Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine–associated myocarditis

"Introduction 

... SARS-CoV-2 vaccine–associated myopericarditis has been reported to occur most frequently in adolescent and young adult males during the first week after the second dose of an mRNA vaccine although it can also occur across demographic groups after a single or third (booster) dose of mRNA vaccination or after non–mRNA-based vaccines. Various estimates of myopericarditis risk after vaccination have been reported, with most recent reports estimating an incidence of 0 to 35.9 and 0 to 10.9 cases per 100,000 for males and females, respectively, across age groups and mRNA vaccine cohorts...

To better understand the underlying pathology in SARS-CoV-2 LNP-mRNA vaccine–associated myopericarditis, we conducted a multimodal study of patients with acute myocarditis and/or pericarditis using unbiased approaches that define the maladaptive immune signatures during disease...

Results 

Our clinical cohort consists of 23 patients with vaccine-associated myocarditis and/or pericarditis...

Patients had largely noncontributory past medical histories and were generally healthy before vaccination. Most patients had symptom onset 1 to 4 days after the second dose of the mRNA vaccine... 

Symptom presentation was consistent with acute myocarditis and/or pericarditis, including chest pain, palpitations, fever, shortness of breath, headaches, myalgia, diaphoresis, fatigue, nausea/emesis, and/or congestion...

Discussion

Although rare, vaccine-associated myopericarditis has emerged as an important area of investigation with implications for scientists and physicians working to optimize vaccination strategies. Understanding how and whether these rare adverse events result from maladaptive immune responses induced by vaccine-vectored antigens, or whether they instead result from immune responses triggered by elements of the LNP-mRNA vaccine delivery platform is a question of key importance given the enormous clinical potential for this effective vaccine modality...

[Our] results argue that neither overexuberant nor cross-reacting humoral responses are likely explanations of the pathogenesis.

Instead, using an unbiased and system-based approach, we reveal that vaccine-associated myopericarditis patients are characterized by systemic cytokinopathy and activated cytotoxic lymphocytes with distinct transcriptional signatures consistent with their potential to mediate heart tissue damage...

Longitudinal clinical follow-up months after vaccination revealed persistent cardiac imaging abnormalities in some patients, most notably LGE [late gadolinium enhancement] on CMR [cardiac magnetic resonance] imaging, suggesting cardiac fibrosis. We additionally observed elevations in various serum extracellular matrix remodeling enzymes, increased inflammatory classical monocytes carrying a profibrotic signature, and elevation in sCD163, indicative of cardiac macrophage activation. Our clinical, cellular,and molecular findings potentially point to ongoing wound healing, tissue remodeling, and scar formation after cardiac injury in these patients."