By Jessica Rose PhD, MSc, BSc1 & Peter A.McCullough MD, MPH Article in Press/Preproof: Current Problems In Cardiology
Following the global rollout and administration of the Pfizer Inc./BioNTech BNT162b2 and Moderna mRNA-1273 vaccines on December 17, 2020, in the United States, and of the Janssen Ad26.COV2.S product on April 1st, 2021, in an unprecedented manner, hundreds of thousands of individuals have reported adverse events (AEs) using the Vaccine Adverse Events Reports System (VAERS). We used VAERS data to examine cardiac AEs, primarily myocarditis, reported following injection of the first or second dose of the COVID-19 injectable products. Myocarditis rates reported in VAERS were significantly higher in youths between the ages of 13 to 23 (p<0.0001) with ∼80% occurring in males. Within 8 weeks of the public offering of COVID-19 products to the 12-15-year-old age group, we found 19 times the expected number of myocarditis cases in the vaccination volunteers over background myocarditis rates for this age group. In addition, a 5-fold increase in myocarditis rate was observed subsequent to dose 2 as opposed to dose 1 in 15-year-old males. A total of 67% of all cases occurred with BNT162b2. Of the total myocarditis AE reports, 6 individuals died (1.1%) and of these, 2 were under 20 years of age – 1 was 13. These findings suggest a markedly higher risk for myocarditis subsequent to COVID-19 injectable product use than for other known vaccines, and this is well above known background rates for myocarditis. COVID-19 injectable products are novel and have a genetic, pathogenic mechanism of action causing uncontrolled expression of SARS-CoV-2 spike protein within human cells. When you combine this fact with the temporal relationship of AE occurrence and reporting, biological plausibility of cause and effect, and the fact that these data are internally and externally consistent with emerging sources of clinical data, it supports a conclusion that the COVID-19 biological products are deterministic for the myocarditis cases observed after injection.
Myocarditis is inflammation of the myocardium or ‘musculature’ of the heart.1,2,3,4 The myocardium is made up of many cell types however the greatest mass of tissue is accounted for by cardiomyocytes.4,5,6 Cardiomyocytes are the principal contractile cells and are supported by specialized conduction and stromal cell types.4,5,6,7,8 Both systole and diastole are active processes that expend energetic resources of cardiomyocytes which are organized into myofibrils.8,9,10 Myocarditis can manifest as sudden death, chest pain or heart failure. The symptoms of heart failure from myocarditis include effort intolerance, dyspnea, fatigue, and ankle swelling.1,2,3,4,6,11,12,13 The cause is an inflammation of the heart muscle, often following a viral infection, but not exclusively so. The damaged muscle is prone to lethal cardiac arrythmias as well as having the potential to develop both right and left ventricular dysfunction (cardiomyopathy).3,4,12,13
Myocarditis is a major risk for cardiac death among the young.11 The high-risk age population for myocarditis is from puberty through early 30s, and it is the third leading cause of sudden cardiac death in children and young adults. 1 per 100,000 children per year are affected by myocarditis and it has been reported that 0.05% of all pediatric hospitalizations are for myocarditis. Between 0.5 and 3.5% of heart failure hospitalizations are due to myocarditis. Most cases of myocarditis are identified in young adults with males affected more often than females.12,13,14, 15,16
In the context of COVID-19 respiratory illness, there are a significant number of patients who are otherwise healthy experiencing heart-related complications, including myocarditis, but the majority of clinical reports and diagnoses claim cardiac injury based on ICU-related-related injury to the heart.17,18,19,20,21,22,23,24,25 This is relevant in terms of contextualizing the potential risk of myocarditis from the COVID-19 products against COVID-19 itself and establishing a background rate of myocarditis in specific contexts. Cardiac injuries associated with COVID-19 respiratory illness reveal a set of parameters based on a combination of measurements of troponin levels, electrocardiogram (ECG/EKG), echocardiogram readings, cardiac magnetic resonance imaging (MRI) and clinical symptoms that are different from the clinical picture of vaccine-induced myocarditis. COVID-19-Injection-Related Myocarditis (CIRM) 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. CIRM presents with clinical symptoms (chest pain, effort intolerance) combined with excessively elevated troponin levels, EKG changes (diffuse ST segment elevation) and in some cases left and right ventricular dysfunction on echocardiography. In cases where the echocardiogram is unrevealing, cardiac MRI can detect changes in tissue characterization consistent with myocardial inflammation.22,23,24,25,26,27
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 that may be associated with vaccines.28 The primary purpose for maintaining the database is to serve as an early warning or signaling system for adverse events not detected during pre-market testing. In addition, the National Childhood Vaccine Injury Act of 1986 (NCVIA) requires health care providers and vaccine manufacturers to report to the DHHS specific adverse events following the administration of those vaccines outlined in the Act.1 Under-reporting is a known and serious disadvantage of the VAERS system.28,29,30
An Adverse Event (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 participants’ 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 adverse event 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.28,30,31 These classifications are based on the Code of Federal Regulations. The VAERS handbook states that approximately 15% of reported AEs are classified as severe.28 Myocarditis qualifies as an SAE as it is often associated with hospitalization.
The BNT162b2, mRNA-1273, Ad26.COV2.S products have not been approved or licensed by the U.S. Food and Drug Administration (FDA), having been authorized instead for emergency use by FDA under an Emergency Use Authorization (EUA) to prevent Coronavirus Disease 2019 (COVID-19) for use in individuals 16 years of age and older.232,33,34 Ultimately, the roll-out of COVID-19 injectable biologicals are actively being monitored, but all of the risks are not yet known.16,17,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46
Methods and results
To analyse the VAERS data set the Language and Environment for Statistical Computing, R, was used. The VAERS data set is available for download (https://vaers.hhs.gov/data/datasets) in three separate comma-separated values (csv) files representing i) general data for each report; ii) the reported AEs or ‘symptoms’, and iii) vaccine data including vaccine manufacturer and lot number, for each report. The VAERS dataset is updated approximately once a week and the uploaded set is approximately one week behind the reports. Upon individual reporting of vaccine side effects or adverse events, a VAERS ID number is provided to the individual to preserve confidentiality, and a detailed description of the side effects are transcribed along with the individual’s age, residence by state, past medical history, allergies and gender and many other details. In addition, the vaccine lot number, place of vaccination and manufacturer details are included in the report. In order to maximize the input variables for my analysis, the three files were merged by VAERS ID that is included as a linking variable in all three files. The merged data set comprises data collected pertaining to all reported AEs associated with BNT162b2, mRNA-1273, and Ad26.COV2.S products: the three primary vaccine manufacturers responsible for nCoV-2019 products currently being administered in the U.S. Data was sorted according to vaccine type (data reported for COVID-19) and relevant variables were sorted including VAERS ID, AEs, age, gender, state, vaccination date, date of death, incident of death, dose series, treatment lot number, treatment manufacturer, hospitalizations, emergency department visits and onset date of AEs. Myocarditis as a standalone AE was extracted by keyword and cardiac events were grouped by extracting multiple keywords according to MedDRA nomenclature. Statistical analysis was done using the Student’s t-Test to determine statistically significant differences between ages in the myocarditis AE. Skewing in distribution of data was tested using Pearson’s Skewness Index, I, which is defined as I = (mean-mode)/standard deviation. The data set is significantly skewed if |I|≥1.
Results: General information
To date, approximately 56% of the total US population has been ‘fully vaccinated’ against COVID-19. As of July 9th, 2021, 397,262 AEs have been reported in the VAERS system. This number is very atypical and large when compared to frequencies of AE reports from previous years. Figure 1 illustrates the stark contrast between what the count would be if the trend of past 30 years continued through to the end of 2021: ∼65,000 for the entire 2021 year as opposed to ∼400,000 over 6 months. There are almost 4,000 different AE types reported (to date) in the context of COVID-19 products and among them, many SAES. As previously stated, the VAERS handbook maintains that ∼15% of all the AEs should classify as SAEs yet the percentage holds at 18% for COVID-19-related AEs.
Among these SAEs are cardiac AEs that include cardiac arrest, myocardial infarction, and myocarditis. Myocarditis reports in the context of the COVID-19 products are atypically high in the context of prior vaccine rollouts and in the context of baseline levels with respect to high-risk groups. The number of cases of myocarditis reported to the VAERS database dramatically outnumber case counts seen in previous years with 1 single case having been reported in 2019 and 1 single case being reported in 2020 (Refer to Section 1.4). Figure 2 shows the absolute numbers of myocarditis cases reported for 2021 as per Onset Date. It is clear from this bar plot that the frequency of myocarditis cases reported to VAERS has increased starting at the beginning of June. This is just shortly after the roll-out of injections into children aged 12-15 began. On May 10, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for BNT162b2 vaccine in children aged 12-15. Of note, 67% of myocarditis cases were in the context of administration of BNT162b2.
Incidence rates of myocarditis in youths
As of July 9th, 2021, a total of 559 myocarditis AEs (0.14% of all AEs) have been reported. Of the reports, 80% of the gender classification was male. In general, 71% of all VAERS reports are made by females so this statistic is particularly telling. The increase in myocarditis reports coincides with the COVID-19 injection rollouts in children aged 12-15, thus, we hypothesized that the increased cases of myocarditis were in fact occurring in children of these ages. Figure 3 shows the distribution of myocarditis cases by age grouped by decade. 41% of all myocarditis reports were made for children aged 10 through 20 and 72% of all myocarditis reports were made for young adults aged 10-30 years of age. The distribution is right-skewed toward the younger age groups, and this is statistically significant (I=1.61). This provides strong evidence to support our hypothesis.