Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine

To the Editor

Magen et al. (April 28 issue)1 examined the relative effectiveness of four doses of the BNT162b2 (Pfizer–BioNTech) messenger RNA (mRNA) vaccine as compared with that of three doses among adults 60 years of age or older. The authors evaluated five Covid-19–related outcomes. The first one was linked to the incidence of SARS-CoV-2 infection (confirmed by means of polymerase-chain-reaction assay), whereas the remaining four were related to disease severity (symptomatic Covid-19, Covid-19–related hospitalization, severe Covid-19, and Covid-19–related death).

Even if the reported relative vaccine effectiveness was in the right direction (showing an additional benefit of the adjunctive vaccine dose),2 it overestimated the real effect of the fourth dose on disease severity. Patients who are at risk for Covid-19–related negative consequences (until death from Covid-19) are in fact (and by definition) first infected with SARS-CoV-2. However, the authors considered the whole population of persons who were at risk for infection, rather than only the infected persons (the number of which was substantially different in the two groups), to be at risk for Covid-19–related adverse outcomes (Table 2 in the article). This misleading calculation roughly doubled the estimated additional benefit of the fourth vaccine dose in the studied population.

Andrea Tumminia, M.D., Ph.D.
Marcello Romano, M.D.
Garibaldi Hospital, Catania, Italy

No potential conflict of interest relevant to this letter was reported.

This letter was published on June 29, 2022, at

  1. 1. Magen O, Waxman JG, Makov-Assif M, et al. Fourth dose of BNT162b2 mRNA Covid-19 vaccine in a nationwide setting. N Engl J Med 2022;386:1603-1614.

  2. 2. Bar-On YM, Goldberg Y, Mandel M, et al. Protection by a fourth dose of BNT162b2 against omicron in Israel. N Engl J Med 2022;386:1712-1720.


The authors reply: Tumminia and Romano assert that our estimation of the effectiveness of a fourth dose of the BNT162b2 vaccine for the prevention of severity-related outcomes could have been restricted to persons who were infected with SARS-CoV-2 during follow-up. Neither the randomized trials of the mRNA vaccines1,2 nor our observational emulation of a target trial restricted the analysis to infected persons, for two reasons.

First, the overall benefit of vaccination for the prevention of severe outcomes is a combination of preventing infection (and thus its downstream severe sequelae) and reducing the severity of disease among infected persons. From both public health and individual perspectives, decision makers are interested in this overall benefit — and not only in the reduction of disease severity among infected persons.

Second, restricting the analysis to infected persons would introduce selection bias if unmeasured factors that are not related to vaccination (e.g., genetic predisposition and subclinical immunosuppression) create a predisposition to both infection and severe sequelae. In this case, infection would be affected by both vaccination and those prognostic factors, and, in an analysis conditional on infection, a noncausal association between vaccination and severe sequelae would arise.3,4 We think that it is intuitive that persons who become infected despite having received four doses of vaccine are more likely to be persons with these prognostic factors. Explicit emulation of a target trial helps to prevent this self-inflicted bias in observational analyses.

Jacob G. Waxman, M.D.
Ori Magen, M.D.
Clalit Research Institute, Tel Aviv, Israel

Miguel A. Hernán, M.D.
Harvard T.H. Chan School of Public Health, Boston, MA

Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on June 29, 2022, at

  1. 1. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020;383:2603-2615.

  2. 2. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021;384:403-416.

  3. 3. Hernán MA, Hernández-Díaz S, Robins JM. A structural approach to selection bias. Epidemiology 2004;15:615-625.

  4. 4. Hernán MA, Robins JM. Causal inference: what if. Boca Raton, FL: CRC Press, 2020.

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