Another important study out of Israel may impact thinking about mRNA COVID-19 vaccine safety. Published recently in the New England Journal of Medicine, the authors took advantage of 4.7 million patient records from Clalit Health Services, one of Israel’s largest health care organizations (HCO). Representing 52% of the eastern Mediterranean nation’s population, the real-world retrospective, observational study’s implications cannot be ignored. Led by top cardiologist Dr. Guy Witberg affiliated with Rabin Medical Center, Beilinson Hospital in Petah Tikva, the study centered on the Pfizer-BioNTech mRNA vaccine—BNT162b2. In America, the Food and Drug Administration (FDA) has issued a warning that while rare, some young people, especially males, face some risk of myocarditis and pericarditis. The U.S. Centers for Disease Control (CDC) establishes the incidence at 1.2 per 100,000 for the 18- to 29-year-old range. However, this Israel-based study indicates the estimated incidence is nearly double the rate that the CDC shares with the American population—actually at 2.13 cases per 100,000 persons. Dr. Witberg and the study team report an even higher incidence for the male cohort of 16 to 29 years old. For example, young males 16 to 29 face a major increase in risk with a rate of 10.69 cases per 100,000. Most of the cases are mild to moderate in severity. Do these figures lead to any reconsideration of the mass vaccination policy of young people—especially males—e.g., does the risk-benefit analysis change?

While the study authors report that most of the cases are mild to moderate in severity, nonetheless, the fact that the incidence rate is nearly double the rate promulgated by the CDC should raise an eyebrow, if not an alarm.

TrialSite Point of View

The biggest takeaway is that the Israeli study’s overall incidence rates for myocarditis following at least 1 dose of Pfizer are higher in general- They are higher than what the CDC established as a rate—and significantly higher in young men.

As of late, some countries have paused the use of certain COVID-19 vaccines in younger populations, and others are determining if only 1-dose in the younger populations is a better and safer strategy. Meanwhile, the US is talking about mandating the vaccine in this population.

The Governor of California recently tweeted that it will be mandated in kids once the FDA approves it. Right now, an 18-year-old male might be mandated to get the COVID-19 vaccine to go to college or work a particular job in the US, while other countries are sounding the alarm that the risk for post-vaccination myocarditis might be higher than our gov officials are telling us it is.

These are the hearts of healthy young people. Myocarditis CAN come with scarring of the heart and long-term complications. (We don’t have ANY data on the long-term effects of that.) TrialSite raises the question as to whether it would be unethical to mandate COVID-19 vaccination in a population with such a low risk of hospitalization and/or mortality from the virus given this data.

The Study

Approved by the Clalit Health Services’ institutional review board, the data was retrospective and didn’t require written patient informed consent. The study investigators capitalized on the rich, robust patient data available from Israel’s largest health maintenance—4.7 million patient records representing half of the nation’s population.

Formally a retrospective cohort study, the study team evaluated patient record data stored in the database spanning a period from December 20, 2020, through May 24, 2021. Identifying myocarditis documented within a period 42 days after an initial dose of BNT162b2, the authors utilized the International Classification of Diseases, Ninth Revision (ICD-9; codes 422, 429.0, 398.9 and 391.2 and any relevant subcodes) to identify the suspected medical event. The authors classified myocarditis based on meeting the CDC case definitions for suspected, probable, or confirmed myocarditis. Actual case definitions follow the standards promulgated by the American Heart Association.

Thereafter incorporating data as well from index hospitalization as well as other subsequent health records, the authors performed Kaplan-Meier analysis to estimate the cumulative incidence of the condition, as well as severity levels—stratified based on age and sex—across a spectrum of time at 42 days post the first dose of BNT162b2 in Israel.

The Results

The study team was able to pinpoint 2,558,421 patient members that received at least one dose of the Pfizer/BioNTech mRNA COVID-19 vaccine, with 94% of the total (2,401,605) falling into the fully vaccinated category (two doses).

At first, the study team identified 159 potential myocarditis cases based on the matching to ICD-9 codes within the 42 days once individuals received the first vaccine administration.

However, after applying study criteria, the total number of cases were adjusted to 54 cases of myocarditis—41 were considered mild while 12 classified as intermediate and 1 as categorized as fulminant—meaning severe.

TrialSite includes Table 1. Characteristics of the Study Population and Myocarditis Cases at Baseline.

The authors reported the overall incident rate post 42 days from the first administration of the BNT162b2 mRNA vaccine targeting COVID-19. They calculated that rate at 2.13 cases (95% confidence interval [CI], 1.56 to 2.70) which includes a rate of 4.12 (95% CI, 2.99 to 5.26) for males and 0.23 (95% CI, 0 to 0.49) for females.

Note that the rate for people aged 16 to 29 incidences per 100,000 persons equaled 5.49 (95% CI, 3.59 to 7.39) while the rate plummeted for the 30 and older crowd—1.13 (95% CI, 0.66 to 1.60). For male patients between the ages of 16 and 29—the most at-risk cohort—the rate was 10.69 cases per 100,000 persons (95% CI, 6.93 to 14.46). Note that across the board, male patients, especially younger ones, face higher risk and should be considered in risk-benefit analyses for vaccination.

Funding

The study was funded by the Ivan and Francesca Berkowitz Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute. Pfizer-BioNTech was not involved with this study.

About the Research Center

Established back in 1911, Clalit Health Services was originally called Kupat Holim Clalit—a mutual aid society. With the founding of the State of Israel in 1948, Clalit became instrumental in the provision of health care for the massive immigration at that time. Today Clalit Health Services, a nonprofit, represents the largest provider of health services in the nation.

Clalit Health Services owns and operates 1,500 primary care clinics and 14 hospitals, including 30% of Israel’s hospital acute care beds. They employ almost 35,000 medical professionals, technicians, and administrators.

Established in 2010, the Clalit Research Institute has a mission to transform data into decision-making insights that support good health policy as well as continuously improving and transforming healthcare delivery and clinical practice.

The Clalit Research Institute leverages a sophisticated, robust integrated electronic health record database storing records that in some cases go back to the early 1990s. It’s this database that supports comprehensive real-world data-based research for population-level health analyses and insight.

Lead Research/Investigator

· Guy Witberg, M.D.

· Noam Barda, M.D., Ph.D.

· Sara Hoss, M.D.,

· Ilan Richter, M.D., M.P.H.

· Maya Wiessman, M.D.

· Yaron Aviv, M.D.

· Tzlil Grinberg, M.D.

· Oren Auster, M.Sc.

· Noa Dagan, M.D., Ph.D., M.P.H.,

· Ran D. Balicer, M.D., Ph.D., M.P.H.

· Ran Kornowski, M.D.

Call to Action: Do the findings here impact the push for mass vaccination of young people?