Three decades of messenger RNA vaccine development

Abstract

In the early nineties, pioneering steps were taken in the use of mRNA as a therapeutic tool for vaccination. In the following decades, an improved understanding of the mRNA pharmacology, together with novel insights in immunology have positioned mRNA-based technologies as next-generation vaccines. This review outlines the history and current state-of-the-art in mRNA vaccination, while presenting an immunological view on mRNA vaccine development. As such, we highlight the challenges in vaccine design, testing and administration, key considerations in the design of mRNA-based vaccines and new opportunities that arise when packaging mRNA in nanoparticulate vaccines. Finally, we discuss the mRNA self-adjuvant effect as a critical, but dichotomous parameter that determines the safety, efficacy and strength of the evoked immune response.

mRNA Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection

“…Single-stranded RNA (ssRNA) can trigger the DCs' antiviral activation state through TLR7 and TLR8 recognition during mRNA in vivo transmission [57]. The dsRNA contaminants can also trigger immune activation via TLR3 recognition [19,20]. However, excessive immune response stimulated by mRNA in the cytoplasm would stimulate cells to secrete large amounts of type I IFN and other interferons which can inhibit the translation of mRNA and eventually lead to translational stagnation, RNA degradation, CD8 (cluster of differentiation 8) + T cells activation reduction, and ultimately immune response termination [13,21,58].…”

“…Another unignorable barrier to clinical application of ex vivo-loaded DC mRNA vaccines is that time-and money-consuming production process cannot meet the huge quantity demand of mRNA vaccine for some treatments. Besides, the immune response caused within several hours after mRNA transfection can be lost during the time-consuming in vitro preparation process, leading to reduction of the therapeutic effect of mRNA vaccines [19]. Out of these considerations, diseases that require large amounts of mRNA vaccine treatment in the short term should give preference to delivery systems with a fast production speed.…”

“…Since then, mRNA structure researches and other related technologies have been rapidly developed. Under this condition, several development restrictions stemmed from mRNA instability, high innate immunogenicity, and inefficient in vivo delivery have been mitigated, and now mRNA vaccines have been widely studied in different kinds of diseases ( Figure 1) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. mRNA vaccines have demonstrated many specific advantages that conventional vaccines do not have.…”

“…The in vivo expression of mRNA can also avoid protein and virus-derived contamination [20]. By modifying the mRNA sequence and delivery system, the expression activity and in vivo half-life of mRNA can be effectively regulated [19,21,24]. Thirdly, in comparison with DNA-based vaccines, mRNA vaccines can express target proteins more efficiently because of their expression in the cytoplasm without entering the nucleus [25].…”

“…The market value for the mRNA vaccine field has also increased, reaching up to tens of billions of dollars, which signifies a broad prospect for mRNA-based drugs development, especially mRNA vaccines. In particular, mRNA vaccines have a huge potential on rapidly responding to emerging epidemics, e.g., the global explosion of the coronavirus disease 2019 (COVID- 19), stimulating more interest and research expectations from worldwide scientists [26,27].…”