Although DNA vaccines have considerable potential, this has not been realised primarily due to poor delivery and antigen expression. In addition, they fail to generate a localised inflammatory response, essential for antigen presentation and effective immunity. To address this, we develop an innovative DNA vaccine encoding an immunogen and a cytolytic protein, a mutant form of perforin (PRF), in a bicistronic vector in which the immunogen is expressed in a ratio of 10:1 relative to the PRF. This results in rapid accumulation of the immunogen and slower accumulation of the cytolytic protein that eventually results in necrosis of vaccine-targeted cells. This attracts circulating dendritic cells to the site and results in uptake of the immunogen and damage associated molecular patterns (DAMPs) which act as natural adjuvants. We have shown that this strategy increased the immunogenicity of DNA vaccines which encode HIV- and HCV-specific immunogens, in inbred mice and outbred pigs, and increased protection in mice against challenge with EcoHIV.
These studies were designed to elicit cell mediated immunity (CMI) against capsid or non-structural proteins, but as it is likely that an effective vaccine will also induce humoral responses, we have also induced antibodies against the HIV Tat protein and the HCV envelope proteins E1 and E2 using the IMX313 platform. This approach results in a fusion of the immunogen with the oligomerization domain from the C4 binding protein (C4bp) which is secreted from vaccine targeted cells. This strategy induced anti-Tat neutralizing antibodies and increased the titer of anti-E1/E2 antibodies.
Current studies are designed to induce CMI and humoral responses simultaneously with a DNA vaccine cocktail, and to examine the protective efficacy of these novel approaches.