The largest real-world study of a COVID-19 vaccine to date shows that Pfizer/BioNTech's shot is safe and linked to substantially fewer adverse events than SARS-CoV-2 infection in unvaccinated patients.
A team led by researchers from the Clalit Research Institute in Tel Aviv, Israel, and Harvard University matched vaccinated Israelis 16 years and older (median age, 38) with similar but unvaccinated people infected with SARS-CoV-2 from Dec 20, 2020, to May 24, 2021. They then derived risk ratios (RRs) and risk differences 42 days after vaccination (short- to medium-term) using the Kaplan-Meier estimator.
The analysis of the Pfizer vaccine, which the US Food and Drug Administration fully approved earlier this week, involved 1.7 million vaccinated and 233,000 unvaccinated people.
The vaccine was determined to be safe, with only 4 of the 25 potential side effects that the group examined strongly associated with the vaccine. While the vaccine was associated with a 3.24 RR (or more than triple the risk) for myocarditis, or inflammation of the heart muscle, it was still rare. In contrast, the RR for the condition in unvaccinated COVID-19 patients was 18.28.
"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," senior study author Ran Balicer, MD, PhD, said in a Clalit Research Institute news release.
"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," he added.
Risk of myocarditis much higher with COVID
The strongest tie between the vaccine and an adverse event was myocarditis, with an excess risk of 1 to 5 events per 100,000 people, an RR of 3.24 (95% confidence interval [CI], 1.55 to 12.44), and a risk difference of 2.7 events per 100,000 (95% CI, 1.0 to 4.6). Myocarditis after vaccination was seen mostly in men aged 20 to 34.
In contrast, previous SARS-CoV-2 infection among unvaccinated patients was associated with a significantly elevated risk of myocarditis (RR, 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].
Other vaccine-linked adverse events included swollen lymph nodes (RR, 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 (RR, 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, or shingles (RR, 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]). The increased risk of Bell's palsy (facial-nerve palsy) was small (RR, 1.32).
Previous SARS-CoV-2 infections were also associated with multiple serious adverse events in addition to myocarditis, including pericarditis (inflammation of the sac surrounding the heart), heart rhythm abnormalities, deep vein thrombosis (blood clot), pulmonary embolism (blood clot that travels to a lung artery), heart attack, intracranial hemorrhage (bleeding inside the skull), and thrombocytopenia (low blood platelet count).
The authors quantified the COVID-19–related risks thus: abnormal heart rhythms (a 3.8-fold increase, or an increase of 166 cases per 100,000 infected patients), kidney damage (14.8-fold increase; 125 excess cases per 100,000), pericarditis (5.4-fold increase; 11 excess cases per 100,000), pulmonary embolism (12.1-fold increase; 62 excess cases per 100,000), deep vein thrombosis (3.8-fold increase; 43 excess cases per 100,000), heart attack (4.5-fold increase; 25 excess cases per 100,000), and stroke (2.1-fold increase; 14 excess cases per 100,000).
Assuaging vaccine fears
The study was the largest peer-reviewed assessment of the safety of a COVID-19 vaccine in the setting of a nationwide mass vaccination, according to the authors. They noted that previous vaccine safety evaluation efforts have relied on vaccinated individual self-reports, which are incomplete.
Marc Lipsitch, PhD, of Harvard, study coauthor, said in the release that the big challenge in vaccine safety studies is ensuring "that those we are comparing to identify the vaccine's side effects are similar in the other characteristics that may predict whether they will experience these side effects," which he said is particularly difficult in the context of a rapidly growing, age-targeted vaccine campaign.
"Clalit’s extraordinary database made it possible to design a study that addressed these challenges in a way that provides tremendous confidence in the inferences that come out of the study," he added.
Coauthor Ben Reis, PhD, of Harvard, said that the study results should assuage vaccine hesitancy due to lack of potential information on possible vaccine-related adverse events. "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," he said.
