Moderna Spikevax® myocarditis and pericarditis study

Background: Myocarditis and pericarditis are recognized as possible rare adverse events that may occur following COVID-19 mRNA vaccines, including mRNA-1273.

Objectives: The aim was to characterize the clinical course of myo- and pericarditis of varying origin, including cases associated with mRNA-1273 vaccination and cases not associated with COVID-19 vaccination and to identify risk factors for severe outcomes (cardiac or thromboembolic complications, severe hospital outcomes, all-cause hospital readmission, and death).

Methods: This cohort study utilized secondary health data from the VAC4EU network through five data experts and access partners across four European countries (national registries in Denmark and Norway, VID (Valencia region) and SIDIAP (Catalonia region) in Spain and CPRD Aurum in the UK). It included individuals diagnosed with myo- or pericarditis within 30 days after mRNA-1273 vaccination (exposed) and those that did not receive any COVID-19 vaccine in the 30 days before myo- or pericarditis onset (unexposed), and were enrolled in the database for at least a year. Different follow-up windows at 1, 3, 6 and 12 months after myo- or pericarditis onset were considered in the analysis. Cox regression analyses were used to estimate hazards ratios (HRs) for sequelae.

Results: The number of myo- and/or pericarditis cases in each database varied from 2,700 to 6,908, of which 90 to 158 were associated with mRNA-1273. Exposed cases had lower prevalence of pre-existing comorbidities and shorter hospital stays than unexposed cases. Two percent (2%) of the exposed myocarditis cases compared to 5% of unexposed cases were severe. None of the post-mRNA-1273 pericarditis cases were severe. Cox regression models of the combined exposed and unexposed cases showed that age (HR range: 1.00-1.03), Charlson Comorbidity Index (CCI) score (HR range: 1.18-2.41), and history of cardiac drug use (HR range 1.24-4.00) were risk factors for cardiac complications in both myo- and pericarditis cases across follow-up windows. CCI score (HR range: 1.09-2.11) and previous healthcare use (HR range: 1.13-6.89) were risk factors for severe hospital outcomes and hospital readmission in both myo- and pericarditis cases. Age (HR range: 1.04-1.11) and CCI score (HR range: 1.30-2.32) were the most apparent risk factors for death in both myo- and pericarditis cases.

Conclusions: Post-mRNA-1273 myocarditis cases were less severe and had fewer pre-existing comorbidities compared to unexposed cases. Risk factors for cardiac complications, severe hospital outcomes, and mortality after myo- or pericarditis diagnosis include older age, higher CCI score, and previous healthcare use.

Background: Myocarditis and pericarditis are recognized as possible adverse events following COVID-19 mRNA vaccines, including mRNA-1273. Previous studies indicate these events predominantly occur in young males and after the second dose of the vaccine. However, other risk factors remain to be elucidated.

Objectives: The study aim was to identify associated risk factors in individuals experiencing myocarditis and/or pericarditis after vaccination with mRNA-1273.

Methods: This case-cohort study utilized secondary healthcare data from 5 VAC4EU network data experts and access partners (DEAPs) across 4 European countries (national registries in Denmark and Norway, VID (Valencia region), and SIDIAP (Catalonia region) in Spain and CPRD Aurum in the United Kingdom (UK)). Inclusion criteria for the base cohort were receipt of at least one dose of mRNA-1273 between 1/6/2021 and 8/31/2024, a minimum one-year enrolment in the participating database before vaccination, and no diagnosis of myo- or pericarditis in the six months preceding vaccination. Cases were individuals diagnosed with myo- and/or pericarditis within 30 days following mRNA-1273 vaccination, and 1:4 calendar-time matched controls were selected from the base cohort. We conducted multivariable logistic regression to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs), aiming to identify associated risk factors for myo- and/or pericarditis. Analyses were performed per database and considered age, sex and previous SARS-CoV-2 infection, which are known risk factors, as well as potential confounders selected in a variable selection procedure.

Results: All databases included 5 to 7 million individuals, of which 0.7 to 3.9 million were mRNA-1273-exposed. Males were overrepresented in both myo- and pericarditis cases, but not in controls. Pericarditis cases had more baseline comorbidities, prior ER visits and hospital admissions than matched controls. Myocarditis cases showed no such differences. No differences in vaccination history (against either COVID-19 or other diseases (e.g., influenza)) were observed between myo- and pericarditis cases and their controls. In multivariable logistic regression analyses, a history of cardiac comorbidities was associated with a higher risk of developing myo- and/or pericarditis in 3 databases [UK: OR 2.2 (95% CI 1.1-4.2); VID: OR 5.0 (95% CI 2.5-9.9); Norway: OR 8.5 (95%CI 3.8-19.3)]. Hospital visits in the previous year were associated with a higher risk of myo- and pericarditis in two databases [Denmark: OR 1.9 (95% CI 1.0-3.5); VID: OR 2.6 (95% CI 1.2-5.7)].

Conclusions: History of cardiac comorbidities and prior healthcare utilization were identified as risk factors for developing myo- or pericarditis after mRNA-1273 vaccination.

Myocarditis and pericarditis are recognized as possible adverse events of special interest (AESIs) following mRNA-1273 vaccination. Prior research indicates these events predominantly occur in young males and after the second dose of the vaccine. However, comprehensive studies on other potential risk factors are lacking.

Objectives:

These interim analyses sought to identify possible risk factors for myocarditis and pericarditis among individuals vaccinated with mRNA-1273.

Methods:

This case-cohort study utilized secondary health data from five VAC4EU network data access partners across four European countries (national registries in Denmark and Norway, VID and SIDIAP in Spain and CPRD Aurum in the UK). Inclusion criteria for the base cohort were receival of at least one dose of mRNA-1273 between 6 January 2021 and 31 August 2024, a minimum one year enrolment in the participating databases before vaccination, and no diagnosis of myocarditis/pericarditis in the six months preceding vaccination. Cases were identified within 30 days following vaccination using diagnostic codes, and a 1:4 calendar-time matched control sample was selected from the base cohort. Preliminary analysis included demographic assessments, medical history (comorbidities, medication use, healthcare utilization), and vaccination history for both cases and controls. Federated analyses were performed using the ConcePTION common data model.

Results:

The analysis included the following number of mRNA-1273 recipients (and respective myocarditis and pericarditis cases): 679,702 in Danish national registries (45 and 52 cases); 2,120,376 in VID (20 and 70 cases); 266,558 in SIDIAP (<5 cases each); and 1,544,983 in Norwegian registries (80 and 138 cases). Data from CPRD Aurum (UK) were pending at the time of this report. The proportion of male cases was 70-89% for myocarditis and 65-79% for pericarditis, compared to a more balanced sex distribution in controls (up to 54% males). Myocarditis cases were younger than controls, with no apparent differences in medical history. Pericarditis cases had more pronounced healthcare utilization and comorbidities compared to controls.

Conclusions:

Preliminary findings suggest age and sex to be potential risk factors for the occurrence of myocarditis/pericarditis after mRNA-1273 vaccination. In addition, comorbidities and prior healthcare utilization may be potential risk factors for the occurrence of pericarditis.

Myocarditis and pericarditis are among the identified risks following COVID-19 mRNA vaccination, including the mRNA-1273 vaccine. Most cases occur within 14 days following the second dose of this vaccine, and incidence is highest among young males aged 18 to 39. Additional data are needed to characterize risk factors, natural history and long-term outcomes of these events.

Objectives:

(1) To identify possible risk factors for myocarditis and pericarditis following mRNA-1273 vaccination, and (2) To examine the clinical course of myocarditis and pericarditis of varying origin and to identify prognostic factors in the course of myocarditis and pericarditis.

Methods:

Performed within the VAC4EU association, the study will draw on electronic healthcare records from five data access partners (DAPs) located in Denmark (Aarhus University), Norway (University of Oslo), Spain (IDIAP and FISABIO) and the United Kingdom (DSRU) to create a source population representative of the European population overall. The study is performed using the published ConcePTION common data model (CDM) for all DAPs and analyses will be run locally before performing a pooled meta-analysis of outcomes. All cases will be validated based on criteria from the Brighton Collaboration Case Definition. A case-cohort design will address Objective (1), and will include all cases of myocarditis and pericarditis following mRNA-1273 vaccination, as well as a random sub-cohort of individuals who have received this vaccine as controls. A Cox model with non-proportional hazards, including variables for demographic characteristics, medical history and vaccination history, will be used to investigate risk factors in the case-cohort design. Objective (2) will be addressed through a cohort study including all cases of myocarditis and pericarditis in the data. A Cox model will be used to compare cases following mRNA-1273 vaccination to cases not following COVID-19 vaccination for outcome measures such as cardiac and clinical outcomes, hospital readmission, and death, in this cohort.

Results:

As of April 2022, the source population includes over 6 million vaccinated individuals, and in each study design we expect to include 150 to 1500 cases. Over the course of 2023 and 2024, this study will continue to include individuals in the analyses sets, as to most accurately describe risk factor profiles of interest.

Conclusions:

By drawing from electronic healthcare records from several DAPs and using the ConcePTION CDM, the design of this study allows for identification of risk factors for the development of myocarditis and pericarditis and for comparing the clinical course of cases following mRNA-1273 vaccination to cases not following vaccination.

Myocarditis and pericarditis are among the identified risks following COVID-19 mRNA vaccination, including the mRNA-1273 vaccine. Most cases occur within 14 days following the second dose of this vaccine, and incidence is highest among young males aged 18 to 39. Additional data are needed to characterize risk factors, natural history and long-term outcomes of these events.

Objectives: (1) To identify possible risk factors for myocarditis and pericarditis following mRNA-1273 vaccination, and (2) To examine the clinical course of myocarditis and pericarditis of varying origin and to identify prognostic factors in the course of myocarditis and pericarditis.

Methods: Performed within the VAC4EU association, the study will draw on electronic healthcare records from five data access partners (DAPs) located in Denmark (Aarhus University), Norway (University of Oslo), Spain (IDIAP and FISABIO) and the United Kingdom (DSRU) to create a source population representative of the European population overall. The study is performed using the published ConcePTION common data model (CDM) for all DAPs and analyses will be run locally before performing a pooled meta-analysis of outcomes. All cases will be validated based on criteria from the Brighton Collaboration Case Definition. A case-cohort design will address Objective (1), and will include all cases of myocarditis and pericarditis following mRNA-1273 vaccination, as well as a random sub-cohort of individuals who have received this vaccine as controls. A Cox model with non-proportional hazards, including variables for demographic characteristics, medical history and vaccination history, will be used to investigate risk factors in the case-cohort design. Objective (2) will be addressed through a cohort study including all cases of myocarditis and pericarditis in the data. A Cox model will be used to compare cases following mRNA-1273 vaccination to cases not following COVID-19 vaccination for outcome measures such as cardiac and clinical outcomes, hospital readmission, and death, in this cohort.

Results: As of April 2022, the source population includes over 6 million vaccinated individuals, and in each study design we expect to include 150 to 1500 cases. Over the course of 2023 and 2024, this study will continue to include individuals in the analyses sets, as to most accurately describe risk factor profiles of interest.

Conclusions: By drawing from electronic healthcare records from several DAPs and using the ConcePTION CDM, the design of this study allows for identification of risk factors for the development of myocarditis and pericarditis and for comparing the clinical course of cases following mRNA-1273 vaccination to cases not following vaccination.