Clinical Infectious Diseases E d i t o r i a l C o m mEn t a r y Insights From a Murine Model of Coronavirus Disease 2019 (COVID-19) mRNA Vaccination-Induced Myopericarditis: Could Accidental Intravenous Vaccine Injection Induce Myopericarditis? Kirk U. Knowlton Intermountain Medical Center, Salt Lake City, Utah, USA (See the Major Article by Li et al on pages 1933–50.) Keywords. myocarditis; pericarditis; SARS-CoV-2; COVID-19; vaccine. to According Johns Hopkins the Coronavirus Resource Center, almost 212 million people have tested positive for coronavirus disease 2019 (COVID- 19) worldwide. This has been associated with 4.4 million deaths as of August 2021. Severe acute respiratory syndrome cor- onavirus 2 (SARS-CoV-2) infection is often accompanied by relatively high rates of myocarditis or pericarditis. Fortunately, almost 5 billion vaccine doses have been administered, but large percentages of the population have not been partially or fully vaccinated. Certain geographic areas, such as Africa, have low vaccine penetration. Since vaccination is the key to controlling COVID-19, it is crucial to understand po- tential complications of COVID-19 vac- cination and the mechanisms by which they may occur. As COVID-19 vaccinations have been administered large popula- tions, myocarditis and pericarditis have been identified as rare complications of to Received 23 August 2021; editorial decision 25 August 2021; published online 28 August 2021. Correspondence: K.  U. Knowlton, Intermountain Medical Center, Intermountain Heart Institute, 5121 S Cottonwood St, Salt Lake City, UT 84107 (kirk.knowlton@imail.org). Clinical Infectious Diseases® © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. https://doi.org/10.1093/cid/ciab741 2022;74(11):1951–2 mRNA vaccines produced by Pfizer and Moderna. The Vaccine Adverse Event Reporting System (VAERS) reported a rate of 0.41 cases per 100  000 vaccin- ations based on voluntary reporting of events [1]. The rate reported among ac- tive military was 1.9 cases per 100  000 vaccines [2]. A  recent report from a large healthcare system used diagnosis codes to estimate a rate of 1.0 myocar- ditis cases and 1.9 pericarditis cases per 100  000 vaccinations [3]. A  common finding among all reports is that the clin- ical course of vaccine-associated myocar- ditis and pericarditis generally resolves within days with treatment in most cases. It is rarely, if ever, associated with death. While rare and self-limited, many pa- tients require hospitalization for man- agement and to ensure no other cause for the clinical presentation. Furthermore, the presence of any, albeit rare, complica- tion contributes to hesitancy toward vac- cination in some populations. Therefore, identifying a model system that clarifies mechanisms that contribute to vaccine- associated myocarditis and pericarditis could improve vaccination rates and avoid these rare clinical presentations. For example, in a preprint, Nicolai et  al [4] describe a murine model of an adeno- viral vector vaccine for COVID-19 using the ChAdOx1 nCov-19 vaccine that has been linked to a rare thrombosis with thrombocytopenia syndrome. They dem- onstrate that intravenous injection of this vaccine leads to low platelet counts, clot formation, and platelet activating PF4- polyanion antibodies similar to throm- botic thrombocytopenia. In this issue of Clinical Infectious Diseases, Can et al [5] have described an important and novel murine model of COVID-19 mRNA vaccination with fea- tures of myocarditis and pericarditis— that is, myopericarditis. This murine model has the potential to provide sig- nificant insights into the pathogenesis of myopericarditis after COVID-19 vaccin- ation via intramuscular and intravenous routes. For example, the authors demon- strate in their paper that the inflamma- tion in the myocardium after intravenous injection of the vaccine consists primarily of CD68+ macrophages or histiocytes, but not CD3+ T lymphocytes. In com- parison, evaluation of tissue from 2 pa- tients suspected to have post–COVID-19 mRNA vaccination–related myocarditis demonstrated T cells and macrophages, admixed with eosinophils, B cells, and plasma cells However, the myocarditis in those cases was only temporally associ- ated with the vaccine [6]. Since it is not common to obtain tissue in post-vaccine myopericarditis and since causality can be EDITORIAL COMMENTARY • cid 2022:74 (1 June) • 1951 challenging in isolated clinical cases, the histological information from the mouse model gives valuable insight into the mechanisms of post–vaccine-mediated inflammation. Notably, COVID-19–in- duced murine myocarditis is also associ- ated with macrophage infiltration instead of the T-cell infiltration typically associ- ated with viral myocarditis. Furthermore, the data presented document the patterns of cytokine induction that occur with COVID-19 vaccination in the mouse and the differences that occur over time with intramuscular compared with intravenous injection. This murine model will allow activation and inhibition of specific pro- teins in the inflammatory cascade using novel therapies or disruption of relevant genes through knockout strategies to de- termine the effect on myopericarditis. It is important to note that future ap- plications of the murine model system will likely require further investigation into how well this model represents the rare complication of myopericarditis fol- lowing COVID-19 mRNA vaccination in humans. For example, it is often challen- ging to correlate the dose of a drug when adjusted to body weight between a small mouse and a much larger human. In this case, the mouse received 0.25 μg per gram weight. The Pfizer mRNA vaccine dose in humans is 0.4  ×  10-3 μg per gram for a 70-kg person. Additional investigation will also be needed to determine the effect of murine strain in the model system of myopericarditis. This is particularly true since Balb/c mice, used in the study by Can et  al, have a propensity to develop cardiac calcinosis [7]. Epicardial calcifi- cation was one of the outcomes observed in the vaccinated mice. Calcification of the pericardium is a finding typically ob- served in chronic, constrictive pericardial disease in humans. One of the major conclusions by Can et al relates to differences in the severity of myopericarditis with intravenous in- jection compared with intramuscular that intravenous injection of the vaccine. They dem- onstrated injection of the COVID-19 mRNA vaccine in- creased the severity of vaccine-induced myopericarditis compared with intra- muscular injection. Given the increased following severity of myopericarditis intravenous injection of the vaccine, the authors extend these observations to pro- pose that the rare injection of a vaccine into a vein during planned intramuscular injection could contribute to the onset of myopericarditis. This is a relevant question since it is generally not recom- mended that a person administering the COVID-19 mRNA vaccine aspirate be- fore injecting it into the deltoid muscle. The concern about accidental intra- venous injection during an intended intramuscular injection has been exten- sively studied [8]. Aspiration for a few seconds before injecting the intended drug is a way to avoid accidental intra- venous injection. Most healthcare or- ganizations conclude that the risk of any complication associated with the acci- dental intravenous injection is low since there have not been significant complica- tions when the injection occurs without is often aspiration. Furthermore, pointed out that there are not a plethora of vascular structures in the area of injec- tion in the deltoid muscle. Most organ- izations, such as the Centers for Disease Control and Prevention and the World Health Organization, do not recommend aspiration before injection, citing in- creased pain as a primary reason. it Finally, the data described in the murine model of myopericarditis reinforce the safety of COVID-19 mRNA vaccination. Despite a small difference in weight after vaccination, they report that the mice maintained their healthy appearance and activity with intramuscular or intravenous injection. In addition, even with intra- venous injection and the identification of inflammatory heart disease, there was no report of increased death in the mice reverse during the study. Furthermore, with intra- muscular and intravenous administration of the vaccine, the amount of the mRNA by transcription–polymerase chain reaction in tissue falls precipitously within days of the injection. It is near base- line by 14 days. These findings support the concept that the severe risks of COVID- 19, including the complications of myo- carditis and pericarditis, are far greater than the small risk of myopericarditis after the COVID-19 vaccination. Does accidental intravenous injection of the COVID-19 mRNA contribute to the rare incidence of myopericarditis? The data presented suggest that it is plausible and that it would be appropriate to consider further. However, the rare in- cidence of myopericarditis after vaccin- ation will make it challenging to design a definitive study in humans. Note Potential conflicts of interest. The author: No reported conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Bozkurt  B, Kamat  I, Hotez  PJ. Myocarditis with COVID-19 mRNA vaccines. Circulation 2021; 144:471–84. 2. Montgomery J, Ryan M, Engler R, et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US Military. JAMA Cardiol 2021. doi:10.1001/jamacardio.2021.2833 3. Diaz  GA, Parsons  GT, Gering  SK, Meier  AR, Hutchinson IV, Robicsek A. Myocarditis and pericar- ditis after vaccination for COVID-19. JAMA 2021. doi:10.1001/jama.2021.13443 4. Nicolai  L, Leunig  A, Pekayvaz  K, et  al. Thrombocytopenia and splenic platelet directed immune responses after intravenous ChAdOx1 nCov-19 administration. bioRxiv [Preprint]. June 29, 2021. doi:10.1101/2021.06.29.450356. Available at: https://www.biorxiv.org/content/10.1101/2021.0 6.29.450356v1. Accessed 2 August 2021. 5. Can L. XXX. Clin Infect Dis 2021. 6. Verma  AK, Lavine  KJ, Lin  C-Y. Myocarditis after Covid-19 mRNA vaccination. N Engl J Med 2021. doi:10.1056/NEJMc2109975 7. Glass  AM, Coombs  W, Taffet  SM. Spontaneous cardiac calcinosis in BALB/cByJ mice. Comp Med 2013; 63:29–37. 8. Sepah  Y, Samad  L, Altaf  A, Halim  MS, Rajagopalan N, Javed Khan A. Aspiration in injec- tions: should we continue or abandon the practice? F1000Res 2014; 3:157. 1952 • cid 2022:74 (1 June) • EDITORIAL COMMENTARY