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Association of Receiving a Fourth Dose of the BNT162b Vaccine With SARS-CoV-2 Infection Among Health Care Workers in Israel

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Was there a benefit of vaccinating health care workers with a fourth dose of BNT162b2 vaccine during the Omicron variant outbreak of the COVID-19 pandemic?

Findings  In this multicenter cohort study of 29 611 health care workers in Israel, the breakthrough infection rate among those who received 4 doses was 6.9% compared with 19.8% in those who received 3 doses.

Meaning  These findings suggest that a fourth vaccine dose was effective in preventing breakthrough COVID-19 infections in health care workers, helping to maintain the function of the health care system during the pandemic.


Importance  Despite the high 3-dose vaccination rate among health care workers (HCWs) in Israel, a high rate of SARS-CoV-2 breakthrough infections in this group was observed during the Omicron wave. As a result, the Israeli Ministry of Health decided to recommend a fourth vaccine dose to medical staff.

Objective  To evaluate the benefit of a fourth BNT162b2 vaccine dose on the breakthrough infection rate among HCWs.

Design, Setting, and Participants  This multicenter cohort study was performed in January 2022, the first month of the 4-dose vaccination campaign, during a surge of the Omicron variant wave. All health care workers at 11 general hospitals in Israel who had been vaccinated with 3 doses up to September 30, 2021, and had not contracted COVID-19 before the vaccination campaign were included.

Exposures  Vaccination with a fourth dose of the BNT162b2 vaccine during January 2022.

Main Outcomes and Measures  Breakthrough COVID-19 infections in 4-dose recipients vs 3-dose recipients measured by a polymerase chain reaction test result positive for SARS-CoV-2. Health care workers were tested based on symptoms or exposure.

Results  A total of 29 611 Israeli HCWs (19 381 [65%] female; mean [SD] age, 44 [12] years) had received 3 vaccine doses between August and September 2021; of these, 5331 (18%) received the fourth dose in January 2022 and were not infected by the first week after vaccination. Overall breakthrough infection rates were 368 of 5331 (7%) in the 4-dose group and 4802 of 24280 (20%) in the 3-dose group (relative risk, 0.35; 95% CI, 0.32-0.39). Similar reductions were found in a matched analysis by the exact day of receiving the third vaccine (relative risk, 0.61; 95% CI, 0.54-0.71) and in a time-dependent Cox proportional hazards regression model (adjusted hazard ratio, 0.56; 95% CI, 0.50-0.63). In both groups, no severe disease or death occurred.

Conclusions and Relevance  In this cohort study, the fourth BNT162b2 vaccine dose resulted in a reduced breakthrough infection rate among hospital staff. This reduction was lower than that observed after the third dose; nevertheless, considering the high infectivity of the Omicron variant, which led to critical medical staff shortages, a fourth vaccine dose should be considered to mitigate the infection rate among HCWs.

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Article Information

Accepted for Publication: June 10, 2022.

Published: August 2, 2022. doi:10.1001/jamanetworkopen.2022.24657

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Cohen MJ et al. JAMA Network Open.

Corresponding Author: Allon E. Moses, MD, Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem 91120, Israel (allonm@hadassah.org.il).

Author Contributions: Drs Cohen and Moses had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Cohen and Oster contributed equally to this work as did Drs Spitzer and Benenson.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Oster, Moses, Benenson.

Statistical analysis: Cohen, Spitzer.

Administrative, technical, or material support: Oster, Moses.

Supervision: Moses, Benenson.

Conflict of Interest Disclosures: None reported.

Group Information: The Israeli-Hospitals 4th Vaccine Working Group members appear in the Supplement.

Data Gov. Israeli Ministry of Health COVID-19 data center [in Hebrew]. Accessed June 1, 2022. https://data.gov.il/dataset/covid-19
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