Combined Adaptive Immune Mechanisms Mediate Cardiac Injury After COVID-19 Vaccination
Silvia Fanti, Carlene Dyer, Inga Jóna Ingimarsdóttir, Daniel Harding, Guosu Wang, Antonio d’Amati, Eriomina Shahaj, Aðalbjörg Ýr Sigurbergsdóttir, Helga S. Thórsdóttir, Oddný Brattberg Gunnarsdóttir, Stavroula Kanoni, Paul Wright, John F. Martin, Jamie Chorlton, Zoe Hollowood, Siggeir F. Brynjólfsson, Björn R. Lúdvíksson, Egle Solito, Serena Bert, Jack M. Keane, Saidi Mohiddin, M. Paula Longhi, Federica M. Marelli‐Berg
Abstract
BACKGROUND: The COVID-19 pandemic, caused by SARS-CoV-2, has led to the first approval of mRNA vaccines in humans. By producing the full-length SARS-CoV-2 Spike protein, they induce protective antiviral immunity. Acute myopericarditis (AMP) development after vaccination has repeatedly been reported; however, the pathogenesis of this complication remains elusive. METHODS: In-depth phenotyping of peripheral blood T cells was undertaken in cohorts of patients who developed AMP after mRNA vaccination, patients hospitalized for severe COVID-19, and healthy subjects with no cardiac side effects after mRNA vaccine. Validation studies were carried out using an experimental model of cardiac inflammation, in which a shared epitope elicits functional responses in patients and mice and induces AMP. RESULTS: channel, induced AMP in mice. When functional responses to the Kv2 were analyzed, patients with AMP after mRNA vaccination, but not patients with COVID-19, displayed an expanded pattern of cytokine production similar to that observed in AMP mice and in autoimmune myocarditis. Crucially, T-cell autoimmunity segregates to cardiotropic cMet (c-mesenchymal epithelial transition factor)-expressing T cells and is prevented by cMet inhibition, suggesting that heart homing imprinting, permitted by the unique mRNA vaccine biodistribution, is required for AMP development. CONCLUSIONS: AMP development after mRNA vaccines is mediated by distinct immune components, including molecular mimicry, T-cell receptor affinity, and, importantly, homing imprinting.