The Pfizer COVID-19 mRNA vaccine was found to be associated with a threefold increased risk of myocarditis, according to a real-world case-control study from Israel.
Vaccination had a strong association with an increased risk of myocarditis, as well as increased risks of lymphadenopathy, appendicitis, and herpes zoster infection, reported Dr Ran Balicer of Clalit Health Services in Tel Aviv, and colleagues.
However, in a separate cohort, infection with SARS-CoV-2 was associated with a higher risk of myocarditis , as well as other cardiovascular complications, including acute kidney injury, pulmonary embolism, and intracranial haemorrhage, the authors wrote in The New England Journal of Medicine.
They noted that vaccination was “substantially protective” against anaemia, acute kidney injury, intracranial haemorrhage, and lymphopenia.
Balicer's group examined data from the largest healthcare organisation in Israel to compare incidence of adverse events among vaccinated individuals versus unvaccinated individuals, and estimated the effects of SARS-CoV-2 infection on these adverse events.
Participants in the vaccination cohorts were 16 years old and older, had been in the health organisation for a full year, had no prior COVID-19 infection, and had no contact with the healthcare system in the last seven days. Notably, populations with confounders, such as healthcare workers, long-term care facility residents, or people confined to their home for medical reasons, were excluded.
From 20 December 2020 to 24 May 2021, eligible people vaccinated on a particular day were matched to eligible unvaccinated controls by age, sex, place of residence, socioeconomic status, and population sector. The study included 21 days of follow-up after the first and second doses of Pfizer vaccine. For each adverse event, patients were followed from the day of matching until documentation of the adverse event, 42 days, the end of the study period, or death.
To place the magnitude of the adverse effects of the vaccine in context, Balicer and team also estimated the effects of SARS-CoV-2 infection on these same adverse effects during the 42 days after diagnosis.
Overall, 884,828 people each were included in the vaccination cohort and the unvaccinated cohort, though 235,541 in the unvaccinated cohort had to be rematched following vaccination. The researchers also included 173,106 people with COVID-19 infection matched with the same number of uninfected people.
The median age of the eligible cohort of 1,736,832 people was 43, and 48% were women. Median age in the vaccination cohorts was 38. Median age of the infection cohort was 36, and 54% were women.
The authors cautioned against comparing the risk differences between vaccination and infection. "The effects of vaccination and of SARS-CoV-2 infection were estimated with different cohorts,” they wrote. “Thus, they should be treated as separate sets of results rather than directly compared.”
Limitations to the study included that study participants were not randomly assigned according to exposures, which could introduce confounding and bias, and that the matching process resulted in a study population whose median age was 5 years younger than the eligible population. In addition, certain high-risk populations were excluded from the study.
Study details
Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting
Noam Barda, Noa Dagan, Yatir Ben-Shlomo, Eldad Kepten, Jacob Waxman, Reut Ohana, Miguel A. Hernán, Marc Lipsitch, Isaac Kohane, Doron Netzer, Ben Y. Reis, and Ran D. Balicer.
Published in The New England Journal of Medicine 25 August 2021
Abstract
Background
Pre-approval 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 organizsation 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 haemorrhage, 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.
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