Keywords: COVID 19 mRNA vaccine, myocarditis, pericarditis, vaccine related adverse events
VAERS: US Vaccine Adverse Event Reporting System
ICD: International Classification of disease
CDC: Center for disease control
VSD: Vaccine Safety Data Link
EMR: Electronic Medical Record
In the year 2020, when COVID 19 pandemic broke out there were loss of millions of lives and the medical fraternity was still searching for the most effective treatment approaches to combat the pandemic. It was a time of great uncertainty, but through continuous research and collaboration, significant advancements have been made since then and developed vaccines in real time and made them available to the world. The rapid development of COVID-19 vaccines meant that post-marketing surveillance had limited time for thorough evaluation, which is typically a crucial part of clinical trials. As a result, various adverse events, including myocarditis and pericarditis, were reported following mRNA COVID-19 vaccination.
Table-1: Definition of myocarditis and pericarditis 
Potential mechanism of covid 19 MRA vaccine myocarditis:
SARS COV-2 mRNA vaccine contains nucleoside modified mRNA encoding the viral spike glycoprotein of SARS COV-2, but not live virus or DNA. They are encapsulated in lipid nanoparticles that act as delivery vehicles to transport mRNA into the cells and may include inactive ingredients such as buffers and salts. Once inside the host cells, the vaccine’s mRNA causes the cells to build the spike protein high then stimulates an adaptive immune response to identify and destroy a virus expressing spike protein. Vaccine induced spike protein IgG antibodies prevent attachment of SARS COV-2 to its host cell via spike protein binding to angiotensin converting enzyme 2 receptor, and thereby neutralizing the virus.
Here’s the probable mechanism in few people, the problem in some patients is that in some cases selected mRNA molecules can be immunogenic and stimulate the innate immune system, destroying the mRNA before it reaches target cells, preventing the spike protein and neutralizing antibody production. 
A study by Alagarraju Muthukumar, PhD and his other colleagues reported a 52 year old previously healthy man who presented with acute myocarditis like illness 3 days after the administration of second dose of Moderna’s covid 19 vaccine. The MRI findings are consistent with myocarditis and other potential causes of acute myocardial injury were excluded, as well as other potential infectious causes of systemic autoimmune disease. This case is said to be one of the first reports of possible mRNA based covid 19 vaccine associated myocarditis reported in the medical literature, with in depth clinical and translational investigation and comparison with different control groups. The increase in the number of NK cells and T helper 17 cells-related IL 17 enriched immune signature has been implicated in development of myocarditis and its associated transition of fibrosis to heart failure but such upregulation of IL 17 levels was not observed in this patient. The lack of evidence for upregulation of this cytokine combined with the increased NK cell numbers observed in the case patient, could suggest a distinct vaccine associated immunophenotype with high likelihood of recovery. 
A study by Jay Montgomery et al carried out on US military members, included 23 male patients and 22 previously healthy military members. The study reported myocarditis was observed and reported within 4 days of receiving covid 19 vaccine, who were previously healthy with high level of fitness. Total 20 patients had symptoms following the second dose of covid vaccine with appropriate time space between 2 doses. All 20 patients had significantly elevated cardiac troponin levels. 8 patients out of those 20 patients who underwent cardiac MRI imaging were found consistent with myocarditis. Also additional testing was done to rule out covid 19 infection or cardiovascular manifestation due other infections. The patients also had abnormal ecg findings denoting abnormalities in heart. 
A population based cohort study by Sarah A. Buchan et al, included 297 individuals in Ontario,Canada with myocarditis or pericarditis following COVID 19 vaccination found higher rates among recipients of mRNA-1273 compared with BNT162b2 as second dose, particularly among male individuals aged 18 to 24 years. Higher rates are also observed with those having shorter dosing intervals. All the individuals in Ontario, Canada who had received one dose of mRNA vaccine, which includes Moderna and Pfizer-BioNTech( mRNA-1273 and BNT162b2 respectively) between December 14, 2020 and September 4 2021 and had reported episode of myocarditis or pericarditis following receipt of Covid 19 vaccine during this period were included in this study. 
Table-2: Association between gender and total number of cases, cases after 2nd dose of vaccination 
Table-3: Moderna v/s Pfizer in males
The overall rate for both the vaccine products were significantly higher when the dosing interval was less than 30 days.
Table-4: Comparing dosing intervals of Pfizer and Moderna with associated cases of myocarditis and pericarditis
Between December 14, 2020 and September 4, 2021, there were 19,740,741 doses of mRNA vaccines administered in Ontario and of them 417 cases of myocarditis or pericarditis were reported to the provincial system on adverse events following immunization. Of these 297 cases, 207 occurred following the second dose of vaccine and 228 occurred in male individuals. 
In another study by Kristin Goddard et al, the members of age group 18-39 years from 8 integrated healthcare delivery systems were monitored using data updated weekly and supplemented with medical record review of myocarditis and pericarditis cases. By late May 2021, a higher than expected number of myocarditis reports following mRNA vaccination were submitted to US VACCINE ADVERSE EVENT REPORTING SYSTEM( VAERS), particularly among young males after dose 2, suggesting an increased risk for this rare adverse event.
As part of ongoing COVID-19 vaccine safety monitoring, the vaccine safety datalink(VSD) reported in interim analyses that the incidence of myocarditis and pericarditis was increased approximately 10 fold among 12-39 year olds during the 0 to 7 days after mMRNA vaccination, when compared with the 22-42 days post vaccination. However, whether the risk of myocarditis and pericarditis differs by mRNA vaccine product is not clear.
The study included persons 18-39 years who were members of integrated healthcare organization within VSD and vaccinated with either of mRNA covid 19 vaccines. Potential cases of myocarditis and pericarditis were evaluated in the emergency department and inpatient settings in the days 1-98 after dose 1 or dose 2 of mRNA covid19 vaccine using ICD 10 codes. All identified potential cases underwent medical record review which verified the diagnosis, assessed timing of symptom onset and other relevant clinical details. Clinician adjudication verified that cases met the CDC case definition of confirmed or probable myocarditis, pericarditis or myopericarditis and didn’t have clear alternative ethology.
Table-5: Total number of vaccine beneficiary against those who were affected with myocarditis and pericarditis among them
Table-6: Comparison between both the doses of mRNA vaccine and number of days after which the cases of myocarditis and pericarditis were detected.
Among 18-39 year olds in the large, diverse VSD population, both BNT162b2 and mRNA-1273 COVID 19 vaccines were associated with a significantly increased risk of myocarditis and pericarditis during days 0-7 after vaccination. Notably, each product was associated with an estimated excess of over 20 cases per million second doses. However, during the 0-7 days post vaccination, the estimated excess cases after mRNA-1273 were higher than after BNT162b2, which indirectly suggests that mRNA-1273 was associated with a greater risk of myocarditis and pericarditis than BNT162b2.
In concluding about this study, it was found that in the age group 18- 39 year olds, both mRNA covid 19 vaccines were associated with a substantial increased risk of myocarditis and pericarditis, with higher risk in 0-7 days after dose 2. Most myocarditis and pericarditis cases after vaccination with either product were mild and symptomatically resolved after a short hospital stay. 
Moving on to the next study, titled Myocarditis and Pericarditis After Vaccination for Covid 19 by George A Diaz, et al. In this study subjects from 40 hospitals in Washington, Oregon, Montana and Los Angeles, California, that were part of the Providence health care system and used the same electronic medical record(EMR) were included. All patients with documented COVID 19 vaccinations administered inside the system or recorded in state registries at any time through May 25, 2021, were identified. Vaccinated patient who subsequently had emergency department or inpatient encounters with diagnoses of myocarditis and pericarditis were ascertained from EMRs
.Among 2,000,287 individuals receiving at least 1 covid 19 vaccination,
● 58.9% were women( median age was 57 years),
● 76.5% received more than 1 dose,
● 52.6% received the BNT162b2 vaccine and
● 44.1% received the mRNA-1273 vaccine and 3.1% received the Ad26.COV2.S vaccine.
20 individuals had vaccine related myocarditis ( 1 per 100000) and 37 had pericarditis ( 1.8 per 100000). Myocarditis occurred at a median of 3.5 days after vaccination. 11 cases after mRNA-1273, 9 cases after BNT162b2 vaccination were reported. Out of which 15 individuals were males with a median age of 36 years. 4 patients developed symptoms after the first dose and 16 developed after the second dose. 19 patients were admitted to hospital and all were discharged after 2 days. 
In conclusion, our study observed two distinct self-limited syndromes, myocarditis and pericarditis, following COVID-19 mRNA vaccination. Myocarditis tended to develop rapidly in younger patients, mostly after the second dose, while pericarditis affected older patients later, after either the first or second dose. There is an association between mRNA vaccines and myocarditis, as reported by the Centers for Disease Control and Prevention, primarily in young males within a few days after the second vaccination. Our study suggests a similar pattern, possibly indicating underreporting of vaccine adverse events.
Bozkurt B, Kamat I, Hotez PJ. Myocarditis with COVID-19 mRNA vaccines. Circulation. 2021 Aug 10;144(6):471-84.
Montgomery J, Ryan M, Engler R, Hoffman D, McClenathan B, Collins L, Loran D, Hrncir D, Herring K, Platzer M, Adams N. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. JAMA cardiology. 2021 Oct 1;6(10):1202-6.
Buchan SA, Seo CY, Johnson C, Alley S, Kwong JC, Nasreen S, Calzavara A, Lu D, Harris TM, Yu K, Wilson SE. Epidemiology of myocarditis and pericarditis following mRNA vaccination by vaccine product, schedule, and interdose interval among adolescents and adults in Ontario, Canada. JAMA network open. 2022 Jun 1;5(6):e2218505-.
Goddard K, Lewis N, Fireman B, Weintraub E, Shimabukuro T, Zerbo O, Boyce TG, Oster ME, Hanson KE, Donahue JG, Ross P. Risk of myocarditis and pericarditis following BNT162b2 and mRNA-1273 COVID-19 vaccination. vaccine. 2022 Aug 19;40(35):5153-9.
Diaz GA, Parsons GT, Gering SK, Meier AR, Hutchinson IV, Robicsek A. Myocarditis and pericarditis after vaccination for COVID-19. Jama. 2021 Sep 28;326(12):1210-2.
Writer Dr Dhruv Barai
Editor Dr Heer Patel
Promoter: Dr Kanika Handu