The Safety and Immunogenicity of GTU®MultiHIV DNA Vaccine Delivered by Transcutaneous and Intramuscular Injection With or Without Electroporation in HIV-1 Positive Subjects on Suppressive ART

Abstract

Previous studies have shown targeting different tissues via the transcutaneous (TC) and intramuscular injection (IM) with or without electroporation (EP) has the potential to trigger immune responses to DNA vaccination. The CUTHIVTHER 001 Phase I/II randomized controlled clinical trial was designed to determine whether the mode of DNA vaccination delivery (TC+IM or EP+IM) could influence the quality and function of induced cellular immune responses compared to placebo, in an HIV positive clade B cohort on antiretroviral therapy (ART). The GTU®MultiHIV B DNA vaccine DNA vaccine encoded a MultiHIV B clade fusion protein to target the cellular response. Overall the vaccine and regimens were safe and well-tolerated. There were robust pre-vaccination IFN-γ responses with no measurable change following vaccination compared to placebo. However, modest intracellular cytokine staining (ICS) responses were seen in the TC+IM group. A high proportion of individuals demonstrated potent viral inhibition at baseline that was not improved by vaccination. These results show that HIV positive subjects with nadir CD4+ counts ≥250 on suppressive ART display potent levels of cellular immunity and viral inhibition, and that DNA vaccination alone is insufficient to improve such responses. These data suggest that more potent prime-boost vaccination strategies are likely needed to improve pre-existing responses in similar HIV-1 cohorts (This study has been registered at http://ClinicalTrials.gov under registration no. NCT02457689).

Keywords: HIV-1; electroporation; plasmid DNA; therapeutic vaccine; transcutaneous.

Copyright © 2019 Haidari, Day, Wood, Ridgers, Cope, Fleck, Yan, Reijonen, Hannaman, Spentzou, Hayes, Vogt, Combadiere, Cook, McCormack and Shattock.

Figures

Figure 1

Analysis of IFN-γ responses by ELISpot: (A) Comparison of IFN-ɤ ELISpot responses pre vaccination and at the primary endpoint for all participants (both groups); (B) Comparison of IFN-ɤ response from week 0 to week 14 with all peptide pools together for the EP+IM group (active); (C) Comparison of IFN-ɤ response from week 0 to week 14 with all peptide pools together for the TC+IM group (active) to all peptide pools. Statistical significance is set at p = <0.05 (Wilcoxon matched-pairs signed t test). Each dot joined together by a line is an individual's IFN-ɤ response at week 0 and 14. (D) Scatter dot plot showing baseline IFN-ɤ response at week 0 (pre vaccination) by group. All units are in SFU/M PBMC with background (from negative/mock wells) subtracted. The red dotted line represents the cut off of >55 SFU/M but participants also had to meet the second criteria to be a positive responder (>4 x baseline response if baseline response is more than 0). Viral inhibition assay: (E) IFN-ɤ ELISpot responses to Integrase peptide for both groups receiving active drug at week 0 and week 14. (F) Comparison of viral inhibition (log10) between week 0 and week 14 in the TC+IM group (including placebo). (G) Comparison of viral inhibition between week 0 and week 14 in the EP+IM group (including placebo). The red line represents the cut off for positive inhibition of >1.5 log10. Statistical significance set at p = < 0.05.

Figure 2

ICS analysis of T cell responses to DNA vaccination: (A) CD4+ IFN-ɤ response at primary endpoint (week 14) for all groups to Gag; (B) CD4+ CD154 response at primary endpoint (week 14) for all groups to Rev; (C) CD8+ IFN-ɤ response at primary endpoint (week 14) for all groups to Nef; (D) CD8+ TNF-α response at primary endpoint (week 14) for all groups to Tat; and (E) CD8+ TNF-α response at primary endpoint (week 14) for all groups to Nef. Statistical significance for all result is set at p = <0.05. *p < 0.05, **p <0.01, ***p<0.001.