The promise of mRNA vaccines: a biotech and industrial perspective

Abstract

mRNA technologies have the potential to transform areas of medicine, including the prophylaxis of infectious diseases. The advantages for vaccines range from the acceleration of immunogen discovery to rapid response and multiple disease target manufacturing. A greater understanding of quality attributes that dictate translation efficiency, as well as a comprehensive appreciation of the importance of mRNA delivery, are influencing a new era of investment in development activities. The application of translational sciences and growing early-phase clinical experience continue to inform candidate vaccine selection. Here we review the state of the art for the prevention of infectious diseases by using mRNA and pertinent topics to the biotechnology and pharmaceutical industries.

Keywords: Infectious diseases; Vaccines.

Fig. 1. Two categories of mRNA constructs are being actively evaluated.

Non-replicating mRNA (NRM) constructs encode the coding sequence (CDS), and are flanked by 5′ and 3′ untranslated regions (UTRs), a 5′-cap structure and a 3′-poly-(A) tail. The self-amplifying mRNA (SAM) construct encodes additional replicase components able to direct intracellular mRNA amplification. (1) NRM and SAM are formulated in this illustration in lipid nanoparticles (LNPs) that encapsulate the mRNA constructs to protect them from degradation and promote cellular uptake. (2) Cellular uptake of the mRNA with its delivery system typically exploits membrane-derived endocytic pathways. (3) Endosomal escape allows release of the mRNA into the cytosol. (4) Cytosol-located NRM constructs are immediately translated by ribosomes to produce the protein of interest, which undergoes subsequent post-translational modification. (5) SAM constructs can also be immediately translated by ribosomes to produce the replicase machinery necessary for self-amplification of the mRNA. (6) Self-amplified mRNA constructs are translated by ribosomes to produce the protein of interest, which undergoes subsequent post-translational modification. (7) The expressed proteins of interest are generated as secreted, trans-membrane, or intracellular protein. (8) The innate and adaptive immune responses detect the protein of interest.

Fig. 2. Critical quality attributes (CQAs) have been identified that dictate the performance of the mRNA construct to express the gene of interest efficiently.

Five principal CQAs include 5′ capping efficiency and structure; UTR structure, length, and regulatory elements; modification of coding sequence; poly-A-tail properties; mRNA purity.