Comprehensive genomic and inflammatory profiling of vaccine-associated myocarditis

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Principal Investigator: Amy R. Kontorovich
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $211,250
Funding agency: National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY
The cardiac inflammatory disorder myocarditis is a rare but important complication following vaccination
against COVID-19. Other than younger age and male sex, no risk factors for this adverse outcome have been
found. Recognition of host factors that predispose to vaccine-associated myocarditis (VAM) would highlight
those individuals for whom the risk of vaccination may be higher than the risk of COVID-19 infection and
should therefore avoid or alter vaccination. Furthermore, fundamental insights into the pathogenesis of this
complication and the interaction of innate cardiac immune responses with host genetics are lacking. We
previously discovered that ~16% of adults and children with idiopathic or viral myocarditis harbor rare
putatively damaging variants in a set of cardiac genes. Our findings suggest that genetically-mediated
impairments in the structural integrity of cardiomyocytes render them susceptible to injury by cardiotoxic agents
and, therefore, such variants may similarly underlie VAM. Leading a multi-institution consortium, we will recruit
50 individuals aged ≥ 5 years with VAM and perform exome sequencing to interrogate for relevant variation in
92 myocarditis-related genes, in comparison to exome sequencing of individuals with a history of
uncomplicated COVID-19 vaccination. This directed genomic approach is well-powered to identify host genetic
risk factors for VAM and enable precision risk stratification to minimize potential harms in genetically vulnerable
individuals. Additionally, we will perform multi-scale immunophenotyping via single cell RNA sequencing
(scRNA), cytometry by time of flight (CyTOF), cytokine and autoantibody assays to uncover the pathogenesis
of this condition. Comparing immune responses in those with and without susceptible genotypes will improve
understanding of VAM susceptibility and new prophylactic/treatment strategies.

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