Decoding the Human Genetic and Immunological Basis of COVID-19 mRNA Vaccine-Induced Myocarditis

Excerpt

More than 10 billion doses of COVID-19 vaccines have been administered worldwide in the span of 18 months, providing an unprecedented opportunity to study and understand immunological responses and clinical reactions to vaccines. While severe adverse reactions to live-attenuated viral or bacterial vaccines have been successfully deciphered since the 1950s, with the discovery of a wide range of underlying inborn errors of immunity [1, 2], there is currently no molecular, cellular, and immunological explanation for life-threatening reactions to any other type of vaccine. COVID-19 mRNA vaccines are very effective at preventing hypoxemic COVID-19 pneumonia. For example, their efficacy for preventing invasive mechanical ventilation and in-hospital death has been estimated at 90% (95% CI = 88–91%) [3]. COVID-19 mRNA vaccines are also well tolerated by most people, with either no side effects or mild local/systemic reactions, such as pain at the injection site, fever, or chills in the days following vaccination [4]. However, rare but serious adverse events have been observed, including anaphylaxis, myocarditis, Guillain-Barré syndrome, transverse myelitis, Bell’s palsy, and multisystem inflammatory syndrome [4‐7]. These adverse events have a combined prevalence of about 90 per million doses administered [4]. It is unknown whether they are triggered by the adjuvant (lipid nanoparticles for the mRNA vaccines), the vaccine antigen (the perfusion-stabilized spike protein translated by the human cells), the core components of the vaccine (the nucleoside-modified mRNA), or a combination thereof. Some possible mechanisms have been suggested [8‐10], but the underlying immunopathology and, hence, the risk factors predisposing a minority of vaccinees to experience any of these severe reactions remain unknown. …