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Cited by 142SARS-CoV-2 and COVID-19 ResearchVaccine Coverage and HesitancyCOVID-19 epidemiological studies

Odds of Testing Positive for SARS-CoV-2 Following Receipt of 3 vs 2 Doses of the BNT162b2 mRNA Vaccine

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Patalon, Tal, Gazit, Sivan, Pitzer, Virginia E., Prunas, Ottavia, Warren, Joshua L., Weinberger, Daniel M.·2022·JAMA Internal Medicine
DOI 10.1001/jamainternmed.2021.7382PMC PMC8634151

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Abstract

Importance: With the evidence of waning immunity of the mRNA vaccine BNT162b2 (Pfizer-BioNTech), a nationwide third-dose (booster) vaccination campaign was initiated in Israel during August 2021; other countries have begun to administer a booster shot as well. Objective: To evaluate the initial short-term additional benefit of a 3-dose vs a 2-dose regimen against infection of SARS-CoV-2. Design, Setting, and Participants: This preliminary retrospective case-control study used 2 complementary approaches: a test-negative design and a matched case-control design. Participants were included from the national centralized database of Maccabi Healthcare Services, an Israeli healthcare maintenance organization covering 2.5 million members. Data were collected between March 1, 2020, and October 4, 2021, and analyses focused on the period from August 1, 2021, to October 4, 2021, because the booster dose was widely administered from August 1 onward. Exposures: Either 2 doses or 3 doses of the BNT162b2 vaccine. Main Outcomes and Measures: The reduction in the odds of a positive SARS-CoV-2 polymerase chain reaction (PCR) test at different time intervals following receipt of the booster dose (0-6, 7-13, 14-20, 21-27, and 28-65 days) compared with receiving only 2 doses. Results: The study population included 306 710 members of Maccabi Healthcare Services who were 40 years and older (55% female) and received either 2 or 3 doses of the BNT162b2 vaccine and did not have a positive PCR test result for SARS-CoV-2 prior to the start of the follow-up period. During this period, there were 500 232 PCR tests performed, 227 380 among those who received 2 doses and 272 852 among those who received 3 doses, with 14 989 (6.6%) and 4941 (1.8%) positive test results in each group, respectively. Comparing those who received a booster and those who received 2 doses, there was an estimated odds ratio of 0.14 (95% CI, 0.13-0.15) 28 to 65 days following receipt of the booster (86% reduction in the odds of testing positive for SARS-CoV-2). Conclusion and Relevance: Previous studies have demonstrated that vaccine-derived protection against SARS-CoV-2 wanes over time. In this case-control analysis, we showed an association between receipt of the booster dose and a reduction in the odds of testing positive for SARS-CoV-2, potentially counteracting waning immunity in the short term. Further monitoring of data from this population is needed to determine the duration of immunity following the booster.

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  • The 7-day cutoff for defining breakthrough infection was chosen based on previous research on BNT162b2 vaccine effectiveness.

    “The 7-day cutoff was chosen based on previous research the BNT162b2 vaccine effectivenesss1,11.”

    From Waning effectiveness of the third dose of the BNT162b2 mRNA COVID-19 vaccine (2022) · cites this paper as [11]

    The Statistical Analysis section says the 7- and 14-day cutoffs for assessing third-dose effectiveness were chosen based on second-dose research. It does not describe the 7-day cutoff as a definition of breakthrough infection; it uses the first seven days after the booster as a negative-control period. (LLM, conf=0.85)

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  • The reference group of those unvaccinated with the booster is prone to bias because by the outcome period most of Israel's population had already received the booster.

    “However, as by the outcome period of January 2022 most of Israel’s population had already received the booster, the reference group of those unvaccinated is admittedly prone to bias, as has been discussed in the previous papers11.”

    From Waning effectiveness of the third dose of the BNT162b2 mRNA COVID-19 vaccine (2022) · cites this paper as [11]

    The Limitations section acknowledges potential bias in the booster comparison, including differences in testing behavior and possible confounding because chronically ill patients were prioritized. It does not attribute bias to most Israelis having received a booster. The Data Collection and Study Population section says the analysis ended in October 2021, so the paper does not assess the claimed January 2022 outcome period. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • The third dose of BNT162b2 increases immunogenicity against SARS-CoV-2, as reflected by a rapid and broad immune response.

    “Studies have demonstrated that the third dose increases immunogenicity against SARS-CoV-2 as reflected by a rapid and broad immune response to the third BNT162b2 dose7,11.”

    From Waning effectiveness of the third dose of the BNT162b2 mRNA COVID-19 vaccine (2022) · cites this paper as [11]

    The Results (page unavailable) report that protection against a positive SARS-CoV-2 test increased within two weeks of the third dose, and refer to an apparent immune response. The study measured infection outcomes, however, not immunogenicity or the breadth of the immune response; it therefore does not establish the claimed rapid and broad immune response. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The test-negative design mitigates bias from healthcare-seeking behavior and was chosen for this analysis for that reason.

    “The test-negative design, which does not assume that a lack of a positive test equals a negative test and somewhat adjusts for testing volume, attempts to better mitigate this bias and is the reason we chose this method for this analysis”

    From Waning effectiveness of the third dose of the BNT162b2 mRNA COVID-19 vaccine (2022) · cites this paper as [11]

  • 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.”

    From 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 (2022) · cites this paper as [6]

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Authors
Patalon, T., Gazit, S., Pitzer, V. E., Prunas, O., Warren, J. L., & Weinberger, D. M.
Affiliations
  • Maccabi Healthcare Services (IL)
  • Yale University (US)
Corresponding author
Weinberger, Daniel M.
ORCID
Venue
JAMA Internal Medicine
Publisher
American Medical Association (AMA)
Published
2022-02-01
Volume
182
Issue
2
Pages
179
ISSN
2168-6106 (ISSN-L)
DOI
10.1001/jamainternmed.2021.7382
PMC
PMC8634151
OpenAlex
W3216645551
Cited by
141
References
21
Citations by year
2026: 2 · 2025: 1 · 2024: 11 · 2023: 33 · 2022: 83 · 2021: 11
FWCI
10.93
Type
journal article
Language
en
Open access
Locations
  • JAMA Internal Medicine (publishedVersion)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (UL1TR001863)
  • National Institute of Allergy and Infectious Diseases (R01AI137093)
  • National Center for Advancing Translational Sciences
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 mRNA vaccine, COVID-19 booster vaccination, third dose vaccination, COVID-19 pandemic, vaccine waning, test-negative design, matched case-control studies, PCR-confirmed infection, vaccine effectiveness, older adults, Maccabi Healthcare Services, SARS-CoV-2 variants, Omicron variant, Delta variant
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, BNT162 Vaccine, Adult, Female, Humans, Male, Retrospective Studies, Time Factors, Incidence, Case-Control Studies, Comparative Effectiveness Research

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