In early-treated people with HIV (PWH), the HIV-specific T cell response induced by a combination of DNA.HTI (D), MVA.HTI (M) and ChAdOx1.HTI (C) vaccines was associated with longer time off antiretroviral therapy (ART) during analytical treatment interruption (ATI) (AELIX-002; Bailón L et al. Nat Med 2022). AELIX-003 (NCT04364035) was a double-blind, randomized (2:1), multi-center trial, to evaluate the safety, immunogenicity and efficacy of CCMM and the TLR7 agonist vesatolimod (VES) in early-treated PWH.
PWH who started ART within 6 months of infection and had been suppressed on ART for at least one year were randomized 2:1 to receive vaccines and 10 doses of oral vesatolimod 6 mg or placebo while continuing ART (Fig 1). During a 24-week ATI, ART was resumed if plasma viral load >100,000 c/mL, or >10,000 c/mL for 8 weeks, and/or CD4 < 350 cells/µL. INFg ELISpot on cryopreserved PBMC, SIMOA, multiplex cytokine and intact proviral HIV DNA assays were used to evaluate immunogenicity, VES pharmacodynamic (PD) biomarkers and changes in viral reservoir, respectively.
50 participants were enrolled and 47 entered the ATI (CCMM+VES [n=30] or placebo [n=17]). The intervention was well-tolerated with 1 unrelated SAE. Currently available immune data from 31/47 (66%) participants demonstrated strong immunogenicity. The total peak HTI-specific T cell response increased from baseline in the active arm, with median (range) increase of 2474 spot-forming cells (SFC)/106 PMBC (635 to 9310) vs. 610 SFC/106 PMBC (50 to 3645) in the placebo arm, respectively (p=0.001). Compared to AELIX-002, where HTI vaccines were given alone as DDDMM followed by CCM, peak total HTI-specific responses in AELIX-003 were significantly higher (p=0.027). At time of ATI start, a median (range) of 52% (13% to 100%) of the total anti-HIV-1 T-cell response was HTI-specific in the active arm vs 19% (0% to 100%) in the placebo arm (p=0.01). VES increased the production of antiviral cytokines (IFN-a, IL1RA) and chemokines (ITAC) 24h post-dosing. Decay in total and intact HIV proviral DNA from baseline to ATI was similar between arms. Ten out of 30 (33%) participants in the active arm remained off ART for 24 weeks compared to 24% (4/17) in the placebo arm.
In early-treated PWH, HTI vaccines and VES were safe and induced stronger HTI responses than the more complex AELIX-002 vaccine regimen. Mechanism of action and viral outcome correlate analyses are ongoing.
Figure 1 AELIX-003 study design