Background
CD40.HIVRI.Env is a gp140 Env (Clade C 96ZM65) fused to an anti-CD40 mAb to target CD40-expressing dendritic cells. The ANRS/VRI06 phase I trial (NCT04842682) enrolled 72 non HIV-infected volunteers to receive either 0·3, 1·0, or 3·0 mg of CD40.HIVRI.Env (TLR3-Hiltonol® adjuvanted) alone or co-administered with DNA-HIV-PT123 at weeks (W) 0, 4 and 24, randomized 5:1 active vs. placebo. Results showed good safety and strong immunogenicity of vaccines until W48 regardless dose or combination (Y. Levy et al., eClinicalMedicine, in press).
Methods
Beyond W48 of the trial, active vaccine recipients were again randomized to receive one late boost (LB) of CD40.HIVRI.Env (SC, 0.3mg) either with Hiltonol® (1mg) (V+Adj) or not (V-Adj). Safety and immunogenicity (anti-Env and anti V1/V2 IgG, Neutralizing antibodies (Nabs), T-cell responses) were evaluated at 2 and 24W after LB (LB+02, LB+24).
Results
Forty-five volunteers (mean age 35 years, 56% male) were randomized. Demographics and immune responses were similar between groups at LB visit. LB interval (median; IQR) since VRI06 baseline was 80 W [75;104] in V+Adj (n=22) and 79 W [65;101] in V-Adj (n=23). LB vaccination was safe and well tolerated. IgG response rates (RR) against vaccine-matched (gp140 ZM96) and 9 heterologous gp120/gp140 antigens (Ags) were 50-100% at LB, and 100% and 82-100% at LB+02 and LB+24, respectively. Increases > 1 log10 in the magnitude of IgG responses (MFI) to Ags were observed at LB+02 relative to LB. RR to gp70 V1V2 Ags raised from 0-4% at LB to 45-55% (autologous 96ZM651), 26-27% (92TH02), 61-68% (CE1086), 61-77% (CaseA2) across groups at LB+02. NAb IC50 titers against Tier1 MW965.26 were detected in 14-22% at LB and 78-95% and 35-59% at LB+02 and +24. Frequencies (median [IQR]) of polyfunctional Env-specific CD4 T cells (IL-2+/-IFN-g+/-TNF) were 0.09 [0.05;0.18] at LB and raised to 0.26 [0.15;0.36] and 0.15 [0.11;0.20] at LB+02 and +24, respectively. No consistent substantial differences were noted between Adj+ and Adj- recipients.
Conclusions
Follow-up after initial CD40.HIVRI.Env vaccination showed persistence of immune responses more than one year after the last injection (W26 of the VRI06 trial). A single late boost of CD40.HIVRI.Env, even unadjuvanted, was sufficient to maintain humoral and cellular long-term responses. These results reveal the potency of CD40-DC targeting vaccines to induce durable responses.