General
Before 2020,
no mRNA technology platform (drug or vaccine) had been authorized for use in humans, so there was a risk of unknown effects.
[40] The 2020 coronavirus pandemic required faster production capability of mRNA vaccines, made them attractive to national health organisations, and led to debate about the type of initial authorization mRNA vaccines should get (including
emergency use authorization or
expanded access authorization) after the eight-week period of post-final human trials.
[70][71]
Nucleic acid therapeutics have emerged as promising alternatives to conventional vaccine approaches. The first report of the successful use of
in vitro transcribed (IVT) mRNA in animals was published in 1990, when reporter gene mRNAs were injected into mice and protein production was detected
5. A subsequent study in 1992 demonstrated that administration of vasopressin-encoding mRNA in the hypothalamus could elicit a physiological response in rats
6. However, these early promising results did not lead to substantial investment in developing mRNA therapeutics, largely owing to concerns associated with mRNA instability, high innate immunogenicity and inefficient
in vivo delivery. Instead, the field pursued DNA-based and protein-based therapeutic approaches
7,
8.
Over the past decade, major technological innovation and research investment have enabled mRNA to become a promising therapeutic tool in the fields of vaccine development and protein replacement therapy. The use of mRNA has several beneficial features over subunit, killed and live attenuated virus, as well as DNA-based vaccines. First, safety: as mRNA is a non-infectious, non-integrating platform, there is no potential risk of infection or insertional mutagenesis. Additionally, mRNA is degraded by normal cellular processes, and its
in vivo half-life can be regulated through the use of various modifications and delivery methods
9,
10,
11,
12. The inherent immunogenicity of the mRNA can be down-modulated to further increase the safety profile
9,
12,
13. Second, efficacy: various modifications make mRNA more stable and highly translatable
9,
12,
13. Efficient
in vivo delivery can be achieved by formulating mRNA into carrier molecules, allowing rapid uptake and expression in the cytoplasm (reviewed in Refs
10,
11). mRNA is the minimal genetic vector; therefore, anti-vector immunity is avoided, and mRNA vaccines can be administered repeatedly. Third, production: mRNA vaccines have the potential for rapid, inexpensive and scalable manufacturing, mainly owing to the high yields of
in vitro transcription reactions.