Letter by Cosentino and Marino Regarding Article, “Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis”
Marco Cosentino, Franca Marino - Center of Research in Medical Pharmacology, University of Insubria, Varese (I)
Originally published11 Sep 2023 https://doi.org/10.1161/CIRCULATIONAHA.123.064000 Circulation. 2023;148:906–907
Sir,
We read with interest the recent study showing elevated plasma levels of COVD-19 vaccine-induced free Spike protein in young people with postvaccine myocarditis, but not in asymptomatic COVID-19 vaccinated subjects,1 which constitutes a possibly decisive clue on the role of vaccine-induced Spike in tissue/organ damage in specific individuals.2,3 The authors tentatively explain results as a consequence of vaccine-induced Spike protein evasion of cleavage/clearance, and of antibody recognition, finally contributing to myocarditis. No information however exists regarding systemic clearance of vaccine-induced Spike.3 In addition, it is unlikely that the free Spike in subjects with post-vaccine myocarditis results evasion of antibody recognition. Indeed, also according to the authors, anti-Spike antibodies and T-cell responses are not different in individuals with postvaccine myocarditis and in vaccinated control subjects (Figure 2),1 an observation excluding insufficient binding/neutralizing capacity as a cause of free Spike in postvaccine myocarditis.
Our opinion is rather that the free Spike protein in postvaccine myocarditis results from an excess amount produced due to factors specific to the recipient's organism, such as more efficient protein synthesis especially in younger age and/or localization of COVID-19 vaccine RNA-containing nanoliposomes in tissues/organs with intrinsically high protein synthesis capacity (e.g. liver, ileum, heart, and skeletal muscle),4,5 resulting in excessive protein production, for too long and/or in tissues/organs sensitive to its toxicity, in any case overcoming the binding/buffer capacity of the vaccine-induced antibody response.3
Remarkably, evidence exists supporting the hypothesis of excessive and dystopic production of COVID-19 vaccine-induced Spike protein, for example reports describing: a woman suffering from Moderna-COVID-19-vaccine-induced thrombocytopenia and with high vaccine-induced Spike levels in plasma 10 days after vaccination; a patient with persistent skin lesions due to varicella zoster virus reactivation over three months after COVID-19 vaccination and the Spike protein in dermal keratinocytes and endothelial cells; a woman with diffuse myositis one month after injection of the BioNTech–Pfizer COVID-19 mRNA vaccine into the left deltoid muscle, and the spike protein mRNA in the right deltoid and quadriceps muscles (all reviewed in 3). Most importantly, vaccine-induced Spike has been identified in endomyocardial biopsies of myocarditis patients up to nearly two months following COVID-19 vaccination, strongly supporting the link between inappropriate expression and/or accumulation of Spike protein in sensitive tissues such as the heart and subsequent damage.
Finally, a couple of remarks: the authors define postvaccine myocarditis as a rare complication, occurring with a frequency of 18 cases for every 1,000,000 vaccine doses administered, however the best evidence so far available suggests 8.1—39 cases per 100,000 as the highest incidence of myocarditis in studies using proper stratifiers.6 Moreover, the authors ask for cardiac biopsy tissue analysis as they “would be informative in the future”, however, as also mentioned above, case series have been already published showing vaccine-induced Spike protein in endomyocardial biopsies of post-vaccine myocarditis (reviewed in 3).
In conclusion, the study by Yonker and colleagues1 provides a major contribution to establish the causative role of COVID-19 vaccine-induced Spike protein in subsequent cardiac inflammations. Plasma and possibly also cardiac biopsies should be always analyzed for the presence of the Spike protein in episodes of cardiac inflammations, and proper pharmacokinetic/pharmacodynamic and clinical studies are urgently needed to clarify the mechanisms of Spike protein-induced heart damage and most importantly to find suitable biomarkers to identify high-risk subjects for vaccine-induced Spike protein-dependent tissue/organ damage. Meanwhile, we respectfully disagree with the conclusion that “these results do not alter the risk-benefit ratio favoring vaccination against COVID-19”,1 since at least in healthy young people who are notoriously at minor risk of COVID-19 complications, COVID-19 vaccination-associated risks likely outweigh any possible expected benefits.7
Competing interests: none.
Yonker LM, Swank Z, Bartsch YC, Burns MD, Kane A, Boribong BP, Davis JP, Loiselle M, Novak T, Senussi Y, Cheng CA, Burgess E, Edlow AG, Chou J, Dionne A, Balaguru D, Lahoud-Rahme M, Arditi M, Julg B, Randolph AG, Alter G, Fasano A, Walt DR. Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis. Circulation 2023;147:867-876. doi: 10.1161/CIRCULATIONAHA.122.061025
Trougakos IP, Terpos E, Alexopoulos H, Politou M, Paraskevis D, Scorilas A, Kastritis E, Andreakos E, Dimopoulos MA. Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis. Trends Mol. Med. 2022;28:542-554. doi: 10.1016/j.molmed.2022.04.007
Cosentino M, Marino F. Understanding the pharmacology of COVID-19 mRNA vaccines: playing dice with the spike? Int J Mol Sci 2022;23:10881. doi: 10.3390/ijms231810881
Cross KM, Granados JZ, Ten Have GAM, Thaden JJ, Engelen MPKJ, Lightfoot JT, Deutz NEP. Protein fractional synthesis rates within tissues of high- and low-active mice. PLoS One 2020;15:e0242926. doi: 10.1371/journal.pone.0242926
Anisimova AS, Meerson MB, Gerashchenko MV, Kulakovskiy IV, Dmitriev SE, Gladyshev VN. Multifaceted deregulation of gene expression and protein synthesis with age. Proc. Natl. Acad. Sci. U S A 2020;117:15581-15590. doi: 10.1073/pnas.2001788117
Knudsen B, Prasad V. COVID-19 vaccine induced myocarditis in young males: A systematic review. Eur. J. Clin. Invest. 2022:e13947. doi: 10.1111/eci.13947
Fraiman J, Erviti J, Jones M, Greenland S, Whelan P, Kaplan RM, Doshi P. Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults. Vaccine 2022;40:5798-5805. doi: 10.1016/j.vaccine.2022.08.036