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

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THE NEW ENGLAND JOURNAL OF MEDICINE

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.)

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More than 1 year into the pandemic of coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an unprecedented number of mass vaccination efforts are under way worldwide. Globally, nearly 3.4 billion doses of vaccine have been administered over the 6-month period since the first vaccines were approved.1

Phase 3 clinical trials showed that several Covid-19 vaccines were efficacious and had an acceptable safety profile.2-4 A number of potential adverse events were identified during these trials, including lymphadenopathy and idiopathic facial-nerve (Bell’s) palsy.2,3 Trials of the BNT162b2 vaccine (Pfizer–BioNTech) also showed a mild imbalance between the vaccinated and placebo groups with respect to the number of cases of appendicitis, hypersensitivity reactions, acute myocardial infarction, and cerebrovascular accidents.5 However, phase 3 trials may have inherent limitations in assessing vaccine safety because of a small number of participants and a healthier-than-average sample population. Hence, they are often underpowered to identify less common adverse events. Postmarketing surveillance is required to monitor the safety of new vaccines in real-world settings.

Much effort is currently focused on characterizing the safety profiles of the recently approved Covid-19 vaccines. Passive surveillance systems such as the Vaccine Adverse Event Reporting System (VAERS)6 collect information about adverse events that are potentially related to vaccination. This information is voluntarily reported by health care providers and the public. These systems are useful for quickly identifying potential safety signals, which, along with the findings of phase 3 trials, can be translated to lists of adverse events of interest for further exploration (such as that provided by the Safety Platform for Emergency Vaccines [SPEAC]).7,8 Active surveillance systems such as the Biologics Effectiveness and Safety (BEST) system (part of the Sentinel Initiative)9 aim to compare the incidence of adverse events of interest in large electronic health record databases with the background historical incidence. Although active surveillance can help highlight suspicious trends, the lack of a rigorously constructed comparable control group limits the ability of such surveillance to identify causal effects of vaccination.

The effectiveness of vaccines against SARS-CoV-2 has been confirmed in real-world studies,10,11 but high-quality real-world safety data on the messenger RNA (mRNA)–based Covid-19 vaccines remain relatively sparse in the literature. The results of a study based on data reported by more than 600,000 vaccinated persons were recently published12; that study mainly assessed common and mild side effects. Two additional studies, which were based on surveys of vaccinated participants, involved small cohorts,13,14 and another study analyzed adverse events reported in the VAERS database.15 All these studies lacked controls. One study that did incorporate a control group included 8533 long-term care facility residents who had received the first dose of vaccine.16 The authors of this study concluded that the mRNA-based vaccines had an acceptable safety profile, and no notable adverse events were reported.

As of May 24, 2021, nearly 5 million people in Israel, comprising more than 55% of the population, had received two doses of the BNT162b2 vaccine.1 In this study, we used the integrated data repositories of the largest health care organization in Israel to evaluate the safety profile of the BNT162b2 vaccine. We compared the incidence of a broad set of potential short- and medium-term adverse events among vaccinated persons with the incidence among matched unvaccinated persons. Potential adverse events related to medical interventions are best understood in the context of the risks associated with the disease that these interventions aim to prevent or treat, so we also estimated the effects of SARS-CoV-2 infection on this same set of adverse events.

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