Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine

Abstract

Background: Active immunization with the BNT162b2 vaccine (Pfizer-BioNTech) has been a critical mitigation tool against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (Covid-19) pandemic. In light of reports of waning protection occurring 6 months after the primary two-dose vaccine series, data are needed on the safety and efficacy of offering a third (booster) dose in persons 16 years of age or older.

Methods: In this ongoing, placebo-controlled, randomized, phase 3 trial, we assigned participants who had received two 30-μg doses of the BNT162b2 vaccine at least 6 months earlier to be injected with a third dose of the BNT162b2 vaccine or with placebo. We assessed vaccine safety and efficacy against Covid-19 starting 7 days after the third dose.

Results: A total of 5081 participants received a third BNT162b2 dose and 5044 received placebo. The median interval between dose 2 and dose 3 was 10.8 months in the vaccine group and 10.7 months in the placebo group; the median follow-up was 2.5 months. Local and systemic reactogenicity events from the third dose were generally of low grade. No new safety signals were identified, and no cases of myocarditis or pericarditis were reported. Among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated, Covid-19 with onset at least 7 days after dose 3 was observed in 6 participants in the vaccine group and in 123 participants in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% confidence interval, 89.5 to 98.3).

Conclusions: A third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against Covid-19 as compared with two doses of the BNT162b2 vaccine during a median follow-up of 2.5 months. (Funded by BioNTech and Pfizer; C4591031 ClinicalTrials.gov number, NCT04955626.).

Figure 1. Enrollment and Randomization.

Participants who were included in the withdrawal category discontinued their participation in the trial before the data-cutoff date of October 5, 2021. Because of the early unblinding of the trial results, some of the participants became aware of the trial-group assignments before the 1-month telephone contact. One participant who was assigned to receive the BNT162b2 vaccine actually received placebo and was included in the analysis of the placebo group.

Figure 2. Adverse Events.

Panel A shows the percentage of participants who reported having at least one adverse event after the receipt of a third dose of the BNT162b2 vaccine or placebo. Data regarding any adverse events and adverse events that were deemed by the investigator to be related to either the BNT162b2 vaccine or placebo were collected within 1 month after receipt of the third dose; data regarding severe adverse events, withdrawal, or death were reported before the data-cutoff date of October 5, 2021. Panel B shows adverse events that were reported in the safety population, with the exclusion of participants with stable human immunodeficiency virus infection, who were evaluated separately. The graph on the left shows the percentage of participants with adverse events, and the graph on the right shows the between-group difference (BNT162b2 vaccine minus placebo) in these events as measured in percentage points. The error bars indicate 95% confidence intervals calculated with the Clopper–Pearson method for adverse events and the Miettinen–Nurminen method for risk difference.

Figure 3. Cumulative Incidence of Covid-19 after a Third Dose of BNT162b2.

Shown is the cumulative incidence curve of the first Covid-19 occurrence after dose 3 in the total efficacy population, as calculated by means of the Kaplan–Meier method (Table S1 in the Supplementary Appendix). Each symbol represents the onset of a Covid-19 case; symbols with an S represent severe Covid-19 cases.