Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines

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Abstract
Nucleic acid-based vaccines are being developed as a means to combine the positive attributes of both live-attenuated and subunit vaccines. Viral vectors and plasmid DNA vaccines have been extensively evaluated in human clinical trials and have been shown to be safe and immunogenic, although none have been licensed for human use. More recently, mRNA-based vaccine alternatives have emerged and might offer certain advantages over their DNA-based counterparts. This review describes the two main categories of mRNA vaccines: conventional non-amplifying and self-amplifying mRNA. It summarizes the initial clinical proof-of-concept studies and outlines the preclinical testing of the next wave of innovations for the technology. Finally, this review highlights the versatile functionality of the mRNA molecule and introduces opportunities for future improvements in vaccine design. The prospects for mRNA vaccines are very promising. Like other types of nucleic acid vaccines, mRNA vaccines have the potential to combine the positive attributes of live attenuated vaccines while obviating many potential safety limitations. Although data from initial clinical trials appear encouraging, mRNA vaccines are far from a commercial product. These initial approaches have spurred innovations in vector design, non-viral delivery, large-scale production and purification of mRNA to quickly move the technology forward. Some improvements have already been tested in preclinical models for both prophylactic and therapeutic vaccine targets and have demonstrated their ability to elicit potent and broad immune responses, including functional antibodies, type 1 T helper cells-type T cell responses and cytotoxic T cells. Though the initial barriers for this nucleic acid vaccine approach seem to be overcome, in our opinion, the future and continued success of this approach lies in a more extensive evaluation of the many non-viral delivery systems described in the literature and gaining a better understanding of the mechanism of action to allow rational design of next generation technologies.