Insignificant homology of SARS-CoV-2 spike sequences to myocarditis-associated antigens

By Nidhi Saha, BDSJan 13 2022Reviewed by Benedette Cuffari, M.Sc.

The emergence of the severe acute respiratory coronavirus 2 (SARS-CoV-2) in late 2019, which initiated the coronavirus disease 2019 (COVID-19) pandemic, has resulted in widespread morbidity and mortality. The most common symptoms associated with COVID-19 include dry cough, sore throat, fever, fatigue, myalgia, and loss of taste and smell. However, severe symptoms like low blood-oxygen levels and rare complications such as heart injury have been documented.

As of December 2021, more than eight billion COVID-19 vaccine doses have been administered worldwide. Rare occurrences of myocarditis and pericarditis have been reported with COVID-19 messenger ribonucleic acid (mRNA) vaccines.

Comparatively, viral vector vaccines have precipitated increased frequency of blood clots and, very rarely, myocarditis and pericarditis. Currently, the United States Food and Drug Administration has authorized the use of two mRNA vaccines including the Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273 vaccines, both of which encode for the SARS-CoV-2 spike (S) protein as the vaccine immunogen.

Study: Lack of evidence of significant homology of SARS-CoV-2 spike sequences to myocarditis-associated antigens. Image Credit: Design_Cells / Shutterstock.com

About the study

In a new EBioMedicine study, researchers determine whether specific sequences within the SARS-CoV-2 S protein could lead to a cross-reactive immune response to autoantigens associated with autoimmune myocarditis.

To this end, the researchers selected myocarditis-associated antigens from the Immune Epitope Database (IEDB), including myocarditis-associated epitopes and their respective source antigens. The search revealed 66 human epitopes contained in eight protein antigens.

An additional review of autoimmune myocarditis literature revealed 23 additional antigens that had known associations with myocarditis and four antigens with potential associations with myocarditis. Overall, 35 antigens were identified for this analysis.

The occurrence of peptides in the SARS-CoV-2 S protein with high similarity to peptides in proteins associated with cardiac autoimmunity was evaluated. For this, a set of 1,259 15-mers overlapping by 14 residues encompassing the entire S protein was generated. These 15-mer peptides were compared to 35 cardiac proteins associated with cardiac autoimmunity.

Study findings

No matching peptides with any cardiac antigens were observed in the SARS-CoV-2 S protein; however, a total of 13 matches for peptides were identified from the S protein. In addition, 14 matches from shuffled peptides were identified.

Upon examining the homology of 9-mer peptide fragments at 78% homology or more, three S peptides and one shuffled peptide were found in cardiac proteins. Comparatively, at the 67% homology level, 77 homologous peptides from the S protein and 55 homologous from shuffled peptides were discovered.

Since the enrichment is not statistically significant, the results support the notion that S protein sequences are significantly enriched in peptides that are potential epitopes with significant sequence identity to human self-proteins associated with autoimmune myocarditis. Meanwhile, the analysis identified 13, 15-mer and 77, 9-mer peptides that are speculated to harbor the potential to mediate cross-reactive responses in individuals experiencing post-vaccination myocarditis.

Sets of human proteins matching the cardiac protein set were randomly selected as alternative controls. The findings showed a trend for increased hits in cardiac proteins, rather than in randomly selected proteins. However, this trend was not found to be statistically significant.

When all protein data bank (PDB) files for the myocarditis-associated antigens were compared to the SARS-Cov-2 S protein using the TM-align program, four substructures of these antigens had significant scores. The findings showed that 84.5% of sets fell below the cardiac protein set and 14.5% were at or above it in terms of mean TM-align score, all of which were not significant.

Conclusions

The incidents of myocarditis post-vaccination may not be T-cell-mediated and could have been precipitated by a transient innate response. As the median onset of myocarditis does not correlate to cross-reactive adaptive immunity, future investigations may be aimed towards determining whether other mechanisms like the activation of innate immunity are instead associated with these rare side effects.