Not so cold! Improving the thermostability of mRNA vaccines

Abstract

Introduction: One of the biggest challenges in the mRNA-LNP vaccine field is product stabilization to overcome the logistical hurdles linked to the ultra-cold distribution chain associated with first-generation mRNA SARS-CoV-2 vaccines. Despite recent progress in the field, many R&D efforts remain focused on the development of mRNA-LNP vaccines that would be as stable as liquid formulations for storage at refrigerated or room temperatures. Areas covered: After an overview of the underlying mechanisms of mRNA-LNP instability, this review provides an update on the different approaches that are currently explored to improve mRNA-LNP thermostability, encompassing mRNA sequence optimization, nucleotide modification and mRNA-LNP design strategies as well as formulation process optimization. Alternative approaches for mRNA-LNP stabilization such as lyophilization, dual-vial formulations and the replacement of water with deep eutectic solvents in the mRNA-LNP process and products are also discussed. Expert opinion: Achieving robust thermostability of mRNA vaccines will require a multifactorial optimization strategy, integrating advances in sequence engineering, novel formulation designs, buffer composition, excipient selection and manufacturing processes.