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- Title
Nonclinical safety assessment of an mRNA Covid‐19 vaccine candidate following repeated administrations and biodistribution.
- Authors
Broudic, Karine; Laurent, Sébastien; Perkov, Vladimir; Simon, Charlene; Garinot, Marie; Truchot, Nathalie; Latour, Julie; Désert, Paul
- Abstract
Messenger RNA (mRNA) vaccines have demonstrated efficacy against Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) in humans. mRNA technology holds tremendous potential for rapid control and prevention of emergencies due to its flexibility with respect to production, application, and design for an efficacious and safe use in humans. We assessed the toxicity and biodistribution of MRT5500, an mRNA vaccine encoding for the full‐length of the SARS‐CoV‐2 spike protein and delivered by lipid nanoparticles (LNPs) containing a novel ionizable lipid, Lipid‐1 in preclinical animal models. In the repeated dose toxicity study, rabbits received three intramuscular (IM) injections of MRT5500 at 3‐week interval followed by a 4‐week observation period. In an exploratory biodistribution study in mice receiving a single IM injection of an mRNA encoding luciferase encapsulated in an LNP containing Lipid‐1, the expression of the luciferase protein was monitored in vivo and ex vivo at several time points. In the regulatory biodistribution study in rabbits receiving a single IM injection of MRT5500, the quantification of the mRNA and the ionizable Lipid‐1 were monitored in the same organs and time points as in the exploratory biodistribution study. MRT5500 was safe and well‐tolerated with a transient acute phase response/inflammation and an expected vaccine‐related immunological response, typical of those observed following a vaccine administration. The biodistribution data demonstrated that the mRNA and Lipid‐1 components of the vaccine formulations were mainly detected at the injection site and in the draining lymph nodes. These results support the use of MRT5500 and its deployment into clinical trials. Toxicity and biodistribution of MRT5500, a new Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) mRNA vaccine, were evaluated in three preclinical studies. In the repeated dose toxicity study, three intramuscular injections of MRT5500 at 3‐week interval were well‐tolerated and resulted in transient and nonadverse changes that were indicative of a transient acute phase response/inflammation and consistent with expected immunological responses. In the biodistribution studies, MRT5500 was mainly detected at the injection site and in draining lymph nodes.
- Subjects
SARS-CoV-2; COVID-19 vaccines; ACUTE phase reaction; MESSENGER RNA; INTRAMUSCULAR injections
- Publication
Journal of Applied Toxicology, 2024, Vol 44, Issue 3, p371
- ISSN
0260-437X
- Publication type
Article
- DOI
10.1002/jat.4548