Establishment of a Mouse Model to Evaluate mRNA Vaccine Safety

ABSTRACT

FDA granted emergency use authorization (EUA) for the world's first mRNA vaccine, developed by Pfizer-BioNTech, in December 2020. As a result, many vaccinated people were protected from the fatality of COVID-19, but some people suffered from various side effects of the mRNA vaccine. The EUA was immediately decided to control COVID-19 pandemic and the deregulation of preclinical safety assessment for mRNA vaccine was inevitable. In preclinical phase, efficacy assessment of several mRNA vaccine candidates has been performed by using COVID-19 mouse infection model. However, the guideline of safety assessment for mRNA vaccine in mice has not yet been established. Therefore, it is necessary to identify mRNA vaccineinduced toxicity and clinical symptoms. In this study, we evaluated the clinical and serologic changes induced by the intramuscular injection of 4 types of mRNA vaccines (100 mug/head) with different compositions (C2/LNP90, C2LNP128, C3LNP90, and C3LNP128) in 6-wk-old male and female ICR mice. Five mice per group, a total of 25 male and female mice, respectively, were used in this study. mRNA vaccines were injected twice at an interval of 2 wk and necropsy was carried out 2 d after secondary injection. CBC, blood chemistry analysis, and visual evaluation of whole-body tissues were performed. The results showed that the body weight was decreased for 2 d after the first injection in C2/LNP128 and C3/LNP128- injected mice compared to vehicle-injected mice, but it was almost recovered at 14 d postinjection (dpi). The endpoint blood and serum analysis demonstrated that C2/LNP128 and C3/LNP128 decreased the number of lymphocyte, monocyte, and reticulocyte carrying the abnormal level of liver function indicator such as albumin, AST, ALT, and total protein. Additionally, C2/LNP128 decreased the number of platelets and C3LNP128 decreased the number of red blood cells, respectively. Spleen and inguinal lymph nodes were enlarged in all experimental groups compared to the control group. Notably, C2/ LNP128 and C3/LNP128 induced severe edema in the injection site, the femoral muscle, that was significantly enlarged. Although more detailed analyses should be carried out, these results suggest that the safety assessment of mRNA vaccines must be systematically established with multiple aspects of toxicology and laboratory animal medicine.