Over the past year, results from a series of clinical trials have demonstrated the efficacy and safety of COVID-19 vaccines in preventing serious illness, hospitalizations, and deaths.

Yet, with sporadic reports of rare adverse events, one question has remained unanswered: Just how safe are COVID-19 vaccines in the real world, outside of clinical trials?

Now, a study published Aug. 25 in The New England Journal of Medicine by researchers from Clalit Research Institute in Israel, Harvard Medical School, and the Harvard T.H. Chan School of Public Health answers that question.

The research, which assessed the safety of the Pfizer/BioNTech BNT162b2 mRNA vaccine, is based on analysis of data from nearly 2 million individuals in Israel and represents one of the largest real-world assessments of COVID-19 vaccine safety to date.

The findings, the researchers said, affirm the overall safety of the vaccine and underscore that the risk of adverse consequences from actual infection with SARS-CoV-2 far outweighs potential vaccine risks.

The study involved two analyses: A comparison of adverse events between vaccinated and unvaccinated individuals, and between unvaccinated people infected with SARS-CoV-2 and unvaccinated noninfected people.

The study showed that few adverse events were associated with the vaccine. Myocarditis, or inflammation of the heart muscle, the most serious of them, was rare, with a rate of 2.7 excess cases per 100,000 vaccinated people. This means that for every 100,000 individuals, 2.7 more cases of myocarditis occurred than would be expected, the researchers said.

By contrast, the risk of myocarditis was notably higher among infected but unvaccinated individuals, occurring at a rate of 11 excess cases per 100,000 people.

Coronavirus infection—but not vaccination—was also associated with greatly increased risk of pericarditis (an inflammation of the area around the heart), heart arrhythmias, heart attacks, strokes, pulmonary embolism, deep-vein thrombosis, acute kidney damage, among others.

Vaccine hesitancy

“To date, one of the main drivers of vaccine hesitancy has been a lack of information regarding potential side effects of the vaccine,” said study co-author Ben Reis, HMS assistant professor of pediatrics at Boston Children’s Hospital and director of the predictive medicine group in the Computational Health Informatics Program at Boston Children’s.

“This careful epidemiological study provides reliable information on vaccine safety, which we hope will be helpful to those who have not yet decided about vaccination,” Reis said. 

“Those who have hesitated until now to get vaccinated due to concerns about very rare side effects, such as myocarditis, should be aware that the risks for this very same side effect are actually higher among unvaccinated infected individuals,” Reis said.

The results are based on records from Clalit Health Services in Israel, one of the world’s largest integrated health record databases. The analysis is the largest peer-reviewed evaluation of the safety of a COVID-19 vaccine in a nationwide mass-vaccination setting.            

“The extensive nationwide rollout of Israel’s COVID-19 vaccination campaign provided the Clalit Research Institute with a unique opportunity to assess, through its rich and comprehensive digital datasets, the safety of the vaccine in a real-world setting, without needing to rely on individual-driven active reporting of side effects” said study senior author Ran Balicer, director of the Clalit Research Institute and Chief Innovation Officer for Clalit.

“These results show convincingly that this mRNA vaccine is very safe and that the alternative of ‘natural’ morbidity caused by the coronavirus puts a person at significant, higher, and much more common risk of serious adverse events,” Balicer said.

The results of this real-world study confirm, complement, and build on the previously reported findings of the Pfizer/BioNTech phase 3 randomized clinical trial, which involved 21,720 individuals, the researchers noted.

The comprehensive nature of this new analysis and the sheer volume of data involved offer a more detailed assessment of the vaccine’s safety across a wider range of adverse events.

“These data should facilitate informed individual risk-benefit decision-making, and, in our view, make a strong argument in favor of opting in to get vaccinated, especially in countries where the virus is currently widespread,” added Balicer, who also serves as chairman of Israel’s National Expert Advisory Team on COVID-19 response.

Previous efforts to characterize vaccine safety have relied on voluntary active reporting by vaccinated individuals, known to be incomplete. The new study relies on the analysis of millions of anonymized electronic medical records, which are far more comprehensive.

Parallel analyses

In an effort to provide the proper context that is critical for interpreting vaccine safety findings, the researchers also examine a wide range of adverse events both among vaccinated individuals and among unvaccinated individuals who were infected with the coronavirus, conducting two parallel analyses, assessing the occurrence of 25 adverse events in each of these groups.

In the vaccinated subgroup, the researchers compared the outcomes of 884,828 vaccinated individuals 16 years and older with those of 884,828 unvaccinated individuals based on an extensive set of sociodemographic, geographic, and health-related characteristics.

This analysis took place from Dec. 20, 2020, the launch of Israel’s national vaccination campaign, through May 24, 2021.

Some individuals switched groups based on their changing vaccination status, with 235,541 people moving from the unvaccinated group into the vaccinated group during the study.

To provide context for the vaccine safety findings above, a separate analysis was conducted among unvaccinated individuals. This analysis estimated rates of the same 25 potential adverse events among 173,106 unvaccinated individuals who were infected with SARS-CoV-2, compared with 173,106 carefully matched controls not infected with SARS-CoV-2.

This analysis took place from March 1, 2020, the beginning of the COVID-19 pandemic in Israel, through May 24, 2021.

The vaccine was found to be safe: Out of 25 potential side effects examined. four were found to have a link with the vaccine.

Myocarditis, an inflammation of the heart muscle associated with the vaccine was rare—2.7 excess cases per 100,000 vaccinated individuals. These events were observed mainly among males between the ages of 20 and 34.

In contrast, myocarditis was far more common among unvaccinated individuals infected with SARS-CoV-2. The analysis showed 11 excess cases of myocarditis per 100,000 infected individuals.

Other adverse events moderately associated with vaccination were swelling of the lymph nodes, a mild side effect that is part of a standard immune response to vaccination, with 78 excess cases per 100,000, appendicitis with 5 excess cases per 100,000, likely as a result of swelling of lymph nodes around the appendix.

Reactivation of dormant herpes zoster (chickenpox virus) infection occurred in 16 cases per 100,000.

Unvaccinated risks

These small numbers of adverse events among vaccinated individuals stood in stark contrast with the high rate of multiple and more serious adverse events among unvaccinated individuals infected with SARS-CoV-2.

These included cardiac arrhythmias (a 3.8-fold increase above baseline risk with 166 cases per 100,000 infected patients); kidney damage (14.8-fold increase with 125 excess cases per 100,000); pericarditis (5.4-fold increase with 11 excess cases per 100,000); pulmonary embolism (12.1-fold increase with 62 excess cases per 100,000); deep-vein thrombosis, or a blood clot in the veins (3.8-fold increase with 43 excess cases per 100,000); myocardial infarction, or heart attack (4.5-fold increase with 25 excess cases per 100,000); and stroke (2.1-fold increase with 14 excess cases per 100,000).

Additional investigators on the study included Noam Barda, Noa Dagan, Yair Ben-Shlomo, Eldad Kepten, Jacob Waxman, Reut Ohana, all of the Clalit Research Institute; Doron Netzer of Clalit Health Services; Miguel Hernán and Marc Lipsitch of the Harvard T.H. Chan School of Public Health; and Isaac Kohane of Harvard Medical School.

The research was funded in part by the newly announced Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.