely evidence of the relative vaccine effectiveness of a fourth dose of BNT162b2 vaccine, the study was only able to include 10 weeks of data.

    “Firstly, to provide timely evidence of the relative vaccine effectiveness of a fourth dose of BNT162b2b vaccine, we were only able to include 10 weeks of data.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductreasoning

    Because healthcare seeking behaviour is not a binary variable, this solution is insufficient when applied to real world data analysis.

    “Because healthcare seeking behaviour is not a binary variable, this solution is insufficient when applied to real world data analysis.”
    Quote in the paperNot a substantial claim
42 of 42

  • The paper relies on this without support.

    Sufficient real world evidence indicating the effectiveness of a fourth dose against infection with SARS-CoV-2 and severe covid-19 has been lacking so far.

    “Sufficient real world evidence indicating the effectiveness of a fourth dose against infection with SARS-CoV-2 and severe covid-19 has been lacking so far.”

  • The paper relies on this without support.

    MHS covers 26.7% of the population and provides a representative sample of the Israeli population.

    “MHS, which covers 26.7% of the population and provides a representative sample of the Israeli population, has maintained a centralised database of electronic medical records for three decades, with a disengagement rate of less than 1% among its members, allowing for comprehensive longitudinal medical follow-up.”

  • The paper relies on this without support.

    The MHS database has a disengagement rate of less than 1% among its members, allowing for comprehensive longitudinal medical follow-up.

    “MHS, which covers 26.7% of the population and provides a representative sample of the Israeli population, has maintained a centralised database of electronic medical records for three decades, with a disengagement rate of less than 1% among its members, allowing for comprehensive longitudinal medical follow-up.”
3 of 3

Self-check

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

  • Severe-outcome percentage uses the wrong denominator

    Minor

    The study included 97,499 participants, so 572 participants with severe outcomes represent about 0.59%, not 0.25%. The reported percentage is approximately 572 divided by the 233,582 PCR tests, rather than by participants.

    Reported 0.25 · recomputed 0.586673

  • Percentage of cases with at least three controls is understated

    Minor

    Of the 30,731 matched cases, 7,604 represent 24.74%, which rounds to 25%, not the reported 24%.

    Reported 24 · recomputed 24.743744

2 of 2

No citation lists for this paper

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

References 41 · Cited by 87

Research works printed but not linked: 2

  1. 10.1056/NEJMoa2114255 · DOI · Paper page
  2. 10.1038/s41467-021-26672-3 · DOI · Paper page

Authors
Gazit, S., Saciuk, Y., Perez, G., Peretz, A., Pitzer, V. E., & Patalon, T.
Affiliations
  • Maccabi Healthcare Services (IL)
  • Yale University (US)
Corresponding author
Gazit, Sivan
ORCID
Venue
BMJ
Publisher
BMJ
Published
2022-05-24
Volume
377
Pages
e071113
ISSN
1756-1833 (ISSN-L)
DOI
10.1136/bmj-2022-071113
PMC
PMC9127435
OpenAlex
W4281397711
Cited by
87
References
41
Citations by year
2026: 3 · 2025: 6 · 2024: 14 · 2023: 36 · 2022: 28
FWCI
10.25
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ (publishedVersion, cc-by-nc)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Social Sciences › Health › Vaccine Coverage and Hesitancy
  • Physical Sciences › Mathematics › Modeling and Simulation › COVID-19 epidemiological studies
Keywords
BNT162b2, fourth vaccine dose, booster vaccination, mRNA vaccines, SARS-CoV-2 breakthrough infection, severe COVID-19, vaccine effectiveness, older adults, Omicron variant, waning vaccine effectiveness, Israel, Maccabi Healthcare Services, hospitalization, COVID-19 mortality, test-negative case-control design, matched analysis, multiple comparisons
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, BNT162 Vaccine, Aged, Humans, Israel, Middle Aged, Retrospective Studies, Case-Control Studies

About these checks

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

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

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

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