Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting

Abstract

Background: With large waves of infection driven by the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), alongside evidence of waning immunity after the booster dose of coronavirus disease 2019 (Covid-19) vaccine, several countries have begun giving at-risk persons a fourth vaccine dose.

Methods: To evaluate the early effectiveness of a fourth dose of the BNT162b2 vaccine for the prevention of Covid-19-related outcomes, we analyzed data recorded by the largest health care organization in Israel from January 3 to February 18, 2022. We evaluated the relative effectiveness of a fourth vaccine dose as compared with that of a third dose given at least 4 months earlier among persons 60 years of age or older. We compared outcomes in persons who had received a fourth dose with those in persons who had not, individually matching persons from these two groups with respect to multiple sociodemographic and clinical variables. A sensitivity analysis was performed with the use of parametric Poisson regression.

Results: The primary analysis included 182,122 matched pairs. Relative vaccine effectiveness in days 7 to 30 after the fourth dose was estimated to be 45% (95% confidence interval [CI], 44 to 47) against polymerase-chain-reaction-confirmed SARS-CoV-2 infection, 55% (95% CI, 53 to 58) against symptomatic Covid-19, 68% (95% CI, 59 to 74) against Covid-19-related hospitalization, 62% (95% CI, 50 to 74) against severe Covid-19, and 74% (95% CI, 50 to 90) against Covid-19-related death. The corresponding estimates in days 14 to 30 after the fourth dose were 52% (95% CI, 49 to 54), 61% (95% CI, 58 to 64), 72% (95% CI, 63 to 79), 64% (95% CI, 48 to 77), and 76% (95% CI, 48 to 91). In days 7 to 30 after a fourth vaccine dose, the difference in the absolute risk (three doses vs. four doses) was 180.1 cases per 100,000 persons (95% CI, 142.8 to 211.9) for Covid-19-related hospitalization and 68.8 cases per 100,000 persons (95% CI, 48.5 to 91.9) for severe Covid-19. In sensitivity analyses, estimates of relative effectiveness against documented infection were similar to those in the primary analysis.

Conclusions: A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19-related outcomes among persons who had received a third dose at least 4 months earlier. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).

Figure 1. Selection of Persons in the Four-Dose Group and the Matching Control Group.

Of 258,994 eligible vaccinated persons, 210,265 (81.2%) were successfully matched and included in at least one of the study groups as follows: 182,122 participated as members of the four-dose group and 72,505 participated as members of the control group, with an overlap of 44,362 persons who were initially matched as members of the control group and then were rerecruited as members of the four-dose group after receiving a fourth dose, along with a new matched control. CHS denotes Clalit Health Services.

Figure 2. Cumulative Incidence of Covid-19 Outcomes in the Four-Dose Group and the Matching Control Group.

Shown are cumulative incidence curves (1 minus the Kaplan–Meier estimate) for the five outcomes in persons in the four-dose group (four doses of BNT162b2 vaccine) as compared with those in the control group (three doses of BNT162b2 at least 4 months earlier). Shaded areas indicate the 95% confidence intervals, and tick marks indicate censored data (with a mark appearing at each day of follow-up because of the large sample size). Covid-19 denotes coronavirus disease 2019, PCR polymerase chain reaction, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.

Figure 3. Daily Vaccine Effectiveness in the Primary Analysis and the Poisson Regression Analysis.

Panel A shows daily estimated vaccine effectiveness (1 minus the daily hazard ratio [HR]) against PCR-confirmed SARS-CoV-2 infection after a fourth vaccine dose as compared with a third vaccine dose (≥4 months earlier). 𝙸 bars indicate the 95% confidence interval. The analysis was performed with the bootstrap method (500 repetitions) on the Kaplan–Meier estimate. Panel B shows the daily estimated vaccine effectiveness (1 minus the incidence rate ratio [IRR]) against PCR-confirmed SARS-CoV-2 infection after a fourth vaccine dose as compared with a third vaccine dose (≥4 months earlier). 𝙸 bars indicate the 95% confidence interval. The analysis was performed with the use of Poisson regression as part of a sensitivity analysis. In each panel, values above the dashed line indicate that four doses are more effective than three doses received at least 4 months earlier.