DNA Priming Increases Frequency of T-Cell Responses to a Vesicular Stomatitis Virus HIV Vaccine with Specific Enhancement of CD8 ⁺ T-Cell Responses by Interleukin-12 Plasmid DNA

Abstract

The HIV Vaccine Trials Network (HVTN) 087 vaccine trial assessed the effect of increasing doses of pIL-12 (interleukin-12 delivered as plasmid DNA) adjuvant on the immunogenicity of an HIV-1 multiantigen (MAG) DNA vaccine delivered by electroporation and boosted with a vaccine comprising an attenuated vesicular stomatitis virus expressing HIV-1 Gag (VSV-Gag). We randomized 100 healthy adults to receive placebo or 3 mg HIV-MAG DNA vaccine (ProfectusVax HIV-1 gag/pol or ProfectusVax nef/tat/vif, env) coadministered with pIL-12 at 0, 250, 1,000, or 1,500 g intramuscularly by electroporation at 0, 1, and 3 months followed by intramuscular inoculation with 3.4 ϫ 10 7 PFU VSV-Gag vaccine at 6 months. Immune responses were assessed after the prime and boost and 6 months after the last vaccination. Highdose pIL-12 increased the magnitude of CD8 ϩ T-cell responses postboost compared to no pIL-12 (P ϭ 0.02), while CD4 ϩ T-cell responses after the prime were higher in the absence of pIL-12 than with low-and medium-dose pIL-12 (P Յ 0.05). The VSV boost increased Gag-specific CD4 ϩ and CD8 ϩ T-cell responses in all groups (P Ͻ 0.001 for CD4 ϩ T cells), inducing a median of four Gag epitopes in responders. Six to 9 months after the boost, responses decreased in magnitude, but CD8 ϩ T-cell response rates were maintained. The addition of a DNA prime dramatically improved responses to the VSV vaccine tested previously in the HVTN 090 trial, leading to broad epitope targeting and maintained CD8 ϩ T-cell response rates at early memory. The addition of high-dose pIL-12 given with a DNA prime by electroporation and boosted with VSV-Gag increased the CD8 ϩ T-cell responses but decreased the CD4 ϩ responses. This approach may be advantageous in reshaping the T-cell responses to a variety of chronic infections or tumors. (This study has been registered at ClinicalTrials.gov under registration no. NCT01578889.)

Safety and tolerability of HIV-1 multiantigen pDNA vaccine given with IL-12 plasmid DNA via electroporation, boosted with a recombinant vesicular stomatitis virus HIV Gag vaccine in healthy volunteers in a randomized, controlled clinical trial

“…The safety and tolerability of the prime-boost vaccine regimen is reported here. Immunogenicity results have been reported in a separate publication [ 34 ].…”

DNA Vaccines—How Far From Clinical Use?

“…For example, IL-12 is produced by activated APC to promote Th1 differentiation, but also stimulates APC themselves [ 94 ]. Accordingly, administration of an IL-12 expression construct in combination with a multigene HIV DNA vaccine by intramuscular electroporation resulted in enhanced antigen-specific CD4 + and CD8 + activation in healthy volunteers [ 95 ]. IL-15 is also released by activated DC, and exerts broad stimulatory effects on effector CD4 + and CD8 + T cells, B cells, NK cells as well as DC [ 96 ].…”

Emerging Concepts and Technologies in Vaccine Development

“…In vivo electroporation (permeabilization of the skin by an electric current to allow plasmid DNA uptake) has thus far been shown to have the highest immunogenicity in multiple small animal models (51,54) and has been tested in two phase I clinical trials for HIV vaccination with some promising results. In the first clinical trial, the immune system was primed with a DNA vaccine encoding the IL12 gene followed by a boost dose with the recombinant VSV-based HIV vaccine (55). The second trial evaluated the cellular immunity induced by HIV DNA vaccines through intramuscular injection administered by electroporation (56).…”