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Postmarketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12 to 39 years in Italy: A multi-database, self-controlled case seri [1]

['Marco Massari', 'National Centre For Drug Research', 'Evaluation', 'Istituto Superiore Di Sanità', 'National Institute Of Health', 'Rome', 'Stefania Spila Alegiani', 'Cristina Morciano', 'Matteo Spuri', 'Department Of Infectious Diseases']

Date: 2022-08 

This population-based study of about 3 millions of residents in Italy suggested that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years. According to our results, increased risk of myocarditis/pericarditis was associated with the second dose of BNT162b2 and both doses of mRNA-1273. The highest risks were observed in males of 12 to 39 years and in males and females 18 to 29 years vaccinated with mRNA-1273. The public health implication of these findings should be considered in the light of the proven mRNA vaccine effectiveness in preventing serious COVID-19 disease and death.

We conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of myocarditis/pericarditis between 27 December 2020 and 30 September 2021. Exposure risk period (0 to 21 days from the vaccination day, subdivided in 3 equal intervals) for first and second dose was compared with baseline period. The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose, age, sex, and vaccine product. Calendar period was included as time-varying confounder in the model. During the study period 2,861,809 persons aged 12 to 39 years received mRNA vaccines (2,405,759 BNT162b2; 456,050 mRNA-1273); 441 participants developed myocarditis/pericarditis (346 BNT162b2; 95 mRNA-1273). Within the 21-day risk interval, 114 myocarditis/pericarditis events occurred, the RI was 1.99 (1.30 to 3.05) after second dose of BNT162b2 and 2.22 (1.00 to 4.91) and 2.63 (1.21 to 5.71) after first and second dose of mRNA-1273. During the [0 to 7) days risk period, an increased risk of myocarditis/pericarditis was observed after first dose of mRNA-1273, with RI of 6.55 (2.73 to 15.72), and after second dose of BNT162b2 and mRNA-1273, with RIs of 3.39 (2.02 to 5.68) and 7.59 (3.26 to 17.65). The number of EC for second dose of mRNA-1273 was 5.5 per 100,000 vaccinated (3.0 to 7.9). The highest risk was observed in males, at [0 to 7) days after first and second dose of mRNA-1273 with RI of 12.28 (4.09 to 36.83) and RI of 11.91 (3.88 to 36.53); the number of EC after the second dose of mRNA-1273 was 8.8 (4.9 to 12.9). Among those aged 12 to 17 years, the RI was of 5.74 (1.52 to 21.72) after second dose of BNT162b2; for this age group, the number of events was insufficient for estimating RIs after mRNA-1273. Among those aged 18 to 29 years, the RIs were 7.58 (2.62 to 21.94) after first dose of mRNA-1273 and 4.02 (1.81 to 8.91) and 9.58 (3.32 to 27.58) after second dose of BNT162b2 and mRNA-1273; the numbers of EC were 3.4 (1.1 to 6.0) and 8.6 (4.4 to 12.6) after first and second dose of mRNA-1273. The main study limitations were that the outcome was not validated through review of clinical records, and there was an absence of information on the length of hospitalization and, thus, the severity of the outcome.

Myocarditis and pericarditis following the Coronavirus Disease 2019 (COVID-19) mRNA vaccines administration have been reported, but their frequency is still uncertain in the younger population. This study investigated the association between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccines, BNT162b2, and mRNA-1273 and myocarditis/pericarditis in the population of vaccinated persons aged 12 to 39 years in Italy.

The results provide information that could be helpful for the continuous assessment of the postmarketing benefit/risk profile of the COVID-19 mRNA vaccines and should be considered within the context of the proven mRNA vaccine effectiveness in reducing COVID-19 morbidity and mortality.

The highest risk was seen in males, 0 to 7 days after the first and second dose of mRNA-1273 (RIs of 12.28 (4.09 to 36.83) and 11.91 (3.88 to 36.53), respectively). After the second dose of mRNA-1273 in males, the excess of cases (EC) was 8.8 (4.9 to 12.9) per 100,000 vaccinated individuals.

Within the 21-day risk interval, the relative incidence (RI) was 1.99 (95% confidence interval [CI] 1.30 to 3.05) after the second dose of BNT162b2 and 2.22 (1.00 to 4.91) and 2.63 (1.21 to 5.71) after the first and second doses of mRNA-1273, respectively. Within the 0 to 7-day risk interval, the RI was 6.55 (2.73 to 15.72) after first dose of mRNA-1273 and 3.39 (2.02 to 5.68) and 7.59 (3.26 to 17.65) after the second doses of BNT162b2 and mRNA-1273, respectively.

Competing interests: I have read the journal’s policy and the author of this manuscript have the following competing interests: in the last 36 months, GT coordinated a pharmacoepi team at the University of Messina till Oct 2020 and currently at the academic spin-off INSPIRE that received research grants from PTC Therapeutics, Kiowa Kirin, Chiesi, Daiichi Sankyo for the conduct of observational studies on topics not related to the paper; GT participated to Advisory Board/interview sponsored by Eli Lilly, Amgen, Sanofi, SOBI, Gilead, ABBvie, Verpora and Daiichi Sankyo on topics not related to the paper.

Funding: The Istituto Superiore di Sanità received funding from AIFA (Italian Medicines Agency) www.aifa.gov.it for this study in the framework of the collaboration agreement “Efficacia real world e sicurezza dei vaccini anti Covid-19: studio di coorte e Self-Controlled Case Series” (Effectiveness and safety of COVID-19 vaccines: cohort and Self-Controlled Case Series studies). AIFA is the Italian national regulatory body for drugs and vaccines and a public organization. All authors, including authors affiliated with AIFA are independent from the funder. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability: Data cannot be shared publicly under article 9 of Regulation (EU) 2016/679. Data are available from the Data Protection Officer of Istituto Superiore di Sanità- Dott. Carlo Villanacci, e-mail: responsabile.protezionedati@iss.it , for researchers who meet the criteria for access to confidential data.

Copyright: © 2022 Massari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

To our knowledge, studies examining the association between mRNA-based COVID-19 vaccines in the population resident in Italy have not been published yet. Previous published studies have been conducted in other countries [ 13 – 18 ] and few of them have estimated risks in younger than 40 years by sex and age [ 13 , 14 , 17 ], while none of them have used a SCCS study design, with the exception of the study of Patone and colleagues [ 17 ]. The present study, while attempting to address these gaps, has the objective to investigate the association between mRNA-based COVID-19 vaccines (BNT162b2 and mRNA-1273) and myocarditis/pericarditis in the population of vaccinated persons aged 12 to 39 years, by age and sex, in Italy, during the period 27 December 2020 and 30 September 2021.

Along with the enhanced passive surveillance of the Italian PharmacoVigilance network, an active surveillance, based on regional healthcare claims databases, was set up by the Italian National Institute of Health (ISS) and the Italian Medicines Agency (AIFA) to provide real-world data on SARS-CoV-2 vaccine safety.

In Italy, SARS-CoV-2 vaccines have been administered since late December 2020 and have been offered to the population according to a priority scheme, considering profession, age, and health conditions. Vaccination in adolescent (≥12 years) started on 31 May and 28 July 2021 for BNT162b2 and mRNA-1273, respectively.

In line with these findings, recent published data from large population-based studies from Israel, United States, United Kingdom, and Denmark documented that the risks of myocarditis/pericarditis following mRNA vaccines differ by age groups, sex, and vaccine product with a higher risk in those younger than 40 years ( S1 Table ) [ 13 – 18 ].

In October 2021, further data were available from the Nordic population-based register study on myocarditis and pericarditis in northern Europe that prompted some public health organizations in the Nordic countries (e.g., Sweden, Finland, Norway, Iceland) [ 10 ] either to pause the use of the mRNA-1273 or to recommend the use of the BNT162b2 rather than mRNA-1273 in younger people and/or younger males. In December 2021, the PRAC reassessed the relevant safety signal, based on the Nordic study and on a study conducted using data from the French national health system (Epi-phare) [ 11 ], concluding that the risk for both events is overall “very rare” (up to 1 in 10,000 vaccinated people) and greater in younger males. A further update of product information was recommended, while the benefit/risk was confirmed as positive for the whole indications [ 12 ].

On July 2021, the COVID-19 subcommittee of WHO Global Advisory Committee on Vaccine Safety reported that very rare cases of myocarditis and pericarditis had occurred more often in adolescents or young adults and after the second dose, especially within a few days after COVID-19 mRNA vaccines, and encouraged countries to strengthen the monitoring of myocarditis/pericarditis [ 8 ]. At the same time, EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) began an assessment on signals of myocarditis and pericarditis with BNT162b2 and mRNA-1273 vaccine and concluded that both cardiac conditions can occur in very rare cases following vaccination with the COVID-19 mRNA vaccines. Thus, the Committee recommended to update the product information and the RMP for these vaccines, together with a direct healthcare professional communication to raise awareness among healthcare professionals [ 9 ].

Intensive postmarketing surveillance of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines is ongoing worldwide to provide updated information on their effectiveness and safety, thereby supporting regulatory benefit/risk assessment. Since early phase of the global vaccination campaign, case series [ 1 – 3 ] and pharmacovigilance reports [ 4 , 5 ] on myocarditis and pericarditis following the Coronavirus Disease 2019 (COVID-19) mRNA vaccine administration were published. Both events were included as related to COVID-19 disease in the early and updated Priority List of COVID-19 Adverse events of special interest, developed by Brighton Collaboration Group and Safety Platform for Emergency vACcines (SPEAC), in order to harmonize safety assessment of COVID-19 vaccines in pre- and postmarketing setting [ 6 ]. Moreover, as per core requirements for risk management plan (RMP), they have been periodically monitored through routine pharmacovigilance activities in the Monthly Summary Safety Reports of all COVID-19 vaccines [ 7 ].

This study was approved by the National Unique Ethics Committee for the evaluation of clinical trials of medicines for human use and medical devices for patients with COVID-19 of the National Institute for Infectious Diseases “Lazzaro Spallanzani” in Rome (ordinance n. 335, 17/05/2021 and n. 399, 02/09/2021).

The SCCS model was fitted using unbiased estimating equations to estimate the RIs and their 95% confidence intervals (95% CI). In the following, we will use the term “association” between vaccine exposure and the study event (overall and in a given subgroup) for an RI estimate whose CI does not include the null effect. To handle event-dependent exposures, the SCCS model was properly modified considering a counterfactual exposure history for any exposures arising after occurrence of an event [ 20 , 24 ]. Five 45-day calendar periods were considered as time-varying covariate controlling for the seasonal effect (adjusted model). We also estimated the excess of cases (EC) per 100,000 vaccinated with 95% CIs applying nonparametric bootstrapping (10,000 replications) [ 29 ]. We carried out subgroup analyses by age group (12 to 17, 18 to 29, 30 to 39 years), sex, and vaccine product (BNT162b2 and mRNA-1273). To assess the robustness of the primary analysis, the following sensitivity analyses regarding the modified SCCS method were conducted: (a) observation/exposure time period—we restricted the analysis to the study period from 27 December 2020 to 31 May 2021 [ 20 , 30 ] and to the study period from 1 June 2021 to 30 September 2021; we repeated the primary analysis excluding day 0 from the [0 to 7) day risk interval; we extended the exposure period to 28 days as well reducing it to 14 days; (b) heterologous vaccination—we carried out the primary analysis excluding individuals who received 2 different vaccine products at the first and second dose or censoring at time of second dose individuals who received a different vaccine product at the second dose (in the primary analysis, the second dose was assumed to be of the same product as the first one); (c) SARS-CoV-2 infection—we restricted the analyses to participants without a SARS-CoV-2-positive test before the occurrence of the event (any time) and within 10 days after the event. Further sensitivity analyses were performed exploring different assumptions of the standard SCCS method; (d) beginning observation at exposure; (e) beginning observation at time 0; (f) with prerisk period; (g) removing post event exposure. We conducted also an ancillary analysis reproducing the primary SCCS analysis in the vaccinated persons aged over 40 years.

Characteristics of the cohort of vaccinated persons and myocarditis and pericarditis cases were described by age, sex, and comorbidities. Temporal timing of myocarditis or pericarditis events in relation to first/second dose vaccination dates was described by week.

The exposures of interest were the first or second dose of BNT162b2 and mRNA-1273 vaccines. The exposure risk period was not prespecified in the protocol submitted to the Ethical Committee and it was decided before data collection and analysis. It was defined as [0–21) days after first or second dose administration (vaccination date), which included day 0, the day of vaccination. The risk period was further subdivided into prespecified time periods: [0 to 7), [7 to 14), and [14 to 21) after each exposure date. The unexposed baseline period (reference period) was defined as any time of observation out of the risk periods ( S2 Fig ).

Four Italian Regions (northern Italy: Lombardia, Veneto, Friuli Venezia Giulia; central Italy: Lazio), representing 36% of the population aged 12 to 39 years resident in Italy, contributed data of all vaccinated persons in this age group, in a period ranging from 27 December 2020 to the latest date for which data on outcomes were available, which varied across Regions: Lombardia up to 30 September 2021, Veneto up to 20 June 2021, Friuli Venezia Giulia up to 31 August 2021, and Lazio up to 16 June 2021). We included in the study all the persons aged 12 to 39 years who received a first dose of mRNA vaccines and were admitted to emergency care or hospital with the outcomes of interest. We excluded individuals with missing or inconsistent information on relevant variables (age, sex, vaccine product and dose, date of vaccination, of death and of event). Furthermore, we excluded individuals with a history of myocarditis or pericarditis within 365 days leading up to the start of the study period. The observation period for each case ranged from 27 December 2020 to the end of follow-up, which occurred at the time of death or at the end of Region-specific study period, whichever came first.

In the end, regional pseudonymized datasets were provided to the National Institute of Health for centralized analysis, in compliance with EU General Data Protection Regulation. Over the last 2 years, TheShinISS framework has been employed in several large scale observational studies exploring the association between several exposures and COVID-19 onset/prognosis as well as other drug and vaccine-related research topics and is currently maintained by a collaborative research network [ 19 , 26 – 28 ]. The relational scheme of the study databases as well as TheShinISS flow diagram is described in S1 Fig .

We investigated the association between mRNA-based COVID-19 vaccines and subsequent onset of myocarditis/pericarditis in the population aged 12 to 39 years in the period 27 December 2020 to 30 September 2021 (the latest date for which outcome data were available). Regional claims data were locally transformed into a study-specific common data model and locally processed using TheShinISS.

By using the adapted SCCS method for event-dependent exposures, we estimated the relative incidence (RI) of myocarditis/pericarditis following prespecified windows at risk after vaccination, in a within-person comparison of different time periods. The method allows for the control of all time-independent characteristics of participants. The SCCS method allows also for adjustment of potential time-varying confounders such as seasonal variation in risks.

We used a self-controlled case series (SCCS) design [ 20 – 24 ]. The SCCS design has emerged as a key methodology for studying the safety of vaccines and medicines. This approach only requires information from individuals who have experienced the event of interest and automatically controls for multiplicative time-invariant confounders, even when these are unmeasured or unknown. Originally designed to analyze the association between vaccination and specific events under the key assumption that events do not influence post-event exposures, this method has been adapted to event-dependent exposures, for example, when occurrence of an event may preclude any subsequent exposure (SCCS method for censored, perturbed, or curtailed post-event exposures) [ 23 – 25 ]. This is the case in observational studies of vaccines when the event of interest could be a contraindication to vaccination.

The active surveillance is based on a dynamic multiregional observational cohort. A distributed analysis framework is applied using TheShinISS, an R-based open-source statistical tool, developed by the National Institute of Health [ 19 ], that locally processes data collected and updated periodically from regional healthcare databases according to an ad hoc, study-tailored, common data model.

The ancillary analysis on 2,050 cases aged over 40 years (BNT162b2 n. 1,759; mRNA-1273 n. 291) did not show an increase risk of myocarditis/pericarditis for BNT162b2 and mRNA-1273 after 7 days following the first dose (RI = 0.59, 95% CI: 0.42 to 0.82 and RI = 0.56, 95% CI: 0.23 to 1.36) and the second dose (RI = 0.84, 95% CI: 0.61 to 1.16 and RI = 1.11, 95% CI: 0.57 to 2.17) ( S18 Table ).

All sensitivity analyses, using the modified SCCS method for event-dependent exposure, were consistent with the main results of the study ( S16 Table ). The sensitivity analysis that was conducted to highlight the potential effect of notoriety bias (by restricting the observation period before and after 31 May 2021) indicated that RIs estimates and CIs are largely overlapping, even though we cannot rule out a slight inflation of the estimates in the second period. Additional sensitivity analyses, based on the standard SCCS model, showed an inflation of the estimates, with the exception of the first analysis (standard SCCS beginning observation at exposure) usually used as an alternative approach to the modified SCCS method ( S17 Table ).

In the age group 12 to 17 years, we estimated an additional 1.7 (95% CI: 0.04 to 3.2) EC per 100,000 in the [0 to 7) days following a second dose of BNT162b2. In the age group 18 to 29 years, we estimated an additional 3.4 (95% CI: 1.1 to 6.0) EC per 100,000 in the [0 to 7) days following a first dose of mRNA-1273; an additional 1.1 (95% CI: 0.2 to 2.0) and 8.6 (95% CI: 4.4 to 12.6) EC per 100,000 in the [0 to 7) days following a second dose of BNT162b2 and mRNA-1273, respectively. In the age group 30 to 39 years, we estimated an additional 1.0 EC per 100,000 (95% CI: not estimable-3.3) both in the [0 to 7) days and [7 to 14) days following the first dose of mRNA-1273, respectively.

In the analyses by age group, we estimated an increased risk of myocarditis/pericarditis [0 to 7) days following the second dose of BNT162b2 (RI = 5.74, 95% CI: 1.52 to 21.72) in those aged 12 to 17 years. Number of events was insufficient to fit the SCCS model with mRNA-1273 aged 12 to 17 years. Of note, there were 3 events after the second dose in the [0 to 7) day interval compared to 7 events in the reference period. In the 18 to 29 year age group, we observed an increased risk of myocarditis/pericarditis [0 to 7) days following a first and second dose of mRNA-1273 (RI = 7.58, 95% CI: 2.62 to 21.94 and RI = 9.58, 95% CI: 3.32 to 27.58, respectively) and following the second dose of BNT162b2 (RI = 4.02, 95% CI: 1.81 to 8.91). In the age group 30 to 39 years, we found an increased risk of myocarditis/pericarditis [0 to 7) days (RI = 6.57, 95% CI: 1.32 to 32.63) and [7 to 14) days (RI = 5.87, 95% CI: 1.34 to 25.74) following the first doses of mRNA-1273, while no association was observed with BNT162b2.

In males, we estimated an additional 3.8 (95% CI: 1.5 to 6.3) EC per 100,000 in the [0 to 7) days following a first dose of mRNA-1273, and an additional 1.0 (95% CI: 0.3 to 1.8) and 8.8 (95% CI: 4.9 to 12.9) EC per 100,000 in the [0 to 7) days following a second dose of BNT162b2 and mRNA-1273, respectively. In females, we estimated an additional 0.7 (95% CI: 0.1 to 1.4) EC per 100,000 in the [0 to 7) days following a second dose of BNT162b2.

In males, the risk of myocarditis/pericarditis increased in the [0 to 7) days following a first dose of mRNA-1273 (RI = 12.28, 95% CI: 4.09 to 36.83) and following a second dose of BNT162b2 (RI = 3.45, 95% CI: 1.78 to 6.68) and mRNA-1273 (RI = 11.91, 95% CI: 3.88 to 36.53). In females, we found an increased risk of myocarditis/pericarditis [0 to 7) days following a second dose of BNT162b2 (RI = 3.38, 95% CI: 1.47 to 7.74), while no association was observed with mRNA-1273.

*Considering the small number of cases in the vaccinated with mRNA-1273 of age 12–17 years, it was not possible to provide any estimates; excess cases are not given when the 95% CI of RI included the null effect over the [0–7) day risk interval post vaccination. RI, relative incidence; yrs, years.

Fig 2. Excess of cases per 100,000 vaccinated in the [0–7) days risk period following BNT162b2 and mRNA-1273 vaccination in the vaccinated population aged 12–39 years from 27 December 2020 to 30 September 2021, by sex, age group, and dose (first dose blue, second dose orange).

Table 2 reports the results of the primary analysis from the SCCS model, with RIs adjusted by calendar period, for the 441 cases aged 12 to 39 years. The unadjusted estimates of RI are shown in S4 Table . ECs are reported for RIs with 95% CI not including the null effect. During the 21-day risk interval, there were a total of 114 cases of myocarditis/pericarditis (74 with BNT162b2 and 40 with mRNA-1273), corresponding to RIs of 1.08 (95% CI: 0.70 to 1.67) and 1.99 (95% CI: 1.30 to 3.05) after first and second dose of BNT162b2, respectively, and 2.22 (95% CI 1.00 to 4.91) and 2.63 (95% CI 1.21 to 5.71) after first and second dose of mRNA-1273, respectively. The majority of these cases occurred within the [0 to 7) day risk period after the first or second dose administration of mRNA vaccines (n. 70, 61.4%). An increased risk of myocarditis/pericarditis [0 to 7) days following a first dose of mRNA-1273 was observed (RI = 6.55, 95% CI: 2.73 to 15.72), while no association was found with BNT162b2. An increased risk of myocarditis/pericarditis [0 to 7) days was also observed following a second dose of BNT162b2 (RI = 3.39, 95% CI: 2.02 to 5.68) and mRNA-1273 (RI = 7.59, 95% CI: 3.26 to 17.65). Over the [0 to 7) days postvaccination, we estimated an additional 2.0 (95% CI: 0.8 to 3.6) myocarditis/pericarditis cases per 100,000 vaccinated persons following the first dose of mRNA-1273; following a second dose of the BNT162b2 and mRNA-1273, over the [0 to 7) days post vaccination, we estimated an additional 0.8 (95% CI: 0.4 to 1.4) and 5.5 (95% CI: 3.0 to 7.9) myocarditis/pericarditis cases per 100,000 vaccinated, respectively.

Top (panel A-BNT162b and B-mRNA-1273): days from dose 1, for events occurring before dose 2 if present, or at any time if dose 2 not present. Bottom (panel C-BNT162b and D-mRNA-1273): days from dose 2, for events occurring after dose 1. *Each bar corresponds to 1 week starting from day 0.

During the study period, 441 persons had an emergency care and/or hospital admission related to myocarditis/pericarditis. Of these, 302 (68.5%) were males and 139 (31.5%) were females; there were 346 (78.5%) cases in those vaccinated with BNT162b2 and 95 (21.5%) in those vaccinated with mRNA-1273 ( Table 1 ). Fig 1 describes the temporal trend of the occurrence of the events relative to vaccination date. We observed 1 death, for unknown cause, after 38 days following a pericarditis case that occurred 53 days after the second dose of BNT162b2 vaccine (unexposed period). The median follow-up time after the event was 93 days (IQR 56 to 113).

During the study period, 5,109,231 doses of mRNA vaccines were administered to 2,861,809 persons aged 12 to 39 years (median age 26 years, interquartile range, IQR 19 to 33; 49% females); 2,405,759 (84%) persons received BNT162b2 vaccine and 456,050 (16%) received mRNA-1273 vaccine. Among 24,469,038 doses uploaded on TheShinISS, the proportion of missing or inconsistent observations was 0.7% (n. 172,174) ( S3 Fig ). The vaccinated persons had a median follow-up time of 120 days (IQR 52 to 185). Characteristics of mRNA-vaccinated population aged 12 to 39 years and definition of study comorbidities are reported in S2 and S3 Tables, respectively.

Discussion

Principal findings This first Italian large population-based study covering about 3 million of vaccinated persons aged 12 to 39 years found an association between myocarditis/pericarditis within a week following each dose of mRNA vaccines. The risk of myocarditis/pericarditis is particularly higher after 7 days following the first or second dose of mRNA-1273 vaccine in the overall population. Subgroup analysis by sex suggested that the increased risk was present only in males after both the first and second dose with 3.8 and 8.8 EC per 100,000 vaccinated, respectively. Stratifying by age, greater risks were found in those aged 18 to 29 years with EC of 3.4 and 8.6 per 100,000 following the first and the second doses, respectively. In the age group 12 to 17 years, the number of events was insufficient for risk estimate. We also observed an association between BNT162b2 and myocarditis/pericarditis, but only in the 7 days following the second dose, where the risks remain similar between males and females with 1.0 and 0.7 EC per 100,000 vaccinated, respectively. In the age groups 12 to 17 years and 18 to 29 years, where the increased risks were confined, the estimated EC were 1.7 and 1.1 per 100,000 vaccinated, respectively. Vaccine-associated acute myocarditis is generally attributable to allergic/hypersensitivity reactions as observed in other vaccines [32]. However, the pathophysiology of myocarditis and pericarditis associated to mRNA vaccines is not clearly understood and different mechanisms have been postulated. Molecular mimicry between the spike protein and self-antigens [33], trigger of preexisting dysregulated immune pathways, immune response to mRNA [34] or dysregulated cytokine expression [35] have been proposed. Our results on the increased risk in the 7 days after each dose of mRNA-1273 and the second dose of BNT162b2 are consistent with the onset of viral myocarditis symptoms often reported in the first week from the infection [32,36]. Moreover, it has been postulated that a very high antibody response to mRNA vaccines in predisposed young people may elicit an uncontrolled inflammatory response similar to multisystem inflammatory syndrome observed in children (MIS-C) with SARS-CoV-2 infection [37]. To date, no clear evidence is available, and further studies are needed to clarify which is the exact mechanism of mRNA vaccines-related myocarditis and pericarditis. Furthermore, our observation on the increased risk in young males resembles classical epidemiological features of myocarditis due to other causes [38], included COVID-19-related myocarditis [39], but the exact role of age and sex is still unclear. In a recent review, a possible effect of sex hormones in immune response is summarized, with a possible role of testosterone by a combined mechanism of inhibition of anti-inflammatory cells and commitment to a Th1-type immune response in male and of inhibitory effects of estrogen on proinflammatory T cells in female [40].

Comparison with related studies In line with a previous US study [15], we identified an association between mRNA vaccines and myocarditis/pericarditis in individuals younger than 40 years within the 0- to 7-day period following the first and the second dose. Our results are also consistent with observational studies that documented markedly increased risk of myocarditis in England [16] and myocarditis or myopericarditis in Denmark [18] in the population vaccinated with mRNA-1273. Specifically, in the Danish study, it was reported a strong association between mRNA-1273 and myocarditis or myopericarditis within 28 days from vaccination (hazard ratio, HR = 5.24; 2.47 to 11.12) with an estimated 5.7 EC per 1,000,000 vaccinated. The UK study also suggested a strong association within the 1 to 28 days after first and second mRNA-1273 dose (incidence rate ratio, IRR = 3.89; 1.60 to 9.44; and 20.71, 4.02 to 106.68; respectively) corresponding to 8 and 15 EC per 1,000,000 vaccinated [16]. A recent updated SCCS analysis of English data (preprint publication) [17], stratified by age and sex, also reported a higher risk in male aged less than 40 years (first dose IRR = 2.34; 1.03 to 5.34; second dose IRR = 16.52; 9.10 to 30.00) corresponding to EC of 12 and 101 per 1,000,000, respectively; a markedly increased risk was also observed in females after the second dose of mRNA-1273 (IRR = 7.55; 1.67 to 34.12) with 8 EC per 1,000,000 vaccinated [17]. Our findings are in line with a higher risk observed with mRNA-1273 vaccine in a recently published study conducted in Denmark, Finland, Norway, and Sweden [41]. Results on the association between BNT162b2 and myocarditis/pericarditis are less conclusive. We found an association in the 7 days after the second dose both in males and females. Findings from Israel [14] and England [17] confirmed an association in adolescent and adult males younger than 40 years, but not in female participants. Particularly, the English study, including data on the third dose of BNT162b2, highlighted that in males 12 to 39 years, the risk sequentially increased following each dose of vaccine (IRR = 1.66, 3.41, and 7.60, respectively) with an EC of 3, 12, and 13 per 1,000,000 vaccinated, respectively. No association was found in females and in males older than 40 years [17]. Conversely, a population-based study conducted in Denmark [18], with a more stringent case definition, did not support the association between BNT162b2 and myocarditis or myopericarditis in the 28 days after vaccination, both overall and in the 12 to 39 year group, but an association only in females (HR = 3.73; 1.82 to 7.65) was found.

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