A Comparison of Plasmid DNA and mRNA as Vaccine Technologies

Liu, Margaret A.

Why was there relatively less interest in mRNA compared to plasmid DNA as a platform technology for over a decade? What led to the recent explosion of interest and progress for mRNA? The transient nature of messenger RNA, possibly an asset for the process whereby organisms control the production of desired proteins, is due to RNAses that are widely present [12] . This instability of mRNA has been a significant reason for the lack of interest in mRNA as a drug. In addition, RNA has long been known to be an immunologically active molecule. For example, poly (I:C) (polyinosine-polycytidylic acid) is a synthetic analog of dsRNA (double-stranded RNA) that is an agonist of TLR3 and has long been used as an immunostimulatory mimic of viral infection and tested as an adjuvant to increase immune responses for experimental vaccines [13] [14] [15] . mRNA has a number of immunostimulatory mechanisms, which may be useful-or detrimental-for mRNA used for vaccines or cancer immunotherapeutics (discussed below). However, these properties contributed to the lower degree of interest in mRNA versus plasmid DNA for gene therapy applications when provision of a missing or defective protein with no immune responses against either the protein or the vector delivery system was the goal.