Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines

TLDR

mRNA vaccines promise to address unmet medical needs, but effective intramuscular delivery requires improved lipid nanoparticles, as current LNPs were designed for intravenous siRNA and still leave room for better performance. The authors screened proprietary biodegradable ionizable lipids for expression and immunogenicity in rodents after intramuscular injection, then selected a subset for further tolerability, immunogenicity, and expression testing in rodents and non‑human primates. A lead formulation achieved a robust immune response with better tolerability, demonstrating that heightened innate immune stimulation by LNPs does not compromise vaccine potency.

Abstract

mRNA vaccines have the potential to tackle many unmet medical needs that are unable to be addressed with conventional vaccine technologies. A potent and well-tolerated delivery technology is integral to fully realizing the potential of mRNA vaccines. Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses. Despite progress made over the past several years, there remains significant opportunity for improvement, as the most advanced LNPs were designed for intravenous (IV) delivery of siRNA to the liver. Here, we screened a panel of proprietary biodegradable ionizable lipids for both expression and immunogenicity in a rodent model when administered IM. A subset of compounds was selected and further evaluated for tolerability, immunogenicity, and expression in rodents and non-human primates (NHPs). A lead formulation was identified that yielded a robust immune response with improved tolerability. More importantly for vaccines, increased innate immune stimulation driven by LNPs does not equate to increased immunogenicity, illustrating that mRNA vaccine tolerability can be improved without affecting potency.