Carlo Iavarone, Derek T. O’hagan, Dong Yu, Nicolas F. Delahaye & Jeffrey B. Ulmer
To cite this article: Carlo Iavarone, Derek T. O’hagan, Dong Yu, Nicolas F. Delahaye & Jeffrey
B. Ulmer (2017) Mechanism of action of mRNA-based vaccines, Expert Review of Vaccines, 16:9,
871-881, DOI: 10.1080/14760584.2017.1355245
Live attenuated vaccines have had a substantial impact on human health. However, these vaccines have limitations, such as risk of reversion to virulence and complicated cell- based production processes, which hamper their use against certain pathogens. A more recent approach has been to use individual subunit antigens derived from the pathogen to focus immune responses only against the relevant targets. In general, though, subunit vaccines are less potent and require adjuvants to enhance immune responses. In addition, these vaccines are not effective at eliciting CD8T cell responses in humans, which are important for clearing infections and era- dication of tumors. These limitations have provided the impetus to investigate other vaccine strategies . Nucleic acid-based vaccines represent an attractive alternative to live attenuated and subunit-based vaccines, due to their capacity to triggering both antibody-mediated and cell-mediated immunity, as well as offering the potential for low-cost and simplified production processes .
During the 1990s, the genomic era triggered the expansion of the nucleic acid vaccination strategies; pioneers in this area were Wolff and colleagues  who demonstrated that injec- tion of plasmid DNA (pDNA) or mRNA encoding for reporter genes resulted in local production of protein in myocytes. Subsequently, several reports demonstrated that the immuni- zation with nucleic acids was able to elicit immune responses against the encoded antigens [3–6]. Most ensuing publications focused on the use of pDNA vaccines, but in 1996 Boczowski and coworkers  showed that murine dendritic cells (DCs) pulsed with in vitro transcribed ovalbumin (OVA) mRNA, deliv- ered with N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethylammo- nium methyl-sulfate (DOTAP), were capable of presenting antigen in vitro as well as in vivo, thereby ushering a new cell-based approach to immunotherapy.
More recently, mRNA-based vaccines have been investigated extensively in animal models of infectious and noninfectious dis- ease, and several are in clinical development. Like viral vectors and pDNA vaccines, mRNA-based vaccines can induce both humoral and cellular immunity, but may avoid some of their limitations such as anti-vector immunity and potential integration into the host cell genome. In addition, antigen expression after mRNA vaccination is transient, thereby avoiding T cell exhaustion that may occur with persistent antigen exposure . Finally, RNA func- tions in the cytoplasm and does not need to enter the nucleus of target cells; hence the efficiency of functional cellular delivery of mRNA is likely to be higher . Recent publications have provided insight on mRNA vac- cines innovations [9,10], with particular attention to self-ampli- fying alphavirus RNA vaccines [11,12] and a broad overview on clinical development .
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