Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting

Abstract

Background: Preapproval trials showed that messenger RNA (mRNA)-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations. An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed.

Methods: We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine. For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables. Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan-Meier estimator. To place these results in context, we performed a similar analysis involving SARS-CoV-2-infected persons matched to uninfected persons. The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses.

Results: In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia.

Conclusions: In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).

Figure 1. Study Population for the Vaccination Analysis.

Absolute numbers and percentage changes are shown for each inclusion and exclusion criterion. The chart focuses on the vaccinated population. The derivation group includes the entire population, including unvaccinated persons. The shaded boxes indicate the two study groups. The same exclusion criteria were applied to the unvaccinated persons for each index date on which they were considered for matching. BMI denotes body-mass index, CHS Clalit Health Services, and PCR polymerase chain reaction.

Figure 2. Study Population for the SARS-CoV-2 Analysis.

Absolute numbers and percentage changes are shown for each inclusion and exclusion criterion. The chart focuses on the SARS-CoV-2–infected population. The derivation group includes the entire population, including uninfected persons. The shaded boxes indicate the two study groups. The same exclusion criteria were applied to the uninfected persons for each index date on which they were considered for matching. Covid-19 denotes coronavirus disease 2019.

Figure 3. Risk Ratios for Adverse Events after Vaccination or SARS-CoV-2 Infection.

Estimated risk ratios for adverse events after vaccination or SARS-CoV-2 infection are shown. The risk ratio on the y axis is presented on a logarithmic scale to facilitate comparison of both increased and decreased risk. 𝙸 bars indicate 95% confidence intervals.

Figure 4. Absolute Excess Risk of Various Adverse Events after Vaccination or SARS-CoV-2 Infection.

Point estimates of the risk differences for selected adverse events are shown. Estimates were derived 42 days after vaccination or SARS-CoV-2 infection with the use of the Kaplan–Meier estimator. Risk differences are shown per 100,000 persons and rounded to the nearest integer. Negative differences (decreased risk) are represented as negative values on the y axis, and positive differences (increased risk) are represented as positive values on the y axis. The abbreviation mRNA denotes messenger RNA.