journals.plos.org Abstract
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Citation: Jeon H-E, Lee S, Lee J, Roh G, Park H-J, Lee Y-S, et al. (2024) SARS-CoV2 mRNA vaccine intravenous administration induces myocarditis in chronic inflammation. PLoS ONE 19(10): e0311726. https://doi.org/10.1371/journal.pone.0311726
Editor: Mohammed Misbah Ul Haq, Deccan School of Pharmacy, INDIA
Received: February 3, 2024; Accepted: September 19, 2024; Published: October 10, 2024
Copyright: © 2024 Jeon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: 1. The Ministry of Food and Drug Safety (No. 22213MFDS421, J.H. Nam; 22203MFDS403-1, B.K. Lim). 2. The Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (No. HV22C0160, B.K. Lim) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
1. Introduction
Coronavirus vaccines have been widely used as a critical measure in response to the global coronavirus infection (COVID-19) pandemic. The current COVID-19 mRNA vaccines, including Pfizer-BioNTech and Moderna, were developed and applied for pandemic emerging conditions [1, 2]. These vaccines use a small piece of the virus’s genetic material (mRNA) to stimulate an immune response against COVID-19. This mRNA instructs the cells to produce a harmless piece of the virus called the spike protein. Once the spike protein is produced, the immune system recognizes it as foreign and mounts an immune response by producing antibodies. These antibodies can neutralize the spike protein if the person becomes infected with the virus. The mRNA vaccines effectively prevent COVID-19 infection and severe disease [3, 4]. They have undergone rigorous safety testing and have been authorized for emergency use by regulatory agencies worldwide. Although the mRNA vaccines have been generally well-tolerated, some rare side effects have been reported. However, in recent reported cases, occurrences of cardiac disorders such as myocarditis have been observed following vaccination [5–7]. These side effects have raised concerns about the safety of coronavirus vaccines and highlight the need for further research.
Myocarditis is an inflammation of the heart muscle [8–10]. According to the Centers for Disease Control and Prevention (CDC), cases of myocarditis have occurred more frequently in males under 30 years of age following the second dose of the mRNA vaccines. While the overall incidence of myocarditis following mRNA vaccination is still relatively low, it is important for healthcare providers and the public to be aware of this potential side effect [11–13]. The reason for the increased risk of myocarditis in some individuals is not yet fully understood, and further research is needed to understand this phenomenon better. The risk of myocarditis in the general population has increased after COVID-19 vaccine administration is lower than that caused by SARS-CoV-2 infection [14–16]. Thus, a more comprehensive understanding of the potential risks and underlying mechanisms is needed to provide evidence-based information for facilitating informed decision-making regarding mRNA vaccine administration to this susceptible population [17]. We discuss the possibility of myocarditis as a side effect of coronavirus vaccines. This has become an important issue due to the increasing number of reported cases of myocarditis following vaccination.
We investigate the causes and conditions under which myocarditis can occur. This includes various factors associated with the inflammation of cardiac tissues. In this study, we demonstrated the importance of research on myocarditis related to the side effects of coronavirus mRNA vaccines in the chronic inflammation model. mRNA vaccine intravenous (IV) injection develops myocarditis and pericarditis but is weak from intramuscular (IM) injection. It highlights the need for additional research and response strategies to ensure heart health and safe vaccine administration.
2. Materials and methods
2.1. Preparation of mRNA vaccine
The antigen was designed using a DNA encoding the spike protein of the SARS-CoV-2 Omicron variant. The mRNA vaccine plasmid was produced by inserting the antigen DNA into multiple cloning sites on the mRNA platform. It was produced using the EZ T7 High Yield In vitro Transcription Kit (Enzynomics, Daejeon, Korea), according to the manufacturer’s protocol. Total mRNA was precipitated using lithium chloride and purified using cellulose, which was previously described [18]. mRNA was formulated using NanoAssemblr® IgniteTM (Precision Nanosystems, BC, Canada) by mixing the aqueous and organic solutions at 3:1 and a total flow rate of 10 mL/min. LNPs were formulated using the solution of LNPs [19] and were concentrated by ultrafiltration using Amicon Ultra centrifugal Filter (UFC9030, Merck Millipore, MA, USA) following the manufacturer’s instructions.
2.2. Establishment of the chronic inflammatory mouse model
Male or female Balb/c and C57BL6 mice at the age of 6–8 weeks were obtained from the Dae-Han Bio link Co. (Eum-seong, Korea) and were housed in a controlled environment (inverted 12-h daylight cycle) with free access to food and water. All procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Samsung Biomedical Research Institute (SBRI, #2022032201). SBRI is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International) and abides by the Institute of Laboratory Animal Resources (ILAR) guide. Mice were fed a normal-fat diet (containing 5% fat) and were simultaneously treated with LPS from Escherichia (Sigma, St Louis, MO, USA). The surgical procedure for inserting the osmotic pump followed the previous report. The mice were implanted with an osmotic pump (Alzet model 1004; DURECT Corp., Cupertino, CA, USA) that was filled with either Tween-saline (0.9% NaCl and 0.1% Tween 80 in distilled water, Sigma) normal saline control or LPS diluted in Tween-saline infused at 400 μg/kg/day for 4 weeks (LPS group, n = 5) [20].
2.3. Immunization
The pump-implanted animals were randomly assigned to 6 groups for the administration of intramuscular (IM) or intravenous (IV) SARS-CoV2 mRNA vaccine or normal saline control (Groups: saline, saline pump + mRNA vaccine IM or IV, LPS pump, LPS pump + mRNA vaccine IM or IV, N = 5 each group). The mice were immunized intramuscularly or intravenously with 10 μg of Omicron Spike mRNA vaccines encoding the sequence of spike protein from the SARS-CoV-2 Omicron variant. The mRNA expression platform was previously described [18]. The immunization schedule consisted of two injections: an initial prime injection, followed by a boost injection, with a two-week interval between them. Once the immunization protocol was completed, the mice were euthanized two days post injection (dpi) after immunization and whole blood samples and tissues were collected.
2.4. Histological analysis
The heart and liver tissues of osmotic pump-implanted mice were fixed in 10% neutral formalin. After fixation, these samples were embedded in paraffin and stained with hematoxylin and eosin (H&E). We evaluated the percentage area of myocardial inflammation by computer-assisted analysis. Two different areas of each heart were quantified by ImageJ software1.45s (NIH, MA, USA) as described previously [21]. In addition, the pericarditis was evaluated by individual mouse heart surface inflammation. The procedures were carried out by investigators unaware of the sample identities…
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