PS 2-3 : DNA Vaccine Encoding HCV Nonstructural Proteins Enhances Virus-Specific Cellular Immune Responses in Patients with Chronic Hepatitis C

Aims: Although direct-acting antivirals (DAA) are successfully used for the treatment of chronic hepatitis C, there are DAA-resistant cases. Furthermore, DAA-treated patients do not develop protective immunity against HCV re-infection. To complement DAA therapy, we developed a DNA vaccine (VGX- 6150) containing three plasmids encoding HCV genotype 1 NS3, NS4 and NS5A consensus immunogens and plasmid encoding IL-28B as a molecular adjuvant. In the present study, we performed a phase I clinical trial of VGX-6150 in patients with chronic hepatitis C (n=18) who had failed interferon (IFN)-based treatment. Methods: VGX-6150 was administered 4 times in 4-week intervals with in vivo electroporation to three groups of patients (n=6 for 1, 3, and 6 mg/dose groups, respectively) followed by a 6 mg boost 24 weeks later. Significant side effects were not reported. Cellular immune responses of peripheral blood mononuclear cells (PBMCs) were evaluated by IFN-g ELISpot assays using overlapping peptides spanning NS3~NS5A and staining with HCV-specific HLA class I pentamers. Results: The IFN-g spot number specific to NS3~NS5A was increased in 3 and 6 mg/dose groups after the initial vaccination and in all three groups after the boosting vaccination. However, the frequency of HCV-specific HLA class I pentamer+ CD8+ T-cells was not increased by the vaccination. Moreover, the frequency of PD-1+ cells in the gate of HLA class I pentamer+ CD8+ T-cells was not changed by the vaccination. Interestingly, the frequency of CD4+CD25+Foxp3+ regulatory T-cells (Treg) was significantly decreased after the vaccination, consistent with a previous report regarding the effect of an IL-28B-encoding plasmid adjuvant. Conclusions: In the present study, we demonstrate that VGX- 6150 enhances HCV antigen-specific T-cell responses without significant side effects. The inclusion of IL-28B as an immune adjuvant was associated with a decrease in Treg cells that may have provided greater immune activation in chronic HCV infec-tion.