Post-marketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12-39 years in Italy: a multi-database, self-controlled case series study

Objectives To investigate the association between SARS-CoV-2 mRNA vaccines, BNT162b2 and mRNA-1273, and myocarditis/pericarditis. Design Self-Controlled Case Series study (SCCS) using national data on COVID-19 vaccination and emergency care/hospital admissions. Setting Italian Regions (Lombardia, Friuli Venezia Giulia, Veneto, Lazio). Participants 2,861,809 individuals, aged 12-39 years, vaccinated with the first doses of mRNA vaccines (2,405,759 BNT162b2 and 456,050 mRNA-1273) between 27 December 2020 and 30 September 2021. Main outcome measures First diagnosis of myocarditis/pericarditis within the study period. The incidence of events in the exposure risk periods (0-21 days from the vaccination day, subdivided in three equal intervals) for first and second dose was compared with baseline period. The SCCS model was fitted using conditional Poisson regression to estimate Relative Incidences (RI) and Excess of Cases (EC) per 100,000 vaccinated by dose, age, gender and brand. Results During the study period, 441 participants aged 12-39 years developed myocarditis/pericarditis (346 BNT162b2 and 95 mRNA-1273). During the 21-day risk interval there were 114 cases of myocarditis/pericarditis (74 BNT162b2 and 40 mRNA-1273) corresponding to a RI of 1.27 (0.87-1.85) and 2.16 (1.50-3.10) after first and second dose, respectively. An increased risk of myocarditis/pericarditis at (0-7) days was observed after first [RI=6.55; 95% Confidence Interval (2.73-15.72); EC per 100,000 vaccinated=2.0 (1.5-2.3)] and second dose [RI=7.59 (3.26-17.65); EC=5.5 (4.4-5.9)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.39 (2.02-5.68); EC=0.8 (0.6-1.0)]. In males, an increased risk at (0-7) days was observed after first [RI=12.28, 4.09-36.83; EC=3.8 (3.1-4.0)] and second dose [RI=11.91 (3.88-36.53); EC=8.8 (7.2-9.4)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.45 (1.78-6.68); EC=1.0 (0.6-1.2)]. In females, an increased risk at (0-7) days was observed after second dose of BNT162b2 [RI=3.38 (1.47-7.74); EC=0.7 (0.3-0.9)]. At (0-7) days an increased risk following second dose of BNT162b2 was observed in the 12-17 years old [RI=5.74, (1.52-21.72); EC=1.7 (0.7-1.9)] and in 18-29 years old [RI=4.02 (1.81-8.91); EC=1.1 (0.6-1.3)]. At (0-7) days an increased risk after first [RI=7.58 (2.62-21.94); EC=3.5 (2.4-3.8)] and second [RI=9.58 (3.32-27.58); EC=8.3 (6.7-9.2)] dose of mRNA-1273 was found in 18-29 years old and after first dose in 30-39 years old [RI=6.57 (1.32-32.63); EC=1.0 (0.3-1.1)]. Conclusions This population-based study indicates that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years, whereas no association was observed in older subjects. The risk increased after the second dose and in the youngest for both vaccines, remained moderate following vaccination with BNT162b2, while was higher in males following vaccination with mRNA-1273. The public health implication of these findings should be weighed in the light of the overall efficacy and safety profile of both vaccines.