A Comparison of Plasmid DNA and mRNA as Vaccine Technologies

Liu, Margaret A.

For DNA vaccines, despite the ease with which preclinical studies demonstrated efficacy for a variety of disease models, the potency in humans proved generally disappointing. This led to a number of approaches to increasing the potency by increasing the amount of protein produced through redesigns of the plasmid. Additionally, adjuvants and other immunostimulants were included (such as cytokines and co-stimulatory molecules) either as recombinant proteins or encoded by plasmid DNA, by various formulations and delivery devices, and by strategies such as prime-boost combinations (generally using plasmid DNA as a prime followed by a heterologous boost with a viral vector or protein). The DNA plasmids themselves were optimized by trying different promoters, adding CpG motifs, (cytosine connected via a phosphodiester bond to guanine-such CpG motifs are pathogen-associated molecular patterns) (see below), codon optimization, etc. As noted above, the initial work by Felgner [6] demonstrated that the expression of protein encoded by plasmid DNA was highest in muscle following intramuscular injection versus expression in other tissues after intravenous or subcutaneous injection. Likewise, immune responses were highest with direct i.m. syringe injection of naked plasmid DNA rather than via intravenous (i.v.), intradermal (i.d.), or subcutaneous (s.c.) injections [7] . Early delivery devices for plasmid DNA included a biolistics gene gun that propelled DNA-coated gold particles into cells [32] . In addition to simple i.m. injection, approaches now include pressurized devices (such as the Biojector® or Stratis®), or electroporation, which supplies an electric current to cause temporary fenestration of membranes to increase the passage of plasmid into the cells and the nuclei.