A Comparison of Plasmid DNA and mRNA as Vaccine Technologies

Liu, Margaret A.

While both DNA and mRNA vaccines are often thought of as simply an expression system for the desired protein, neither is immunologically inert. Both DNA vectors (which are based on bacterial plasmids) and in vitro transcribed mRNA activate the innate immune system. DNA plasmids do so via their CpG motifs, which stimulate TLR9. While CpG was successfully used as an adjuvant [46] for a recombinant protein-based Hepatitis B vaccine licensed in 2018, the impact on the immunogenicity of DNA vaccines by increasing the number of CpG motifs in the plasmid has been less clear. In fact, for certain DNA vaccine efforts, notably those of Steinman's group, as therapies for autoimmune diseases, they specifically switched CpG motifs for GpG motifs (guanine connected via a phosphodiester bond to another guanine; these compete with CpG motifs for binding to TLR9 receptors) in an effort to specifically decrease the Th1 help for their human clinical studies (see below) [47] . The double-stranded structure of the DNA plasmid is also thought to be an immune stimulant [48] through non-TLR mechanisms. In fact, plasmid DNA also acts on the TBK1-STING pathway through cytosolic receptors [49, 50] . This results in the generation of Type 1 interferons, which then act as adjuvants for the generation of immune responses against the antigen(s) encoded by the plasmid DNA vaccine.