Determinants of COVID-19 vaccine-induced myocarditis

Myocarditis is inflammation of the myocardium or ‘musculature’ of the heart.^1,2 The myocardium is made up of many cell types; however, the greatest mass of tissue is accounted for by cardiomyocytes.^3,4 Cardiomyocytes are the principal contractile cells and are supported by specialized conduction and stromal cell types including cardiac pericytes.⁵ All of these cell types can be damaged by inflammation.⁶

Myocarditis can manifest as chest pain, heart failure, or sudden death.^1,2,7–11 Myocarditis is a major risk for cardiac death among the young.¹² The high-risk age population for myocarditis is from puberty through the early 30s, and it is the third leading cause of sudden cardiac death in children and young adults. Four per million children every year were affected by myocarditis before the pandemic.¹³ It has been reported that 0.05% of all pediatric hospitalizations are for myocarditis. Most cases of myocarditis are identified in young adults with males affected more often than females.^9,12,14 Multiple vaccines have been associated with myocarditis in the past including influenza and smallpox.¹⁵

Cases of myocarditis have been reported after Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection before the advent of coronavirus disease 2019 (COVID-19) vaccines.^16,17 In the context of COVID-19 critical illness, multiple studies have reported cardiac injury defined by clusters of International Classification of Diseases (ICD) codes related to cardiac troponin measurement.^18–20 None of these reports used clinical adjudication in addition to troponin levels or ICD codes with physician review of symptoms, electrocardiogram (ECG/EKG), echocardiography, cardiac magnetic resonance imaging (MRI), and clinical symptoms.

COVID-19 vaccine-induced myocarditis can be defined as the onset of clinical myocarditis that is temporally associated with COVID-19 mRNA or adenoviral DNA vaccine administration and in the absence of another known cause. Common clinical symptoms after vaccination include chest pain, palpitations, and effort intolerance.²¹ Thus, the clinical diagnosis calls for characteristic symptoms of cardiac arrest, elevated troponin levels, ECG changes (diffuse ST-segment elevation), and in some cases left and right ventricular dysfunction on echocardiography. In cases where the diagnosis is not secure, cardiac MRI can detect changes in tissue characterization (late gadolinium enhancement) consistent with myocardial inflammation.^22–28

Vaccines have been instrumental in advancing immunology, paving the way for preventive measures and reducing the impact of infectious diseases. Even with effective vaccines, favorable safety profiles are not guaranteed. The vaccine adverse event reporting system (VAERS) was created and implemented in 1990 by the Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) to receive reports about adverse events (AEs) that may be associated with vaccines.²⁹ The primary purpose for maintaining the database is to serve as an early warning or signaling system for AEs not detected during pre-market testing. In addition, the National Childhood Vaccine Injury Act of 1986, which was created because vaccines cause ‘unavoidable harm’, requires healthcare providers and vaccine manufacturers to report to the Department of Health and Human Services (DHHS)-specific AEs following the administration of those vaccines outlined in the Act.³⁰ Under-reporting is a known and serious disadvantage of the VAERS system.^30–32

An AE is defined as any untoward or unfavorable medical occurrence in a human study participant, including any abnormal physical exam or laboratory finding, symptom, or disease, temporally associated with the participant’s involvement in the research, whether or not considered related to participation in the research. A serious or severe adverse event (SAE) is defined as any AE that results in death, is life-threatening, or places the participant at immediate risk of death from the event as it occurred, requires, or prolongs hospitalization, causes persistent or significant disability or incapacity, results in congenital anomalies or birth defects, or is another condition which investigators judge to represent significant hazards.^31,33 These classifications are based on the Code of Federal Regulations. The VAERS handbook states that 10–15% of reported AEs are classified as severe for any given set of data.²⁹ Myocarditis qualifies as an SAE as it can be associated with hospitalization and unpredictable cardiac arrest with sudden death.

Approximately 81% of the United States population has received at least one COVID-19 shot, according to CDC data as of 10 May 2023.³⁴ The BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Janssen) products have not been fully licensed by the U.S. FDA and have instead been authorized for emergency use by the FDA under an Emergency Use Authorization to prevent COVID-19 in individuals 6 months of age and older.³⁵ The COVID-19 injectable products have not been approved to reduce transmission. There are no prospective, double-blind, randomized, placebo-controlled trials of COVID-19 injectable products demonstrating reductions in COVID-19 hospitalizations and deaths as primary or secondary endpoints. Thus, myocarditis resulting in hospitalization and death attributable to the COVID-19 vaccines may be viewed as an excess risk of the injection program.

The roll-out of COVID-19 injections is actively being monitored by regulatory agencies but all of the risks are not yet known.^36–39 Recently, the Israeli Ministry of Health announced that approximately 1 in 4500 men ages 16–24 who received BNT162b2 developed myocarditis.³⁹ In prospective cohort studies with measures before and after the second and third injections, Mansanguan et al.⁴⁰ and Buergin et al.⁴¹ reported rates of possible myocarditis of 2.3% and 2.8%, respectively. There is great concern regarding a causal link between myocarditis and the COVID-19 injections.^42–44 Thus, we set out to describe the raw data in VAERS and the COVID-19 vaccines as potential determinants of myocarditis.

We found that myocarditis cases reported to VAERS had a strong and sharp rise in 2021 that coincided with the roll-out of COVID-19 vaccines. Most reported cases in VAERS were young men with the highest incidences occurring following the second injection. There has been no alternative explanation provided for these cases other than the COVID-19 injections. Given the close temporal relationship and the context of the reporting, it seems clear that the COVID-19 vaccines are deterministic for myocarditis. These cases are reported to VAERS largely by healthcare workers who are concerned the event happened as a result of vaccination.⁴⁷ There may be less bias in reports created by healthcare workers compared to patients who self-report.

In addition to COVID-19 vaccine-induced heart damage, there is a risk of further cardiac involvement from SARS-CoV-2 infection even in individuals deemed healthy with no preexisting medical conditions,^16–20 highlighting the need to accurately report the number of vaccine-induced myocarditis cases. A PubMed literature search for COVID-19 vaccine myocarditis yields over 800 peer-reviewed studies. Because of the spontaneous reporting of events to VAERS, we can assume that the cases reported thus far are not rare, but rather, just the tip of the iceberg. Under-reporting is a known and serious disadvantage of the VAERS system.⁴⁸ Thus, VAERS alone without adjustment cannot be used to estimate population incidence. Based on the 3078 reports of myocarditis filed to VAERS as of 11 August 2023, using an under-reporting factor of 31,⁴⁸ we estimate that the actual number of myocarditis cases in the United States and other countries that use VAERS may be around 95,418.

The strong signal of a five times higher risk of myocarditis in 15-year-olds following dose 2 is indicative of a dose–response relationship. If the effects of each dose were the same, then we would expect to see the same number of reports filed following each dose. This indicates that the effects of dosing a second time may be more damaging and cumulative with each additional dose. In such cases, it is possible that myocarditis was subclinical after dose 1 and became symptomatic after dose 2. We found 70% of all reports of myocarditis were filed within 7 days and 43% were made within 48 h. Following dose 2, 77% of reports were filed within 7 days and 48% within 48 h, thus providing more evidence of clinical concern and a temporal relationship with the injections.

The clinical implications of acute myocarditis in younger individuals as a result of uncontrolled production of the SARS-CoV-2 spike protein within cardiac myocytes and cardiac support cells are unknown. If myocarditis has developed after the first injection, then subsequent administrations should be avoided at all costs. Sustained elevations of cardiac troponin, reduction in left and right ventricular function, large areas of inflammation or scar on imaging, and cardiac arrhythmias all portend a poor prognosis for the development of heart failure and cardiac death.^49–52 Because the duration of action of genetic material coding for spike protein is unknown, long-term follow-up with cardiology consultation may be advised in cases with possible repeat imaging and biomarkers.

The modified mRNA lipid nanoparticle (LNP) platform has never before been implemented for use in human subjects on a global scale in the context of vaccination, and it has recently been shown that the LNPs bio-distribute and accumulate to transfect whichever cells are in proximity.⁵³ The payload-modified mRNA is translated into the foreign Spike protein which induces damage within cells, at the cell surface, and through circulation with endothelial damage and thrombosis.^54–56 Castruita et al.⁵⁷ have found circulating mRNA in the bloodstream for up to 28 days after injection. Swank et al.⁵⁸ have found circulating Spike protein among the vaccinated with post-acute sequelae for up to 1 year. Yonker et al.⁵⁹ have reported that the circulating Spike protein is not effectively bound by antibodies in children with myocarditis whereas those with no clinical disease have effectively bound Spike protein. Finally, Baumeier et al.⁶⁰ have shown the presence of Spike protein and inflammation in the myocardium of young persons suffering from COVID-19 vaccine myocarditis.

The typical timeline is up to 10 years for a proper safety and efficacy assessment of a novel genetic product.⁶¹ The COVID-19 vaccines were rushed through phase I–III trials in about 10 months with the Operation Warp Speed initiative.⁶¹ Safety signals emerging from VAERS were apparent in January of 2021.⁴⁵ Reports of death after product administration should prompt market withdrawal. Historically, there are many examples of biological product recalls. In 2010, rotavirus vaccines licensed in the United States were found to contain porcine circovirus type 1 and were subsequently suspended.⁶² In 2010, an increased risk of narcolepsy was found following vaccination with a monovalent H1N1 influenza vaccine that was used in several European countries during the H1N1 influenza pandemic.⁶³ Between 2005 and 2008, a meningococcal vaccine was suspected to cause Guillain–Barré syndrome.⁶⁴ In 1998, a vaccine designed to prevent rotavirus gastroenteritis was associated with childhood intussusception after being vaccinated.^65,66 Finally, in the early 2000s, a hepatitis B vaccine product was linked to multiple sclerosis.⁶⁷

At the time of writing, the CDC recommends everyone 6 months and older to receive an updated COVID-19 booster.⁶⁸ However, children have a negligible risk for COVID-19,⁶⁹ and yet they are a high-risk group for myocarditis from COVID-19 vaccination as shown by our results. The World Health Organization’s current vaccination advice states that healthy young people ages 6 months to 17 years are a ‘low priority group’ and that vaccinating this group has limited impact on public health.⁷⁰ In contradistinction from the CDC, given the very low SARS-CoV-2 infection fatality rate in children with robust natural immune responses^69,71 and the presence of effective medical treatment,^72,73 we believe COVID-19 vaccination may pose more harm to children than theoretical benefit. This corroborates actions taken by Sweden, Norway, and Finland in 2021 when health officials suspended the use of Moderna injections in young people due to the detection of safety signals for an increased risk of myocarditis.⁷⁴ Husby et al.⁷⁵ found a higher risk of myocarditis in those who received the Moderna product (100 mcg dose) compared to those who were injected with Pfizer (30 mcg dose), which indicates a possible dose–response relationship. Fairweather et al.⁷⁶ also found a higher risk of myocarditis with mRNA products, particularly with the Moderna injections. Although the CDC states that the COVID-19 products are safe and effective in all age groups,⁶⁹ Parry et al.⁷⁷ concluded that the COVID-19 injection program should be immediately suspended due to excess risks, including myocarditis. Moreover, Fraiman et al.⁷⁸ conducted a re-analysis of serious AEs reported in the phase III randomized clinical trials of Pfizer and Moderna mRNA COVID-19 products and found that there is an excess risk of AEs following vaccination. Cardiac abnormalities have been detected for at least a year after the initial diagnosis of COVID-19 vaccine-induced myocarditis, indicating the possibility of long-term effects with unknown consequences.⁷⁹ Formal risk–benefit assessments need to be conducted to clarify these findings. Also, the exact mechanisms of action for induction and progression of COVID-19 vaccine-induced myocarditis need to be elucidated to ensure appropriate management.

Our study has all the limitations of safety databases with spontaneously reported events. There are also limitations when comparing myocarditis rates between two time periods, including less effective myocarditis detection tools in the previous period and extensive worldwide acknowledgment of myocarditis during the COVID-19 era that might skew reporting. We recognize that myocarditis has been keyed for reporting in VAERS since the 2021 U.S. FDA warnings⁸⁰ were placed on the COVID-19 mRNA products. Nonetheless, we believe VAERS data are grossly under-reported due to the lack of clinical recognition, unavailable vaccine cards, and clinician fear of professional reprisal given the emergency nature of vaccination. Despite myocarditis being the MedDRA code listed in VAERS, the diagnosis of myocarditis might be incorrect without clinical adjudication. As a general rule, the ICU cardiac injury described in COVID-19 illness is subclinical and common to many non-COVID ICU illnesses largely reflecting a minor nonspecific troponin elevation and not myocarditis. This is distinctly different than the ambulatory setting after vaccination where the presentation is obvious, and the clinical ECG laboratory and imaging findings are diagnostic of myocarditis.²¹

We found a very strong safety signal for COVID-19 vaccine-induced myocarditis, particularly in children and young adults, that resulted in hospitalization and death. COVID-19 vaccines induce an uncontrolled expression of potentially lethal SARS-CoV-2 spike protein within human cells, have a close temporal relationship of events, and are internally and externally consistent with emerging sources of clinical and peer-reviewed data supporting the conclusion that COVID-19 vaccines are deterministic for myocarditis, including fatal cases. Further investigation into the underlying mechanisms of COVID-19 vaccine-induced myocarditis is imperative to create effective mitigation strategies and ensure the safety of COVID-19 vaccination programs across populations.

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