Background:  Almost 2 decades ago, it was first demonstrated that the direct injection of a plasmid DNA vaccine encoding a foreign antigen resulted in plasmid uptake, protein expression, and the induction of an antigen-specific cellular and humoral immune response. In the interim, the ability of DNA vaccine-elicited immune responses to protect against viral and bacterial infections, parasites, cancers, and autoimmune diseases has been well-documented in numerous animal models.  Phase I human clinical trials have shown that experimental DNA vaccines are safe and well tolerated, however, these preliminary studies indicate that measures must be taken to improve vaccine immunogenicity. Over the last decade, a wide variety of approaches have been taken to augment and modulate the immunogenicity and efficacy of plasmid DNA vaccines. These approaches have included the identification of improved promoter-enhancer elements, targeting pDNA vaccines to antigen-presenting cells (APC), enhancing foreign antigen transcription and translation, targeting the expressed foreign antigen to APC, enhancing foreign antigen processing and MHC-restricted presentation through ubiquitination, and targeting to the proteosome. One particularly promising approach to improve the immunogenicity of DNA vaccines is through the co-delivery of cytokine expression plasmids as genetic adjuvants.  Studies in a variety of animal models clearly demonstrate that plasmid DNA encoded immunomodulatory cytokines (interleukin [IL] -12, IL-15) not only alter the magnitude and direction of the DNA vaccine-elicited immune response, but can also improve vaccine efficacy. These studies suggest that the use of immunomodulatory cytokines with plasmid DNA vaccines may allow clinicians to tailor the resulting immune response to more closely resemble the correlates of protection for a given pathogen. Another approach to improve the immunogenicity of DNA vaccines is through the optimization of in vivo pDNA delivery. Recently, in vivo electroporation, ie, the application of short electrical pulses, has been shown to enhance gene delivery and dramatically improve the induction of vaccine antigen-specific cell-mediated and humoral immune responses.

Conclusions:  Collectively, improved pDNA expression vectors, co-delivery of plasmid-based immunomodulators and improved DNA delivery bring the field closer to the design and development of an efficacious DNA vaccine for the prevention and treatment of HIV-1 infection.