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Immune signatures of adolescents diagnosed with myocarditis shortly after mRNA COVID-19 vaccination

BNT162b2 (Pfizer- BioNTech) and mRNA 1273 (Moderna) vaccines were the first messenger RNA (mRNA)-based vaccines ever approved. In both vaccines, a mRNA sequence determines the structure and assembly of the immunogen, the SARS-CoV-2 spike (S) glycoprotein. The mRNA is protected from degradation by lipid nanoparticles (LNPs) and taken up by the cells as an LNP-mRNA complex through simple endocytosis. Myocarditis and/or pericarditis are adverse cardiac events observed most frequently in adolescent and young adult males during the first week after the second dose of an mRNA COVID-19 vaccine, but it can occur in other demographic groups after a single or third (booster) dose. In this study, researchers from the United States investigated immune signatures in adolescent patients diagnosed with myocarditis and/or pericarditis shortly (one to four days) after messenger RNA (mRNA) COVID-19 vaccination.

The etiology of vaccine-associated myopericarditis remains unknown. The findings like elevated troponin serum levels, abnormal ST-elevations in the electrocardiogram (ECG), altered ventricle movement in echocardiogram, or late gadolinium enhancements (LGE) on cardiac magnetic resonance imaging (MRI) scans indicate the development of myocarditis. Most reported cases had a clinically mild course, and symptoms resolved without treatment. However, arrhythmic failure, either by cardiac arrest or by ventricular fibrillation, is considered to be the mechanism leading to death.

Early hypotheses suggested that the SARS-CoV-2 S protein, which could be detectable in the blood, may induce cardiac-targeted autoantibodies through molecular mimicry. Other possible mechanisms are hypersensitivity or autoimmune myocarditis driven by T-helper (Th) type 17 responses, but there is no evidence to support this pathology yet. Other arguments suggest that aberrant immune responses, both innate and adaptive, were triggered by the mRNA and/or LNPs.

Notably, a recent in vitro study demonstrated that both, mRNA-1273 and BNT162b2 COVID-19 vaccines induced cardiotoxic effects and functional disturbances in isolated cardiomyocytes, but with fundamentally different pathophysiological mechanisms. mRNA-1273 vaccine induced arrhythmic and irregular contractions through extensive disruption of sarcoplasmic calcium release, whereas the BNT162b2 vaccine induced a pattern of cell contraction through chronic activation of protein kinase A, consistent with catecholamine-induced cardiomyopathy.  https://discovermednews.com/cardiotoxic-effects-mrna-1273-bnt162b2-induce-disturbances-of-contractile-function-in-rat-cardiomyocytes/

About the study

The authors compared immune profiles of patients diagnosed with myopericarditis shortly after mRNA COVID-19 vaccination and healthy vaccinated control individuals. In most patients, symptoms of myopericarditis developed one to four days after the second dose of the BNT162b2 mRNA vaccine. The symptoms were consistent with acute myocarditis and/or pericarditis, including chest pain, palpitations, fever, shortness of breath, headaches, myalgia, fatigue, and nausea. 

At hospital admission, patients diagnosed with myopericarditis tested negative on reverse transcription polymerase chain reaction (rt-PCR) of nasopharyngeal swabs for SARS-CoV-2 and did not have antibodies to SARS-CoV-2 nucleocapsid protein.

Results

The clinical cohort included 23 patients with vaccine-associated myocarditis and/or pericarditis and 16 healthy vaccinated individuals. The group was mostly male (87%) with an average age of 16.9 ± 2.2 years (ranging from 13 to 21 years). Before the vaccination, patients were generally healthy.

At hospital admission, most patients had elevated levels of troponin, C-reactive protein, and B-type natriuretic peptide, indicating acute systemic inflammation with direct myocardial injury. Some patients also had leukocytosis.

The echocardiogram showed borderline low or abnormally reduced left ventricle ejection fraction in several patients at admission. Most patients underwent cardiac MRI during acute hospitalization, which demonstrated abnormalities consistent with acute or subacute myocarditis and/or pericarditis. Patients were treated with nonsteroidal anti-inflammatory drugs, and some received steroids and intravenous immunoglobulins.

After one to six days, they were discharged home with improved symptoms and clinical and laboratory findings. However, some imaging abnormalities persisted in the majority of patients, including LGE at MRI scans at least two months after hospital discharge. These findings are consistent with data reported in another PET/ MRI study which also found myocardial inflammation and edema in a small proportion of participants with acute myocarditis approximately two months after mRNA COVID-19 vaccination. https://discovermednews.com/pet-and-mri-myocardial-sequlae-myocarditis-after-anti-sars-cov-2-vaccination/

Immune signatures in adolescents who developed myocarditis and/or pericarditis shortly after COVID-19 vaccination

Contrary to early theories, there were no features of hypersensitivity myocarditis. Patients with myopericarditis did not have eosinophilia or high levels of Th2 cytokines, making hypotheses of hypersensitivity or eosinophilic myocarditis unlikely.

The analysis of humoral response showed no evidence of immune targeting of cardiac autoantigens in patients with myocarditis compared to healthy vaccinated controls. 

Analysis of circulating inflammatory mediators demonstrated an increase of  interleukin-1 (IL-1) family cytokines (IL-1β and IL-1RA), suggesting acute, systemic inflammation, and IL-15, a potent activator of NK and T cells.

The activated CD4+and CD8+cytotoxic T cells (PD-1+and CD38+/HLA-DR+) were significantly expanded early after vaccination, further expressing the chemokine receptors CXCR3 and CCR5, whose ligands, CXCL10 and CCL4, respectively, were concomitantly elevated in patients’ sera. In myopericarditis, these chemokines play a central role in recruiting lymphocytes.

The results also showed an activation signature of NK cells with dysregulation of the activating receptor NKG2D, mostly expressed in cells of the cytotoxic arm of the immune system. Ligands of NKG2D are normally of low abundance but can be induced in response to stressors, such as infection and oncogenic transformation. There was also an increase in inflammatory classical monocytes with markers related to migration (CCR2) and phagocytosis (CD163+), carrying a profibrotic signature.

Serum levels of extracellular matrix remodeling enzymes, matrix metalloproteinase 1 (MMP1), MMP8, MMP9, and tissue inhibitor of matrix metalloproteinase 1 were also increased. 

Conclusion

This investigation of immune signatures in patients diagnosed with myocarditis shortly (one to four days) after mRNA COVID-19 vaccination demonstrated elevated systemic levels of cytokines, increased frequency of activated T and NK cells, and induction of inflammatory monocytes with profibrotic features, consistent with published biopsy reports describing predominate macrophage and lymphocytic infiltrates in affected heart tissue. There was no evidence of immune targeting of cardiac autoantigens.

According to the results, there is a potential link between immune profiles and LGE findings on MRI, persisting for months after vaccination. This indicates ongoing wound healing, tissue remodeling, and scar formation after cardiac injury. Therefore, these findings underscore the need for careful long-term monitoring of patients with myocarditis and/or pericarditis after mRNA COVID-19 vaccination, especially if they exhibit signs of cardiac fibrosis.

This article was published in Science Immunology.

 

Journal Reference

Barmada A et al. Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine–associated myocarditis. Science Immunology. Sci. Immunol. 8, eadh3455 (2023) (Open Access)   https://www.science.org/doi/10.1126/sciimmunol.adh3455

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