T cell-based therapeutic vaccination is a potential approach to achieving durable control of HIV. It is assumed, but has not been thoroughly evaluated, that inclusion of Env antigens in a therapeutic vaccine may blunt immunologic responses to key conserved Gag and Pol targets. We evaluated the impact of including Env on Gag- and Pol-specific T cell responses in an HIV-1 DNA therapeutic vaccine trial.
We conducted a two-site randomized, blinded, placebo-controlled clinical trial (‘PENNVAX’, NCT03606213) of people with HIV (PWH) on suppressive ART for ?2 years who initiated ART ?6 months after infection. Participants were randomized 1:1:1 to receive DNA vaccine encoding multiclade consensus HIV-1 Gag+Pol (G/P)+IL-12, Gag+Pol+Env (G/P/E)+IL-12, or placebo delivered by intramuscular injection/electroporation, stratified on CD4 nadir (<200 or ?200 cells/mm[sup]3[/sup]) and enrollment site. Vaccine/placebo was administered at Weeks 0, 4, 8, and 12. T cells in peripheral blood mononuclear cells (PBMCs) reactive to vaccine-matched peptide pools or pools spanning highly conserved regions of Gag and Pol were measured pre- and post-vaccination (Week 14) by IFN? ELISpot. Inducible HIV reservoir measurements were evaluated by differentiation quantitative viral outgrowth assay (dQVOA).
Forty-five participants were enrolled, with mean age 51.3 years, 51 (91%) male, 13 (23%) Hispanic/Latinx, and 7 (13%) Black. Vaccination was safe with no unexpected adverse events. Among G/P recipients, median (interquartile range, IQR) fold change (FC) in the magnitude of vaccine-matched Gag- and Pol-specific T cell responses were 2.10 (0.99-3.11; p=0.027) and 2.44 (0.90-3.62; p=0.04), respectively. G/P vaccination also appeared to increase T cell responses to conserved Gag and Pol regions. In contrast, G/P/E vaccination did not significantly increase Gag- or Pol-specific T cell responses. Overall, 62% (8/13) of G/P, 47% (7/15) of G/P/E, and 20% (3/15) of placebo recipients had a ?2-fold increased magnitude of either vaccine-matched Gag- or Pol-specific T cell responses. Vaccination did not impact inducible HIV levels.
We demonstrate that the inclusion of Env sequences in a DNA therapeutic vaccine for HIV hampers enhancement of T cell responses to Gag and Pol in long-term ART-suppressed PWH. While DNA vaccination can boost HIV-specific T cell responses, overall vaccine responses were modest, without impact on the inducible HIV reservoir.