Epidemiology of Myocarditis and Pericarditis Following mRNA Vaccination by Vaccine Product, Schedule, and Interdose Interval Among Adolescents and Adults in Ontario, Canada

This cohort study estimates rates of myocarditis and pericarditis after receipt of an mRNA COVID-19 vaccine among individuals in Ontario, Canada, stratified by recipients’ age and sex and by the vaccine product, schedule, and interdose interval.


Introduction
2][3][4][5] In Ontario, Canada (with a population of approximately 14.7 million), enhanced surveillance for myocarditis or pericarditis following receipt of mRNA vaccines began in early June 2021.This surveillance comprised health care professional communication from the provincial government and public health agency, hospital-led algorithms for clinical investigations and management, and instructions on reporting events to the passive vaccine-safety surveillance system.This enhanced surveillance directive coincided with a number of changes to Ontario's COVID-19 vaccination program, including expansion of vaccine eligibility to young adults and adolescents (Health Canada authorized BNT162b2 for individuals aged 12-15 years on May 5, 2021), a large acceleration in second-dose administration due to increased vaccine supply, permissive language from Canada's National Advisory Committee on Immunization with regard to heterologous mRNA vaccine schedules (first and second doses with different vaccines), 6 and, during summer 2021, a gradual return to scheduling second doses in accordance with product monograph intervals following a period of extended intervals between the first and second doses (ie, interdose intervals) that had been used to maximize the number of individuals protected with a first dose of vaccine. 6These programmatic changes provided an opportunity to examine the risk of myocarditis or pericarditis in association with a number of factors.Preliminary analyses reported in August 2021 were limited in scope. 7r objective was to examine rates of reported myocarditis or pericarditis following mRNA vaccination by age, sex, vaccine product, dose number, interdose interval, and homologous (first and second doses with the same vaccine) or heterologous vaccine schedule using passive vaccine-safety surveillance data.

Methods
In this cohort study conducted from December 2020 to September 2021, we used the Public Health Case and Contact Management Solution, the electronic reporting system in Ontario, Canada for COVID-19 adverse events following immunization, to identify myocarditis and pericarditis after COVID-19 vaccination reported between December 14, 2020 (start of the vaccination program), and September 4, 2021.In Ontario, the reporting of adverse events following immunization by health care professionals is mandated by legislation; voluntary reporting by vaccine recipients or caregivers also occurs. 8Reports are submitted to local public health units, which conduct additional Events were identified through a keyword search (ie, "myocarditis" or "pericarditis") or if cardiovascular injury, myocarditis, or pericarditis was selected from a list of predefined adverse events.A case-level review of all reports was completed by specialized nurses and physicians on Public Health Ontario's vaccine safety team to assign a level of diagnostic certainty using Brighton Collaboration (BC) case definitions for myocarditis and pericarditis. 10The BC case definitions for myocarditis and pericarditis have been adopted by the Public Health Agency of Canada for passive vaccine-safety surveillance activities. 11,12We restricted our analyses to events meeting BC levels 1 to 3 of diagnostic certainty.In sensitivity analyses that examined only myocarditis, reports of adverse events following immunization with physician diagnoses of myocarditis, myopericarditis, or perimyocarditis were included only if the BC case definition (levels 1-2) for myocarditis was met.We included all reports following vaccination, regardless of time since vaccination, in crude rates.We obtained information on receipt of vaccines from the provincial COVID-19 vaccine registry, COVaxON.

Statistical Analysis
We calculated rates and 95% CIs of reported cases of myocarditis or pericarditis per 1 000 000 mRNA vaccine doses administered by age, sex, dose number, and vaccine product for strata with at least 1 event.The 95% CIs were calculated using the Poisson exact method.Our primary analysis was restricted to individuals who initiated their vaccine series on or after June 1, 2021, to account for potential increases in reporting of adverse events following immunization after heightened awareness resulting from media reports and the provincial enhanced surveillance directive for myocarditis or pericarditis that began in early June 2021.This timing coincided with other changes to the vaccination program, including implementation of heterologous mRNA schedules (eFigure 1 in the Supplement).We repeated these analyses for sensitivity analyses that included myocarditis only and both myocarditis and pericarditis for the period from December 14, 2020, to September 4, 2021.
We also calculated these rates stratified by homologous or heterologous vaccine schedule and by interdose interval, restricted to individuals who received their second dose (regardless of the first dose date) on or after June 1, 2021, to maximize our sample of second-dose recipients during the period of enhanced surveillance.We selected the interval groupings by examining the distribution of intervals among individuals receiving a second dose and to align with the product monographs and programmatic decisions (ie, extended interdose intervals).We assessed statistical significance using nonoverlapping 95% CIs.We repeated this analysis for male individuals aged 18 to 24 years given the large number of reported events in this age group.
To compare the rates following the second dose by vaccine product, we also used Poisson regression to calculate age-and sex-stratified rate ratios and 95% CIs, adjusting for first-dose product and interdose interval.Data were analyzed using SAS Enterprise Guide, version 8.2 (SAS Institute).
All tests were 2-sided and used a significance level of P < .05.

Results
Between December 14, 2020, and September In our primary analysis focusing on those who initiated their vaccination series on or after June 1, 2021, the rate of myocarditis or pericarditis tended to be higher after the second dose of the mRNA vaccine than after the first dose, particularly for individuals who received mRNA-1273 as the second dose of the series (Table 2).The highest rate of myocarditis or pericarditis was observed among male individuals aged 18 to 24 years following mRNA-1273 as the second dose (299.their second dose of BNT162b2 (97.3 cases per 1 000 000 doses [95% CI, 60.3-148.8cases per 1 000 000 doses]).In the sensitivity analysis restricted to myocarditis only, the observed patterns remained unchanged (eTable 2 in the Supplement).The results were also similar for myocarditis or pericarditis for the period from December 14, 2020, to September 4, 2021 (eTable 3 in the Supplement; rates following the second dose by age in years and by vaccine product are shown in eFigure 3 in the Supplement).
To explore differences in the rate of myocarditis or pericarditis following the second dose of mRNA-1273 vs BNT162b2, we also examined rates by mixed schedule and interdose interval (Figure ; additional data are shown in eTable 4 in the Supplement).Among all ages and sexes combined, rates of myocarditis or pericarditis were significantly higher for individuals with shorter interdose intervals for either vaccine received as the second dose (for intervals Յ30 days: BNT162b2, 52.This trend was also observed among male individuals aged 18 to 24 years across vaccine product combinations (eTable 5 in the Supplement).Overall, 95% CIs overlapped when comparing homologous with heterologous schedules within second-dose products.

Discussion
Using passive vaccine-safety surveillance data, we identified 297 cases of myocarditis or pericarditis that met the BC case definition following receipt of an mRNA vaccine since the start of the COVID-19 vaccination program in Ontario, Canada.Consistent with other surveillance systems and studies, 13,14 we found that rates of myocarditis or pericarditis were highest among young male individuals following a second dose and that events were tightly clustered within the first week after vaccination.Rates were higher following a second dose of either mRNA-1273 or BNT162b2 compared with a first dose, and the rates following a second dose of mRNA-1273 were higher than those  following a second dose of BNT162b2, in particular for young male individuals.In addition to productspecific insights for age or sex groups at highest risk of myocarditis or pericarditis after COVID-19 vaccination, our analyses suggest that interdose intervals and vaccine schedule combinations may also be associated with the risk of myocarditis or pericarditis.These observations suggest that there may be programmatic strategies in terms of vaccine product, interval, and schedule that may reduce the risk of myocarditis or pericarditis following receipt of mRNA vaccines.
The crude rates of reported cases of myocarditis and pericarditis after receipt of an mRNA COVID-19 vaccine in Ontario are consistent with estimates from other passive vaccine-safety surveillance systems and other data sources, [2][3][4][5]15 although there is variability in age-specific rates across systems and countries. In srael, where only BNT162b2 was used with a 21-day interdose interval, the rate of myocarditis (using the BC definition) following dose 2 among male individuals aged 16 to 19 years was 150 cases per 1 000 000 doses between December 2020 and May 2021, although this period included both active and passive surveillance periods. 2 In the present study, the rate of myocarditis or pericarditis in Ontario among male individuals aged 12 to 17 years who received 2 doses of BNT162b2 at an interval of 30 days or less was similar at 159.7 cases per 1 000 000 doses.
In the UK, the rate of reported cases of myocarditis after both the first and second doses across all ages was estimated at 10 cases per 1 000 000 doses of BNT162b2 and 36 cases per 1 000 000 doses of mRNA-1273 based on events submitted as of November 17, 2021, 4 and for individuals aged 19 to 29 years, rates of myocarditis following dose 2 were 22 and 69 cases per 1 000 000 doses for BNT162b2 and mRNA-1273, respectively.This trend of an increased case rate after receiving mRNA-1273 is consistent with our findings, although the overall case rate in the UK study was lower than in our study.The UK used an extended interdose interval, 16 and the overall results may be more comparable with those of our subgroup analyses examining rates among individuals with 8 or more weeks between doses.Rates across data sources in the US vary.With the use of data from 4 US Food and Drug Administration Biologics Effectiveness and Safety claims databases among male individuals aged 18 to 25 years, the rate of myocarditis or pericarditis within 7 days following a second dose of mRNA-1273 ranged from 72.4 cases per 1 000 000 doses (95% CI, 23.2-228.1 cases per 1 000 000 doses) to 283.7 cases per 1 000 000 doses (95% CI, 145.2-573.5 cases per 1 000 000 doses) across these 4 databases. 17In Ontario, we estimated a similar rate of myocarditis or pericarditis at 299.5 cases per 1 000 000 doses following a second dose of mRNA-1273 among male individuals aged 18 to 24 years.With the use of data from the Vaccine Adverse Event Reporting System, a passive reporting system, the rate of reported cases of myocarditis per 1 000 000 vaccine doses among male individuals with symptom onset within 7 days of a second dose of mRNA-1273 was much lower than estimated in the Biologics Effectiveness and Safety databases, at 38.5 cases per 1 000 000 doses. 18The case rate per 1 000 000 doses following a second dose of BNT162b2 in the Vaccine Adverse Event Reporting System data was 36.8 for male individuals aged 18 to 24 years, 69.1 for male individuals aged 16 to 17 years, and 39.9 for male individuals aged 12 to 15 years. 18Data from the US also include those from the active surveillance system Vaccine Safety Datalink, which has rates higher than in the Vaccine Adverse Event Reporting System. 19In a head-to-head analysis of BNT162b2 and mRNA-1273 among individuals aged 18 to 39 years, the Vaccine Safety Datalink reported that the adjusted rate of myocarditis or pericarditis within 7 days of dose 2 was 2.72 times greater (95% CI, 1.25-6.05times greater) for those who received mRNA-1273 compared with BNT162b2, with an excess of 13.3 cases per 1 000 000 second doses of mRNA-1273 vs BNT162b2. 20There are several possible explanations for the differences in rates across systems, including outcomes studied (ie, myocarditis only vs myocarditis or pericarditis), time from vaccination to symptom onset for cases included in the analyses, different case definitions used to classify outcomes, completeness in reporting, and health system context (ie, access to publicly funded health services).In addition, our analyses suggest that country-specific differences in the interdose interval and heterologous vaccine schedules may also be associated with variability in rates across jurisdictions.
Following extensive review and discussion of the product-specific differences identified from passive vaccine-safety surveillance, Ontario modified its COVID-

a
Abbreviations: BNT162b2, Pfizer-BioNTech Comirnaty; mRNA-1273, Moderna Spikevax.a Data are presented as the number (percentage) of patients unless otherwise indicated.b Two reports with unknown time to onset were excluded from this calculation.c Includes myocarditis or pericarditis (2 patients), myopericarditis (81 patients), and perimyocarditis (24 patients).

Figure .
Figure.Overall Rate of Reported Myocarditis or Pericarditis Among People Who Completed the 2-Dose Vaccine Series With the Second Dose on or After June 1, 2021 Myocarditis and Pericarditis Following mRNA Vaccination in Ontario, Canada Public Health Ontario Ethics Review Board determined that this study did not require research ethics committee approval or informed consent because the study activities were conducted in fulfillment of Public Health Ontario's legislated mandate "to provide scientific and technical advice and support to the health care system and the Government of Ontario in order to protect and promote the health of Ontarians" (Ontario Agency for Health Protection and Promotion Act, S.O. JAMA Network Open.2022;5(6):e2218505.doi:10.1001/jamanetworkopen.2022.18505(Reprinted) June 24, 2022 2/12 Downloaded from jamanetwork.comby guest on 12/31/2023 investigations and obtain supporting information (eg, laboratory findings and diagnostic imaging).

Table 2 .
Crude Rate of Reported Myocarditis or Pericarditis per Million Vaccine Doses Administered by Vaccine Product, Dose Number, Age, and Sex With Series Initiation on or After June 1, 2021 Abbreviations: BNT162b2, Pfizer-BioNTech Comirnaty; mRNA-1273, Moderna Spikevax; NA, not applicable; NR, not reported.aEstimates were not provided for strata with 0 reported events.bEstimates for mRNA-1273 were not provided for individuals aged 12 to 17 years because this product was not used for this age group in Ontario.

Table 3 .
Adjusted Rate Ratios for Myocarditis or Pericarditis, Comparing mRNA-1273 With BNT162b2 as the Second COVID-19 Vaccine Dose by Age and Sex Among Individuals Receiving Their Second Dose on or After June 1, 2021 a Adjusted for first dose product and interdose interval.
19 vaccine program on September JAMA Network Open | Public Health Myocarditis and Pericarditis Following mRNA Vaccination in Ontario, Canada eTable 1. Clinical Diagnosis and Severity of Myocarditis and Pericarditis eTable 2. Crude Rate of Reported Myocarditis Meeting BC Level 1 and 2 Only per Million Doses Administered and 95% CI by Vaccine Product, Dose Number, Age, and Sex: Series Initiated on or After June 1, 2021 eTable 3. Crude Rate of Reported Myocarditis and Pericarditis per Million Doses Administered and 95% CI by Vaccine Product, Dose Number, Age, and Sex: Series Initiated on or After December 14, 2020 eFigure 3. Rate of Reported Myocarditis and Pericarditis per Million Doses Administered and 95% CI Following Dose 2 of mRNA Vaccine for All Sexes in Ontario as of September 4, 2021 eTable 4. Rate of Reported Myocarditis and Pericarditis per Million Doses Administered and 95% CI by Dose 2 Product and Interdose Interval, for Individuals Receiving Dose 2 on or After June 1, 2021 eTable 5. Rates of Reported Myocarditis and Pericarditis per Million Doses Administered and 95% CI Among Males Aged 18-24 Years by Vaccine Product and Interdose Interval With Dose 2 on or After June 1, 2021