Clinical Course, Outcomes, and Risk Factors of Myocarditis and Pericarditis Following Administration of mRNA-1273 Vaccination: A Protocol for a Federated Real-World Evidence Vaccine Safety Study Using Data from Five European Data Sources

Laura C Zwiers^{1

2}, Diederick E Grobbee^{1

2}, Rob Schneijdenberg², Corine Baljé³, Samantha St Laurent⁴, Daina B Esposito⁴, Lei Zhu⁴, Veronica V Urdaneta⁴, Magalie Emilebacker⁴, Daniel Weibel⁵, Felipe Villalobos⁶, Carlo Alberto Bissacco⁶, Arantxa Urchueguía Fornes^{7

8}, Juan José Carreras-Martínez^{7

8}, Anteneh A Desalegn⁹, Angela Lupattelli⁹, Lei Wang¹⁰, Jannik Wheler¹⁰, Vera Ehrenstein¹⁰, Denise Morris^{11

12}, Catherine Fry^{11

12}, Marjolein Jansen², Brianna M Goodale², David S Y Ong^{1

2

13}

Affiliations

¹ Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.
² Julius Clinical, 3703 CD Zeist, The Netherlands.
³ Clin-Q B.V., 9723 DJ Groningen, The Netherlands.
⁴ ModernaTX, Inc., Cambridge, MA 02142, USA.
⁵ Vaccine Monitoring Collaboration for Europe (VAC4EU), 1000 Brussels, Belgium.
⁶ Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), 08029 Barcelona, Spain.
⁷ Vaccine Research Department, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO-Public Health), 46020 Valencia, Spain.
⁸ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Instituto de Salud Carlos III, 28029 Madrid, Spain.
⁹ Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, 0313 Oslo, Norway.
¹⁰ Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, 8200 Aarhus, Denmark.
¹¹ Drug Safety Research Unit, Southampton SO31 1AA, UK.
¹² School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2UP, UK.
¹³ Department of Medical Microbiology and Infection Control, Franciscus Gasthuis & Vlietland, 3045 PM Rotterdam, The Netherlands.

PMID: 40733732
PMCID: PMC12299067
DOI: 10.3390/vaccines13070755

Clinical Course, Outcomes, and Risk Factors of Myocarditis and Pericarditis Following Administration of mRNA-1273 Vaccination: A Protocol for a Federated Real-World Evidence Vaccine Safety Study Using Data from Five European Data Sources

Laura C Zwiers et al. Vaccines (Basel). 2025.

. 2025 Jul 16;13(7):755.

doi: 10.3390/vaccines13070755.

Authors

Affiliations

¹ Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.
² Julius Clinical, 3703 CD Zeist, The Netherlands.
³ Clin-Q B.V., 9723 DJ Groningen, The Netherlands.
⁴ ModernaTX, Inc., Cambridge, MA 02142, USA.
⁵ Vaccine Monitoring Collaboration for Europe (VAC4EU), 1000 Brussels, Belgium.
⁶ Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), 08029 Barcelona, Spain.
⁷ Vaccine Research Department, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO-Public Health), 46020 Valencia, Spain.
⁸ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Instituto de Salud Carlos III, 28029 Madrid, Spain.
⁹ Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, 0313 Oslo, Norway.
¹⁰ Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, 8200 Aarhus, Denmark.
¹¹ Drug Safety Research Unit, Southampton SO31 1AA, UK.
¹² School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2UP, UK.
¹³ Department of Medical Microbiology and Infection Control, Franciscus Gasthuis & Vlietland, 3045 PM Rotterdam, The Netherlands.

PMID: 40733732
PMCID: PMC12299067
DOI: 10.3390/vaccines13070755

Abstract

Background: Myocarditis and pericarditis are recognised risks following COVID-19 vaccination, including the mRNA-1273 vaccine. Most cases occur shortly following the second dose of this vaccine, and incidence is highest among young males. However, little is known about risk factors beyond age and sex and about the longer-term clinical course. This study aims to identify possible risk factors for myocarditis and pericarditis following mRNA-1273 vaccination, to characterise the clinical course of myocarditis and pericarditis, both associated with mRNA-1273 vaccination and not associated with vaccination, and to identify risk factors for severe outcomes (i.e., cardiac or thromboembolic complications, severe hospital outcomes, all-cause hospital readmission, and death). Methods: This study is being conducted within the Vaccine Monitoring Collaboration for Europe (VAC4EU) association using routinely collected healthcare data from five data sources from four European countries (Denmark, Norway, Spain, and the United Kingdom). The study is being performed using a common data model, and all analyses are performed separately in each data source in a federated manner following a common protocol. A case-cohort analysis set is identified within each data source for identifying potential risk factors for myocarditis and pericarditis following mRNA-1273 vaccination using logistic regression analysis. The clinical course of myocarditis and pericarditis is being assessed using a cohort study design and describes all cases (i.e., cases associated with mRNA-1273 and unexposed cases). Cox regression analysis is applied to assess the associations between risk factors and several follow-up outcomes. Conclusions: This protocol describes the study methodology of an international collaborative initiative with the aim of assessing the risk factors and clinical course of myocarditis and pericarditis following mRNA-1273 vaccination using a federated network of five European data sources.

Keywords: COVID-19 vaccines; myocarditis; pericarditis; safety; vaccination.

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Conflict of interest statement

L.C.Z., D.E.G., R.S., M.J., B.M.G., and D.S.Y.O. work or have previously worked (part-time) for Julius Clinical Ltd., which is an Academic CRO that receives financial support from Moderna Ltd. to conduct research on the cardiovascular safety of COVID-19 vaccination. CB works for Clin-Q, which is subcontracted by Julius Clinical Ltd. S.S., D.B.E., L.Z., V.V.U., and M.E. are employees of Moderna, Inc., and hold stock/stock options in the company. D.W. is secretary general of VAC4EU. VAC4EU has contracts with Pfizer, Moderna, AstraZeneca, JnJ, and Hipra to conduct COVID-19 vaccine PASS studies. L.W., J.W., and V.E. are employees of Aarhus University or Aarhus University Hospital, which provides research services, via institutional research grants, to multiple public and private stakeholders including regulators, governmental agencies, contract research organisations and pharmaceutical companies and received institutional funding as a subcontractor to Julius Clinical Ltd. D.M. and C.F. are employees of the Drug Safety Research Unit (DSRU). The DSRU is an independent charity (No. 327206) which works in association with the University of Portsmouth. The DSRU is a member of VAC4EU and receives funding from VAC4EU as a Data Expert and Access Provider. The funder had an advisory role in the design of this study, but had no role in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

**Figure 1**
Graphical representation of both study designs.

See this image and copyright information in PMC

References

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1. Lee G.M., Hopkins R.H. COVID-19 Vaccine Safety Technical (VaST) Work Group. Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC); Atlanta, GA, USA: 2021.
1. Patone M., Mei X.W., Handunnetthi L., Dixon S., Zaccardi F., Shankar-Hari M., Watkinson P., Khunti K., Harnden A., Coupland C.A.C., et al. Risks of Myocarditis, Pericarditis, and Cardiac Arrhythmias Associated with COVID-19 Vaccination or SARS-CoV-2 Infection. Nat. Med. 2022;28:410–422. doi: 10.1038/s41591-021-01630-0. - DOI - PMC - PubMed

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Clinical Course, Outcomes, and Risk Factors of Myocarditis and Pericarditis Following Administration of mRNA-1273 Vaccination: A Protocol for a Federated Real-World Evidence Vaccine Safety Study Using Data from Five European Data Sources

Affiliations

Clinical Course, Outcomes, and Risk Factors of Myocarditis and Pericarditis Following Administration of mRNA-1273 Vaccination: A Protocol for a Federated Real-World Evidence Vaccine Safety Study Using Data from Five European Data Sources

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources