“The risk of acute myocarditis associated with COVID-19 mRNA vaccination has garnered intense (social) media attention. However, myocarditis after COVID-19 mRNA vaccination is rare and usually resolves within days or weeks. Moreover, the risks of hospitalization and death associated with COVID-19 are greater than the risk associated with COVID-19 vaccination. Therefore, COVID-19 vaccination should be recommended in adolescents and adults….
Myocarditis that results from enterovirus or human herpesvirus (HHV4 and HHV6) infection is generally more severe with younger age and male sex. This type of myocarditis can be associated with an immune–genetic background that increases the likelihood of developing acute myocarditis after viral injury, such as genetic variants in genes encoding HLA factors and, in a minority of patients, genetic variants in genes encoding desmosomal, cytoskeletal or sarcomeric proteins1. The generation of autoantibodies and hormone-related factors contribute to the sex-specific differences observed in both COVID-19 mRNA-vaccination-related myocarditis and in non-COVID-19 viral myocarditis. Publications in the past year describe similar factors predisposing to acute myocarditis after COVID-19 mRNA vaccination9.
mRNA vaccines against COVID-19 contain nucleoside-modified mRNA that encodes the viral spike glycoprotein of SARS-CoV-2 and is encapsulated in lipid nanoparticles, but do not contain live virus or DNA. The viral spike protein, once produced in the cell after mRNA-vaccine entry, induces an adaptive immune response to identify and destroy viruses that express the spike protein. Vaccine-induced spike-protein IgG antibodies prevent the attachment of SARS-CoV-2 to the host cell (which occurs via spike-protein binding to the angiotensin-converting enzyme 2 receptor) and thereby neutralize the virus. The three main mechanisms by which COVID-19 mRNA vaccines might induce hyperimmunity9 are mRNA immune reactivity, antibodies to SARS-CoV-2 spike glycoproteins cross-reacting with myocardial contractile proteins, and hormonal differences. All of these mechanisms can be influenced by immune–genetic background, age and sex.
The immune system might detect the mRNA in the vaccine as an antigen, resulting in the activation of pro-inflammatory cascades and immunological pathways in the heart. Although nucleoside modifications of mRNA reduce their innate immunogenicity, the immune response to mRNA might still drive the activation of an aberrant innate and acquired immune response, which can explain the stronger immune response seen with mRNA vaccines than with other types of COVID-19 vaccine. However, this hypothesis is not supported by the lack of immune-related adverse effects in other organs in which the mRNA vaccine is being uptaken. Molecular mimicry between the spike protein of SARS-CoV-2 and cardiac self-antigens is another possible mechanism. Antibodies directed to SARS-CoV-2 spike glycoproteins might cross-react with structurally similar human protein sequences, including myocardial α-myosin heavy chain9. These autoantibodies might be innocent bystanders resulting from myocardial inflammation and injury, or might reflect a certain immune–genetic background that predisposes to developing hyperimmunity and myocarditis upon any trigger. Finally, given the increased incidence among male patients, differences in hormone signalling might be involved in the pathophysiology of COVID-19 mRNA-vaccination-related myocarditis. Testosterone can inhibit anti-inflammatory immune cells and promote a more aggressive T helper 1 cell-type immune response1. By contrast, oestrogen has inhibitory effects on pro-inflammatory T cells, resulting in a decrease in cell-mediated immune responses1. …”
Heymans S, Cooper LT. Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms. Nat Rev Cardiol. 2022 Feb;19(2):75-77. doi: 10.1038/s41569-021-00662-w. PMID: 34887571; PMCID: PMC8656440.
