Six-Month Follow-up after a Fourth BNT162b2 Vaccine Dose

To the editor:

In a prospective cohort study involving healthcare workers described above,1 we evaluated the humoral response and vaccine effectiveness of a fourth dose of the BNT162b2 (Pfizer-BioNTech) vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during a 6-month follow-up period in which omicron (mainly BA .1 and BA.2) was the predominant variant in Israel.two Absence of prior SARS-CoV-2 infection was verified by SARS-CoV-2 testing and serological follow-up testing (see Table S1 and Supplementary Methods in the Supplementary Appendix, available with the full text of this letter at NEJM .org). The humoral response (assessed by measuring IgG and neutralizing antibodies) after receiving the fourth dose of vaccine was compared with the response after receiving the second and third doses. Vaccine efficacy was assessed by comparing infection rates among participants who had received a fourth dose of vaccine over various time periods (days 7 to 35, days 36 to 102, or days 103 to 181 after receiving the fourth dose). with infection rates among those who had received three doses. Participants had to have received the third dose of the vaccine at least 4 months earlier. A Cox proportional hazards regression model was used, adjusting for age, sex, and professional role; Calendar time was used as the time scale to account for differences in infection prevalence over time (details are provided in the Supplementary Appendix). No participant died or was lost to follow up.

Six-month follow-up of immunogenicity and vaccine efficacy after a fourth dose of BNT162b2 vaccine.

Panels A and B show IgG and neutralizing antibody titers, respectively, up to 26 weeks after the second, third, and fourth doses of the BNT162b2 vaccine (Pfizer-BioNTech). Locally weighted scatterplot smoothing is overlaid. Panel C shows the vaccine efficacy against any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from 7 to 35 days, from 36 to 102 days, from 103 to 181 days, and from 7 to 181 days. (representing the entire study period). [darker-shaded area]) after the fourth dose of vaccine (administered at least 4 months after receiving the third dose) compared with the efficacy of three doses of vaccine. Vaccine effectiveness (measured as 1 minus the hazard ratio) is estimated from a Cox proportional hazards regression model, adjusting for age, sex, and occupational role. Calendar time was used as the time scale to further adjust for different prevalences of infection over time. A dashed horizontal line is shown with a hazard ratio of 1, indicating no effect. The 𝙸 bars indicate 95% confidence intervals. BAU indicates antibody binding units.

Among participants who had not had prior SARS-CoV-2 infection, 6,113 were included in the humoral response analysis and 11,176 in the vaccine effectiveness analysis (Fig. S1 and Tables S2 and S3). The antibody response peaked at approximately 4 weeks, decreased to levels seen prior to the fourth dose at 13 weeks, and stabilized thereafter. Throughout the 6-month follow-up period, weekly adjusted IgG and neutralizing antibody levels were similar after receiving the third and fourth doses and were markedly higher than the levels observed after receiving the second dose (Figure 1A and 1B and Table S4).

The cumulative incidence curve is shown in Figure S2, and the vaccine effectiveness is shown in Figure 1C. Reception of the fourth dose of the BNT162b2 vaccine conferred more protection against SARS-CoV-2 infection than that provided by receipt of three doses of the vaccine (with receipt of the third dose at least 4 months earlier) (effectiveness vaccine overall, 41%, 95% confidence interval [CI], 35 to 47). Time-specific vaccine effectiveness (which, in our analysis, compared infection rates among participants who had not yet been infected since vaccination) decreased over time, falling from 52% (95% CI, 45 to 58) during the first 5 weeks after vaccination to -2% (95% CI, -27 to 17) at 15 to 26 weeks.

The study has several limitations. First, although our cohort consisted of a diverse population that included older adult volunteers, a cohort composed of healthcare workers may not be representative of the general population. Furthermore, only healthcare workers who had not had a previous SARS-CoV-2 infection were included, further limiting generalizability. Second, the potential confounding of unrecognized hybrid immunity may have remained, despite extensive history taking and serologic evaluation. Third, the decision to receive the fourth dose could be related to health-seeking behaviors that were not well captured in our data, possibly resulting in additional residual confounding. Fourth, we were unable to estimate effectiveness against serious outcomes of infection due to the absence of such outcomes in our study cohort; A third dose of the BNT162b2 vaccine has been shown to confer long-lasting protection against such outcomes.3 Previous studies have shown greater efficacy of a fourth dose against severe outcomes during short-term follow-up,4.5 but whether this additional efficacy is similarly diminished by protection against infection remains to be determined.

In this prospective cohort study, a third dose of the BNT162b2 vaccine led to an enhanced and sustained immune response compared with two doses, but the additional immunological advantage of the fourth dose was much smaller and completely disappeared 13 weeks after vaccination. . This finding correlated with decreased vaccine efficacy among recipients of a fourth dose, culminating in no substantial additional efficacy over a third dose between 15 and 26 weeks post-vaccination. These results suggest that the fourth dose, and possibly future boosters, should be intelligently timed to coincide with waves of illness or to be available seasonally, similar to the influenza vaccine. Whether multivalent booster doses will result in increased durability remains to be seen.

Dr Michael Canetti
Noam Barda, MD, Ph.D.
Maya Gilboa, MD
Sheba Tel Hashomer Medical Center, Ramat Gan, Israel

Victoria Indenbaum, Ph.D.
Ministry of Health, Ramat Gan, Israel

Keren Asraf, Ph.D.
Tal Gonen, MD
Yael Weiss-Ottolenghi, Ph.D.
Dr Sharon Amit
Ram Doolman, MD
Sheba Tel Hashomer Medical Center, Ramat Gan, Israel

Ella Mendelson, Ph.D.
Ministry of Health, Ramat Gan, Israel

Laurence S. Freedman, Ph.D.
Yitshak Kreiss, MD
Sheba Tel Hashomer Medical Center, Ramat Gan, Israel

Yaniv Lustig, Ph.D.
Ministry of Health, Ramat Gan, Israel

Gili Regev-Yochay, MD
Sheba Tel Hashomer Medical Center, Ramat Gan, Israel
[email protected]

Disclosure forms provided by the authors are available with the full text of this letter at

This letter was published on November 9, 2022 on

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  2. two. Kliker L, north zuckerman, atari north, et al. COVID-19 vaccination and advanced BA.1 infection induce neutralizing antibodies that are less efficient against omicron BA.4 and BA.5 variants, Israel, March-June 2022. Euro Surveill 2022;27:22005592200559.

  3. 3. fence n, dagan n, cohen c, et al. Efficacy of a third dose of the BNT162b2 mRNA COVID-19 vaccine in preventing severe outcomes in Israel: an observational study. Lancet 2021;398:20932100.

  4. Four. Magen O, Wax Man JG, Makov-Assif M, et al. Fourth dose of the BNT162b2 mRNA Covid-19 vaccine in a national setting. N English J Med 2022;386:16031614.

  5. 5. Bar-On YM, Goldberg and, Manuel M., et al. Protection by a fourth dose of BNT162b2 against omicron in Israel. N English J Med 2022;386:17121720.

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