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 series study

  1. Marco Massari
  2. Stefania Spila Alegiani
  3. Cristina Morciano
  4. Matteo Spuri
  5. Pasquale Marchione
  6. Patrizia Felicetti
  7. Valeria Belleudi
  8. Francesca Romana Poggi
  9. Marco Lazzeretti
  10. Michele Ercolanoni
  11. Elena Clagnan
  12. Emanuela Bovo
  13. Gianluca Trifirò
  14. Ugo Moretti
  15. Giuseppe Monaco
  16. Olivia Leoni
  17. Roberto Da Cas
  18. Fiorella Petronzelli
  19. Loriana Tartaglia
  20. Nadia Mores
  21. Giovanna Zanoni
  22. Paola Rossi
  23. Sarah Samez
  24. Cristina Zappetti
  25. Anna Rosa Marra
  26. Francesca Menniti Ippolito
  27. on behalf of the TheShinISS-Vax|COVID Surveillance Group

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Abstract

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.

Methods and findings

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.

Conclusions

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.

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  1. Version published to 10.1371/journal.pmed.1004056
  2. ScreenIT

    SciScore for 10.1101/2022.02.07.22270020: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The analyses were performed using R version 4.1.2 (R Core Team 2021) with SCCS package31 and STATA version 16.1.
    STATA
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Strengths and limitations: Our study strengths include the large sample size, the broad geographical distribution of the cohort and the availability of data on SARS-CoV-2 diagnosis and outcomes, comorbidities and patients’ demographic characteristics from health care databases. The large sample size (about 3 million vaccinated people aged 12-39 years) allowed to look at fine risk intervals following vaccinations and carrying several subgroup analyses. Since data were collected from routinely collected data in the claims databases, irrespective of research question, there is no potential for recall or selection bias. Another methodological strength of our study is the choice of the SCCS method modified to handle event-dependent exposures. This method properly controls for the estimate inflation occurring when vaccination is markedly delayed or cancelled (i.e. myocarditis/pericarditis is a contraindication of vaccination). Conversely, the standard SCCS method adapted by including a pre-vaccination risk period is a strategy working for short term delays.21,23,24 However, our study also has limitations. First, there is the possibility of notoriety bias due to overdiagnosis of cases of myocarditis/pericarditis because of the increased public and medical awareness of these potential adverse events following mRNA vaccination. Such bias is probably minimal and the effect observed in the sensitivity analysis could be partly explained by a different age profile and characteristics of t...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2022.02.07.22270020 on medRxiv