Article

Elevated circulating levels of free full-length SARS-CoV-2 spike protein in adolescents and young adults with myocarditis after mRNA vaccination

A new study from the US scientists detected elevated circulating levels of free full-length SARS-CoV-2 spike (S) protein in adolescents and young adults with myocarditis after mRNA vaccination. These results show an association between a myocardial injury and elevated circulating levels of the free full-length S protein, which evades antibody recognition.

Epidemiological reports describe myocarditis after SARS-CoV-2 mRNA vaccination, but, the immune response driving postvaccinal myocarditis is still unclear.

A growing body of in vitro data shows that the S protein by itself can stimulate the dysfunction of cardiac pericytes or endothelium. The underlying mechanisms include down-regulation of angiotensin-converting enzyme-2 expression, changes in the bioavailability of endothelial nitric oxide, or activation of integrin-mediated inflammation with hyperpermeability of the endothelial cell layer.

In addition, some investigators indicate that immune system inevitably recognizes as a threat and kills every human cell that intakes the lipid nanoparticles and translates the viral protein (in case of the mRNA vaccines). The cellular immune response triggered by T-cell activation, which occurs within days of vaccination, leads to the death of cells presenting the S protein.

If the cardiac myocytes internalize the mRNA contained in the lipid nanoparticles, and these cells produce the S protein, the resulting inflammation would likely lead to myocardial necrosis, which is proportional to the number of cells involved. Consequently, the S protein will be released into the bloodstream (Scand J Immunol 2022;00:e13160)  https://onlinelibrary.wiley.com/doi/10.1111/sji.13160

 

About the study

This study involved 61 adolescents and young adults who either developed myocarditis (n=16) or had no vaccine-related complications following vaccination with either the Pfizer BNT162b2 or Moderna mRNA-1273 COVID-19 mRNA vaccine. Patients were 12 to 21 years of age (16 years on average). The study provided a detailed immunoprofile of adolescent patients who have developed postvaccinal myocarditis.

The majority of individuals with postvaccinal myocarditis were male. Symptoms usually occur within the first week following vaccination (median 4 days). In the postvaccinal myocarditis cohort, the majority of subjects developed myocarditis after the second dose of SARS-CoV-2 mRNA vaccine. All patients had chest pain, and all had elevated levels of cardiac troponin T and C-reactive protein.

The results showed elevated levels of free S protein, not bound by anti-spike antibodies, in the blood of adolescents and young adults who developed myocarditis after SARS-CoV-2 mRNA vaccination. High levels of free S protein appear to correlate with levels of cardiac troponin T and innate immune activation with cytokine release.

Extensive antibody profiling and T-cell responses in the individuals who developed postvaccinal myocarditis were essentially indistinguishable from those in vaccinated control subjects, despite a slight increase in cytokine production. Analysis of serological responses showed no difference in levels of anti-receptor binding protein or anti-spike immunoglobulins. Also, there was no difference in autoantibody levels in the myocarditis group compared to the healthy vaccinated control group.

Adaptive immunity and T-cell responses were essentially indistinguishable from those of asymptomatic control subjects of the same age. Characterization of T-cell responses showed no difference in the frequencies of naive, central memory, effector memory, and terminally differentiated effector memory T cells between the two groups except that individuals with myocarditis had slightly higher frequencies of effector memory cells.

However, individuals with myocarditis had significantly higher levels of IL-8, IL-6, tumor necrosis factor-α, IL-10, interferon-γ, and IL-1β and lower levels of IL-4 compared to vaccinated healthy controls. Although mostly within the normal ranges of both cohorts, the total number of leukocytes, specifically neutrophils, was significantly higher in individuals with postvaccinal myocarditis than in vaccinated controls. Platelet counts decreased in the myocarditis group compared to the vaccinated controls.

Adolescents who develop myocarditis had significantly higher levels of free full-length S protein in their plasma (33.9±22.4 pg/ml), whereas asymptomatic vaccinated control subjects had no detectable free S protein. The authors could not detect any free or antibody-bound S protein in the healthy adult samples.

Both free and antibody-bound S protein remained detectable up to 3 weeks after vaccination in patients who developed vaccine-induced myocarditis. Although the majority of individuals with postvaccinal myocarditis were male, higher levels of free full-length S protein have been observed equally in affected females and males.

Conclusion

The results of this study show an association between a myocardial injury and elevated circulating levels of the free full-length S protein, which evades antibody recognition. The findings also show marked differences in the adolescent responses to mRNA vaccination compared to adults that warrant further investigation.

This article was published in the scientific journal Circulation. Yonker LM. Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis. Circulation. 2023;147:00–00. (Open Access).  https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.061025 https://www.ahajournals.org/doi/epdf/10.1161/CIRCULATIONAHA.122.061025