Background:
RV144 study identified anti-HIV Env V1/V2 binding IgG and Env-specific CD4 T cells as immune correlates of protection. We tested here a new way of antigen (Ag) delivery to improve vaccine immunogenicity by targeting Ag to CD40-expressing dendritic cells. CD40.HIVRI.Env vaccine is a fully humanized mAb fused to Clade C ZM96 Env. We hypothesized that administration of different doses of CD40.HIVRI.Env vaccine adjuvanted with TLR3 Poly-ICLC Hiltonol® will be safe and immunogenic.
Methods:
VRI06 is a first-in-human phase I, placebo-controlled, dose-escalation trial (NCT04842682) in France and Switzerland. Twelve healthy volunteers were included per group (randomized 5:1 active vs. placebo) to receive either 0.3, 1, or 3 mg CD40.HIVRI.Env SC with Hiltonol® (1mg) at weeks (W) 0, 4 and 24. Safety, immunogenicity (anti-Env and anti V1/V2 IgG assessed by binding antibody multiplex assay, Neutralizing Abs (nAbs), IgG functionality, T-cell responses) were evaluated at W6, W26 and W48.
Results:
Thirty-six volunteers were enrolled (mean 34 years, 64% male). Vaccine was safe and well tolerated. Two SAE were not related to vaccination. IgG response rates (RR) against vaccine-matched (gp140 ZM96) and 6 mismatched gp140 and gp120 were 80-100% at W6 and 100% at W26 across groups. Magnitude of IgG responses (MFI) to Ags was high at all time points, peaked at W6 and/or W26 across groups (Figure) and remained flat or decreased slightly at W48. At W26, the RR to heterologous V1V2 Ags ranged from 60-100% (92TH02), 70-80% (CE1086), 50-100% (CaseA2) across groups. IgG3 anti-Env and V1/V2 response kinetics were similar, although lower than total IgG. nAb IC50 titers against Tier1 MW965.26 were detected in 50 (0.3 mg group) and 100% (1 and 3 mg groups) vaccinees at W26. Polyfunctional Env-specific CD4 T cells (IL-2+ or IFN-g+ or TNF-α+) were detected in all vaccinees at all time points. At W26, median (%) [IQR]) were 0.14 [0.12-0.23]; 0.3 [0.19-0.44]; 0.4 [0.32-0.53] in 0.3, 1, 3 mg groups, respectively (P< 0.05 for all comparisons to W0).
Conclusions:
CD40.HIVRI.Env was safe and induced early, potent and durable anti-Env and V1/V2 IgG and polyfunctional CD4 T-cell responses, markers associated with reduced risk of infection in RV144. Co-administration of CD40.HIVRI.Env with DNA HIV-PT-123 is currently assessed in additional groups of the trial. CD40-DC targeting Env-based vaccines may be instrumental in strategies combining vaccine regimens, particularly Env protein-based vaccines, to induce durable responses.
Magnitude of IgG responses across groups and time points