Background
Vaccination to enhance HIV-specific T-cell immunity may be important for HIV cure strategies. GS-1966+GS-1144 is a novel heterologous vaccine regimen comprising GS-1966 (chimpanzee adenovirus vector) and GS-1144 (self-amplifying mRNA-lipid nanoparticle), both encoding a novel conserved HIV-1 immunogen that spans Gag, Pol, and Nef. This regimen was safe and well tolerated in a phase 1b study in virologically suppressed people with HIV on antiretroviral therapy (ART). To better understand the impact of GS-1966+GS-1144 on antigen-specific T-cell quality, we assessed changes in breadth, T-cell phenotype, and polyfunctionality.
Methods
The study included 3 cohorts randomized 2:1 to receive GS-1966+GS-1144 or placebo. Two doses of GS-1966+GS-1144 were evaluated. Cohorts 1 (low dose) and 2 (high dose) received a monovalent HIV-1 immunogen; cohort 3 (high dose) received a bivalent version. Participants maintained ART. T-cell breadth was evaluated by interferon-γ ELISpot assay using 16 peptide mini-pools covering vaccine epitopes. Polyfunctionality was assessed by intracellular cytokine staining and cells were analyzed via LSR flow cytometer and CellEngine software. Antigen-specific polyfunctionality was evaluated for each participant at days 1 and 183 using COMPASS.
Results
Although no significant increase in breadth of the vaccine-specific T-cell response was observed over time or between cohorts, the median number of mini-pool responses was numerically highest for cohort 3 at day 183 (median of 3 for cohort 3 compared with 1.5, 1.0, and 2.0 for placebo, cohort 1, and cohort 2, respectively). GS-1966+GS-1144 induced a CD8+ T-cell dominant response; vaccine-specific CD4+ T cells were also detected. No changes in the frequency of effector memory subsets were observed. COMPASS analysis revealed an increase in polyfunctionality of Gag-specific CD4+ T cells in cohorts 2 and 3, and in Gag-specific CD8+ T cells in cohort 3 at day 183 compared with baseline.
Conclusions
Breadth of the vaccine-specific T-cell response was not significantly different over time or between cohorts. Significant differences in Gag-specific T-cell polyfunctionality were noted for both CD4+ and CD8+ T-cell responses in cohort 3, suggesting that GS-1966+GS-1144 is able to induce highly functional T-cell responses to a key vaccine region. These results expand our understanding of T-cell response quality induced by GS-1966+GS-1144, a novel vaccine regimen for HIV cure.