DNA vaccines: ready for prime time?

Abstract

Since the discovery, over a decade and a half ago, that genetically engineered DNA can be delivered in vaccine form and elicit an immune response, there has been much progress in understanding the basic biology of this platform. A large amount of data has been generated in preclinical model systems, and more sustained cellular responses and more consistent antibody responses are being observed in the clinic. Four DNA vaccine products have recently been approved, all in the area of veterinary medicine. These results suggest a productive future for this technology as more optimized constructs, better trial designs and improved platforms are being brought into the clinic.

Figure 1. DNA vaccines: optimization strategies to enhance immunogenicity

DNA vaccine technology has been the target of ongoing efforts to optimize the platform to increase antigen expression and vaccine immunogenicity (see main text for a detailed explanation of each step). There are currently several ways in which antigen expression and immunogenicity can be improved for the DNA vaccine platform. These include: optimization of the transcriptional elements on the plasmid backbone (1); strategies to improve protein expression of the gene of interest (2), including factors to avoid (for example, chi-sites, which are sequences that encourage crossing-over to occur at that site); inclusion of formulation adjuvants (3) or immune plasmid adjuvants (4); and the use of next-generation delivery methods (5). Several formulations have been developed and are being testing at all stages of preclinical and clinical development for their ability to enhance antigen expression and immunogenicity. These mechanisms include encapsulation and protection of DNA from extracellular degradation through to particle trapping and high-velocity delivery, with the ultimate goal of introducing the plasmid directly into the cytosol of target cells. In addition, immune adjuvant classes that encode immune modulatory molecules that target death receptors, growth factors, adhesion molecules, cytokines and chemokines as well as Toll receptor ligands exist. It should be noted that many of these plasmid optimization and formulation strategies, as well as the adjuvant systems, are used in combination with novel delivery mechanisms that result in an overall enhanced vaccine platform.