Clinical Infectious Diseases

E d i t o r i a l C o m m e n ta r y

Insights From a Murine Model of Coronavirus Disease

2019 (COVID-19) mRNA Vaccination-Induced
Myopericarditis: Could Accidental Intravenous Vaccine
Injection Induce Myopericarditis?

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Kirk U. Knowlton
Intermountain Medical Center, Salt Lake City, Utah, USA

(See the Major Article by XXXX).

Keywords. myocarditis; pericarditis; SARS-CoV-2; COVID-19; vaccine.

According to the Johns Hopkins mRNA vaccines produced by Pfizer and been linked to a rare thrombosis with
Coronavirus Resource Center, almost Moderna. The Vaccine Adverse Event thrombocytopenia syndrome. They dem-
212 million people have tested positive Reporting System (VAERS) reported onstrate that intravenous injection of this
for coronavirus disease 2019 (COVID- a rate of 0.41 cases per 100 000 vaccin- vaccine leads to low platelet counts, clot
19) worldwide. This has been associated ations based on voluntary reporting of formation, and platelet activating PF4-
with 4.4 million deaths as of August 2021. events [1]. The rate reported among ac- polyanion antibodies similar to throm-
Severe acute respiratory syndrome cor- tive military was 1.9 cases per 100 000 botic thrombocytopenia.
onavirus 2 (SARS-CoV-2) infection is vaccines [2]. A recent report from a In this issue of Clinical Infectious
often accompanied by relatively high rates large healthcare system used diagnosis Diseases, Can et al [5] have described an
of myocarditis or pericarditis. Fortunately, codes to estimate a rate of 1.0 myocar- important and novel murine model of
almost 5 billion vaccine doses have been ditis cases and 1.9 pericarditis cases per COVID-19 mRNA vaccination with fea-
administered, but large percentages of the 100 000 vaccinations [3]. A common tures of myocarditis and pericarditis—
population have not been partially or fully finding among all reports is that the clin- that is, myopericarditis. This murine
vaccinated. Certain geographic areas, such ical course of vaccine-associated myocar- model has the potential to provide sig-
as Africa, have low vaccine penetration. ditis and pericarditis generally resolves nificant insights into the pathogenesis of
Since vaccination is the key to controlling within days with treatment in most cases. myopericarditis after COVID-19 vaccin-
COVID-19, it is crucial to understand po- It is rarely, if ever, associated with death. ation via intramuscular and intravenous
tential complications of COVID-19 vac- While rare and self-limited, many pa- routes. For example, the authors demon-
cination and the mechanisms by which tients require hospitalization for man- strate in their paper that the inflamma-
they may occur. agement and to ensure no other cause for tion in the myocardium after intravenous
As COVID-19 vaccinations have the clinical presentation. Furthermore, injection of the vaccine consists primarily
been administered to large popula- the presence of any, albeit rare, complica- of CD68+ macrophages or histiocytes,
tions, myocarditis and pericarditis have tion contributes to hesitancy toward vac- but not CD3+ T lymphocytes. In com-
been identified as rare complications of cination in some populations. Therefore, parison, evaluation of tissue from 2 pa-
identifying a model system that clarifies tients suspected to have post–COVID-19
mechanisms that contribute to vaccine- mRNA vaccination–related myocarditis
Received 23 August 2021; editorial decision 25 August
associated myocarditis and pericarditis demonstrated T cells and macrophages,
2021; published online 28 August 2021.
Correspondence: K. U. Knowlton, Intermountain Medical could improve vaccination rates and admixed with eosinophils, B cells, and
Center, Intermountain Heart Institute, 5121 S Cottonwood St, avoid these rare clinical presentations. plasma cells However, the myocarditis in
Salt Lake City, UT 84107 ([email protected]).
For example, in a preprint, Nicolai et al those cases was only temporally associ-
Clinical Infectious Diseases®  2021;XX(XX):1–2
© The Author(s) 2021. Published by Oxford University Press for [4] describe a murine model of an adeno- ated with the vaccine [6]. Since it is not
the Infectious Diseases Society of America. All rights reserved. viral vector vaccine for COVID-19 using common to obtain tissue in post-vaccine
For permissions, e-mail: [email protected].
https://doi.org/10.1093/cid/ciab741 the ChAdOx1 nCov-19 vaccine that has myopericarditis and since causality can be

EDITORIAL COMMENTARY • cid 2021:XX (XX XXXX) • 1

challenging in isolated clinical cases, the injection of the vaccine. They dem- during the study. Furthermore, with intra-
histological information from the mouse onstrated that intravenous injection muscular and intravenous administration
model gives valuable insight into the of the COVID-19 mRNA vaccine in- of the vaccine, the amount of the mRNA
mechanisms of post–vaccine-mediated creased the severity of vaccine-induced by reverse transcription–polymerase
inflammation. Notably, COVID-19–in- myopericarditis compared with intra- chain reaction in tissue falls precipitously
duced murine myocarditis is also associ- muscular injection. Given the increased within days of the injection. It is near base-
ated with macrophage infiltration instead severity of myopericarditis following line by 14 days. These findings support the
of the T-cell infiltration typically associ- intravenous injection of the vaccine, the concept that the severe risks of COVID-
ated with viral myocarditis. Furthermore, authors extend these observations to pro- 19, including the complications of myo-
the data presented document the patterns pose that the rare injection of a vaccine carditis and pericarditis, are far greater
of cytokine induction that occur with into a vein during planned intramuscular than the small risk of myopericarditis after

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COVID-19 vaccination in the mouse and injection could contribute to the onset the COVID-19 vaccination.
the differences that occur over time with of myopericarditis. This is a relevant Does accidental intravenous injection
intramuscular compared with intravenous question since it is generally not recom- of the COVID-19 mRNA contribute to
injection. This murine model will allow mended that a person administering the the rare incidence of myopericarditis?
activation and inhibition of specific pro- COVID-19 mRNA vaccine aspirate be- The data presented suggest that it is
teins in the inflammatory cascade using fore injecting it into the deltoid muscle. plausible and that it would be appropriate
novel therapies or disruption of relevant The concern about accidental intra- to consider further. However, the rare in-
genes through knockout strategies to de- venous injection during an intended cidence of myopericarditis after vaccin-
termine the effect on myopericarditis. intramuscular injection has been exten- ation will make it challenging to design a
It is important to note that future ap- sively studied [8]. Aspiration for a few definitive study in humans.
plications of the murine model system seconds before injecting the intended
Note
will likely require further investigation drug is a way to avoid accidental intra- Potential conflicts of interest. The author:
into how well this model represents the venous injection. Most healthcare or- No reported conflicts of interest. The author has
rare complication of myopericarditis fol- ganizations conclude that the risk of any submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the
lowing COVID-19 mRNA vaccination in complication associated with the acci-
editors consider relevant to the content of the
humans. For example, it is often challen- dental intravenous injection is low since manuscript have been disclosed.
ging to correlate the dose of a drug when there have not been significant complica-
adjusted to body weight between a small tions when the injection occurs without References
1. Bozkurt B, Kamat I, Hotez PJ. Myocarditis with
mouse and a much larger human. In this aspiration. Furthermore, it is often COVID-19 mRNA vaccines. Circulation 2021;
case, the mouse received 0.25 μg per gram pointed out that there are not a plethora 144:471–84.
2. Montgomery J, Ryan M, Engler R, et al. Myocarditis
weight. The Pfizer mRNA vaccine dose in of vascular structures in the area of injec-
following immunization with mRNA COVID-19
humans is 0.4 × 10-3 μg per gram for a tion in the deltoid muscle. Most organ- vaccines in members of the US Military. JAMA
70-kg person. Additional investigation izations, such as the Centers for Disease Cardiol 2021. doi:10.1001/jamacardio.2021.2833
3. Diaz GA, Parsons GT, Gering SK, Meier AR,
will also be needed to determine the effect Control and Prevention and the World Hutchinson IV, Robicsek A. Myocarditis and pericar-
of murine strain in the model system of Health Organization, do not recommend ditis after vaccination for COVID-19. JAMA 2021.
doi:10.1001/jama.2021.13443
myopericarditis. This is particularly true aspiration before injection, citing in- 4. Nicolai L, Leunig A, Pekayvaz K, et al.
since Balb/c mice, used in the study by creased pain as a primary reason. Thrombocytopenia and splenic platelet directed
immune responses after intravenous ChAdOx1
Can et al, have a propensity to develop Finally, the data described in the murine nCov-19 administration. bioRxiv [Preprint]. June
cardiac calcinosis [7]. Epicardial calcifi- model of myopericarditis reinforce the 29, 2021. doi:10.1101/2021.06.29.450356. Available
at: https://www.biorxiv.org/content/10.1101/2021.0
cation was one of the outcomes observed safety of COVID-19 mRNA vaccination.
6.29.450356v1. Accessed 2 August 2021.
in the vaccinated mice. Calcification of Despite a small difference in weight after 5. Can L. XXX. Clin Infect Dis 2021.
the pericardium is a finding typically ob- vaccination, they report that the mice 6. Verma AK, Lavine KJ, Lin C-Y. Myocarditis after
Covid-19 mRNA vaccination. N Engl J Med 2021.
served in chronic, constrictive pericardial maintained their healthy appearance and doi:10.1056/NEJMc2109975
disease in humans. activity with intramuscular or intravenous 7. Glass AM, Coombs W, Taffet SM. Spontaneous
cardiac calcinosis in BALB/cByJ mice. Comp Med
One of the major conclusions by Can injection. In addition, even with intra- 2013; 63:29–37.
et al relates to differences in the severity venous injection and the identification 8. Sepah Y, Samad L, Altaf A, Halim MS,
Rajagopalan N, Javed Khan A. Aspiration in injec-
of myopericarditis with intravenous in- of inflammatory heart disease, there was tions: should we continue or abandon the practice?
jection compared with intramuscular no report of increased death in the mice F1000Res 2014; 3:157.

2 • cid 2021:XX (XX XXXX) • EDITORIAL COMMENTARY