Biodistribution of mRNA vaccines in rats: Enrichment in injection site and lymph tissues and rapid clearance without tissue persistence

Abstract Messenger RNA (mRNA) vaccines using lipid nanoparticles (LNPs) are well-established and globally approved with acceptable safety profiles for preventing respiratory disease. Other mRNA-LNP product concepts are also emerging as novel treatments for broader clinical use. Here, we describe mRNA-LNP vaccine tissue distribution and kinetics after intramuscular dosing using three products formulated with same LNP matrix: mRNA-1273 (Spikevax™), mRNA-1647 (a candidate cytomegalovirus [CMV] vaccine), and a reporter mRNA (nascent peptide-luciferase) drug product. Consistent biodistribution patterns were observed across studies: tissues with highest exposures were the injection site, draining lymph nodes, and spleen, with minimal distribution to non-lymphoid tissues. Vaccine components cleared rapidly from circulation and tissues, with complete elimination simulated to occur by ∼2 weeks. Following mRNA-1273 vaccination, Spike protein levels were transiently observed (elimination <5 days) and did not accumulate with repeated dosing. The ionizable lipid in the LNP matrix, Lipid H, underwent biotransformation and was excreted renally and hepatically, with no human-specific metabolites. Collectively, these results indicate that the LNP composition, not mRNA cargo, governs biodistribution. Furthermore, in a SARS-CoV-2 infection-free model, there was no evidence of Spike protein persistence. Overall, the data establish a framework that justifies leveraging biodistribution data across products and supports eliminating redundant animal studies. Competing Interest Statement SMGG, CR, YL, and NC are employees of and shareholders in Moderna, Inc.