A Comparison of Plasmid DNA and mRNA as Vaccine Technologies

Liu, Margaret A.

At this stage, it is perhaps useful to review the structure of the mRNA as designed for drug and vaccine delivery, which incorporates elements to improve both stability and protein expression. The mRNA comprises a 5 cap, a 5 untranslated region (UTR) (also called leader RNA), the coding sequence with a stop signal, a 3 UTR, and a poly(A) tail. This molecule provides the template in the cytoplasm of a cell for translation by the ribosome and tRNA into the encoded protein, making multiple copies of the protein from each mRNA template. This amplification provides a quantitative advantage per molecule compared to providing individual proteins. However, offsetting that numeric advantage is that, in addition to the instability of the mRNA, it is thought that only one out of 10,000 molecules of mRNA will escape an endosome into the cytoplasm [5] . The amplification by translation of the mRNA into protein has to overcome the losses and the inefficiencies of degradation and the transduction process. Another obvious implication for this is that, compared to plasmid DNA, which must enter the nucleus of a cell, the mRNA only needs to be present in the cytoplasm, which eliminates the additional cellular (i.e., nuclear) membrane that plasmid DNA needs to cross. On the other hand, plasmid DNA is more stable than mRNA, and each DNA molecule results in the production of multiple mRNA molecules, thus the theoretical advantages of one over the other boil down to the realities of the net stability of plasmid DNA versus mRNA in their final formulation, as well as the efficiencies of targeting to the desired cell, the transduction to the cytoplasm or nucleus followed by the efficiencies of transcription of the plasmid DNA (resulting in amplification from DNA to mRNA), and the translation of mRNA, whether transcribed from DNA or in vitro-transcribed mRNA, to protein (also resulting in amplification).