Whitley, J. et al. (2022) Development of mRNA manufacturing for vaccines and therapeutics: mRNA platform requirements and development of a scalable production process to support early phase clinical trials. Transl. Res. 242, 38–55. DOI: 10.1016/j.trsl.2021.11.009
Prior to the implementation of SARS CoV-2 mRNA based-vaccines, there was significant progress made in the research and development of mRNA vaccines against infectious diseases in animal models. These include influenza viruses, Zika virus, rabies virus, and HIV-1. In the past decade, researchers have made improvements to enhance protein translation, modulate immunogenicity, and improve delivery of mRNA therapies and vaccines. . Current methods for developing RNA vaccines use host cell machinery to translate mRNA-encoded target immunogens or therapeutic proteins. These methods also use lipid nanoparticle formulations to successfully deliver mRNAs encoding vaccine antigens or therapeutic proteins, and small interfering RNAs (siRNAs) to the cytosol.
More recently, Pfizer, BioNTech and Moderna vaccines for SARS CoV-2 validated the potential of mRNA-lipid nanoparticle (LNP) technology. However, developing these vaccines also highlighted challenges with clinical-enabling manufacturing processes to produce these products. Current production methods are either larger scale and undisclosed, or bench-scale and unsuitable for early phase clinical studies. As it stands, there is a need for a scalable approach that is affordable and GMP compliant.
This study sought to develop a platform for production that could be used at a lab scale and would fall under GMP conditions for the transition to early phase clinical studies. The methods they developed used non-replicating mRNA technology and incorporated a modified nucleoside. Researchers also optimized 5´ and 3´ UTR sequences, had a defined poly(A) tail length, integrated a cap analogue, and improved codon usage. These changes increased half-life, improved translation efficiency, and enhanced RNA stability and translation. Their scalable process was aqueous-based and easily adaptable to GMP manufacturing, and researchers have developed necessary analytical methods for stability testing, quality control and product characterization. Though the study highlights barriers to distribution, such as a need for long-duration stability, mRNA products have improved much in recent years, and results of this study show products developed with these methods provide good potency and protection in animal models.
Keywords: mRNA vaccine development, scalable vaccine manufacturing, mRNA platform, lipid nanoparticles, early phase clinical study