Safety and Comparative Immunogenicity of an HIV-1 DNA Vaccine in Combination with Plasmid Interleukin 12 and Impact of Intramuscular Electroporation for Delivery

TLDR: This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans by using electroporation after PV administration to provide immunogenicity superior to that observed in the trial without Electroporation, despite fewer vaccinations.

Abstract: DNA-based immunization offers several advantages [1]. DNA vaccines contain nonliving, nonreplicating, and nontransmissible material, providing an improved safety profile over live attenuated viral vectors. They do not elicit antivector immunity, retaining potency through multiple boost cycles. In theory, DNA vaccines are simple and relatively inexpensive to construct, readily produced in large quantities, easy to characterize, and stable and can be combined into complex formulations. Despite the early enthusiasm from results of studies in small animals, DNA vaccines have not generated robust immune responses in humans [2–6]. The amount of antigen produced by each transfected cell is low because of the low transcription rate of antigen sequences being driven off the cytomegalovirus promoter [7–9]. One approach to augment the immunogenicity of DNA is to combine the DNA vaccine with a plasmid cytokine adjuvant [10–13]. Interleukin 12 (IL-12) is a key cytokine for the induction of cellular immune responses [14, 15]. Interleukin 15 (IL-15) is a member of the common cytokine receptor γ-chain family [16–18] that fosters development of long-lived memory T-cell responses [19–21]. A newer strategy for increasing immune potency has been to deliver the plasmids with in vivo electroporation. Electroporation enhances uptake of DNA into cells by temporarily generating an electrical field that increases the permeability of cell membranes and moves the macromolecules through the briefly open membrane pores. Clinical applications of electroporation have been tested, especially in cancer treatment and gene therapy [22–24]. Electroporation has elicited HIV-specific cellular immune responses in mice [25] and simian immunodeficiency virus–specific immune responses in macaques [26]. In macaque studies, genetic optimization, electroporation, and IL-12 plasmid adjuvant have improved the immunogenicity of DNA vaccines in vivo [26]. More recently, Vasan et al reported on a trial that showed the potential to increase vaccine-induced cellular responses to a DNA vaccine relative to intramuscular injection alone [27]. However, electroporation remains investigational [28] and has not been licensed by the Food and Drug Administration for clinical use. This is the first report on the combination of these approaches in humans. Here, we summarize the results of 2 trials of an HIV plasmid DNA vaccine, PENNVAX®-B (PV), one investigating HIV consensus clade B Gag, Pol, and Env with IL-12 or IL-15 plasmid cytokine adjuvants delivered by intramuscular injection without electroporation (HIV Vaccine Trials Network [HVTN] study 070) and the other investigating the same vaccine with plasmid IL-12 delivered intramuscularly with electroporation (HVTN study 080). The results illustrate the power of these combined DNA approaches to generate impressive immune responses in humans.