Following the large-scale deployment of messenger ribonucleic acid (mRNA) vaccines developed to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptomatic coronavirus disease 2019 (COVID-19), several cases of myocarditis have been reported, mainly in healthy young people.
A recent study published in the journal Traffic He examines the immunological picture of this scenario, looking for clues about the etiology of this rare and potentially serious complication.
Study: circulation peak protein Detected in post-COVID-19 mRNA vaccine myocarditis. Image Credit: Design_Cells / Shutterstock
Introduction
The development of myocarditis after mRNA vaccination is rare, occurring in less than 2 in 100,000 people. It remains an unpredictable mysterious event. Some have suggested it is linked to overproduction of antibodies or abnormal immune responses.
Autoantibody production due to polyclonal B cell activation and proliferation has also been suggested, as has immune complex formation and inflammation. Finally, some believe that cardiac antigens closely resembling the spike protein are targeted by autoantibodies formed by molecular mimicry.
The immune response to these vaccines in these patients needs to be better understood to determine why and how this occurs. It is imperative to investigate the role of male hormones because young male patients are most commonly affected.
Researchers in this study examined blood samples from 16 patients with myocarditis, who were confirmed to have elevated levels of serum cardiac troponin T. All developed myocarditis after receiving the COVID-19 vaccine, usually within a week of receiving the vaccine. second dose. However, a few got sick after the first dose or the booster dose. More than 80% were men.
They have been studied by antibody profiling, including antibodies against the virus, auto-antibodies or antibodies against the virome, and the analysis of T cells specifically directed against the virus. Additionally, cytokine and antigen profiles were determined. These measurements were compared with those of 45 vaccinated controls of similar age and health.
What did the study show?
All subjects and controls showed increased anti-spike and receptor-binding domain (RBD) antibodies of all immunoglobulin (Ig) subclasses, IgA, IgM, and IgG. Functional differences were also not seen, with Fc effect or functions being similar in both categories. In short, all vaccinated individuals showed evidence of a protective immune response against the virus.
“We found no indication that a specific antibody response is associated with myocarditis.”
Additionally, these patients did not show evidence of increased autoantibody production or antibody production against other respiratory pathogens that differed in magnitude or range from controls.
T cells of all relevant subtypes, including naïve, memory, and effector memory T cells, showed similar distributions in both groups. T cells also showed similar proportions of spike-specific memory CD4 T cells and activated CD4 and CD8 T cells. The only exceptions were the observation of small elevations in memory effector cells and en masse PD-1-expressing CD4 T cells in the myocarditis group.
The results indicated that antibody and T-cell responses could not distinguish between subjects with post-vaccination myocarditis and vaccinated controls. The only significant difference was a slight elevation in cytokine production in the former.
The interesting difference was the elevated level of circulating full-length spike protein in the plasma of patients with myocarditis, at an average of approximately 34 pg/mL. Additionally, the protein was unbound and remained detectable for up to three weeks from the date of vaccination. In contrast, controls had no free spike protein in their blood.
This difference could not be attributed to low neutralization capacity in the myocarditis group, which showed comparable neutralization compared to the control group.
Concordantly, patients with myocarditis had cytokine release patterns resembling those found in multisystem inflammatory syndrome in children (MIS-C). This could indicate that the innate immune response was overactive, leading to elevations in interleukin (IL)-8, IL-10, IL-4, IL-6, tumor necrosis factor (TNF)-α and interferon (INF)-γ compared to healthy controls. IL-8 was most closely associated with elevated levels of cardiac troponin T and antigen.
At the same time, leukocytes, especially neutrophils, were at higher average levels in this group than controls, although still within the normal range.
What are the implications?
The study shows that the immunological response elicited by the mRNA vaccine was very similar in those who developed post-vaccination myocarditis and others. In other words, myocarditis could not be associated with abnormal autoantibodies, viral infections other than SARS-CoV-2, or mRNA vaccine-induced excess antibody production.
In vaccinated patients, virus infection was not likely to be a cause or contributing factor to myocarditis since anti-nucleoprotein IgG was not found in these patients.
In contrast to controls, the finding of elevated levels of full-length unbound spike proteins in patients with myocarditis may indicate the mechanism by which this condition arises. Similarly, MIS-C patients had circulating SARS-CoV-2 antigens.
The spike protein appears to evade the immune system found at normal levels in these patients, with adequate functional and neutralizing capacity. The spike may damage cardiac pericytes or endothelium, possibly by reducing expression of angiotensin-converting enzyme 2 (ACE2), reducing nitric oxide production in the endothelium, or activating inflammation via integrins, which makes the endothelium abnormally permeable.
“Thus, the spike antigen itself, which evades antibody recognition rather than invoking immune hyperactivation, may contribute to myocarditis in these individuals..”
This finding does not constitute evidence against the benefits of vaccination with these vaccines, which effectively protect against the severe consequences of COVID-19. Therefore, current vaccine recommendations are subject to change based on these findings.
“Understanding the immunopathological mechanisms associated with post-vaccination myocarditis will help improve safety and guide the development of future vaccines against coronavirus disease 2019 (COVID-19). These results also suggest that administration of anti-spike antibodies, if spike antigenemia is detected, could potentially prevent or reverse post-vaccination myocarditis..”
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