Therapeutic efficacy of combined active and passive immunization in ART-suppressed, SHIV-infected rhesus macaques

Abstract

The latent viral reservoir is the critical barrier for developing an HIV-1 cure. Previous studies have shown that therapeutic vaccination or broadly neutralizing antibody (bNAb) administration, together with a Toll-like receptor 7 (TLR7) agonist, enhanced virologic control or delayed viral rebound, respectively, following discontinuation of antiretroviral therapy (ART) in SIV- or SHIV-infected rhesus macaques. Here we show that the combination of active and passive immunization with vesatolimod may lead to higher rates of post-ART virologic control compared to either approach alone. Therapeutic Ad26/MVA vaccination and PGT121 administration together with TLR7 stimulation with vesatolimod resulted in 70% post-ART virologic control in SHIV-SF162P3-infected rhesus macaques. These data suggest the potential of combining active and passive immunization targeting different immunologic mechanisms as an HIV-1 cure strategy.

Fig. 1. SHIV plasma virus became fully suppressed in all macaques during ART administration.

a Study schematic. b SHIV viral loads from infection to cessation of ART with the median viral load of each group indicated by a red line.

Fig. 2. Induction of immune responses to treatment interventions.

a Vaccination significantly and durably increased the size of SHIV-specific cellular immune IFN-γ responses over time in comparisons with pre-vaccination responses (“Pre”, week 24). Mean ± standard error is shown. b Vaccination significantly increased the breadth of SHIV-specific cellular immune IFN-γ responses in comparison to sham treatment. Means and standard errors are shown. c Vaccination significantly increased antibody binding to clade C and mosaic (mosaic 1) HIV-1 Env with median indicated. Two-sided Mann–Whitney tests were used to determine significance in non-paired analyses (a, c), and two-sided Wilcoxon matched-pairs sign rank tests were used in paired analyses (b). Sham = sham treatment; ‘bNAb’ or ‘PGT121 + VES’ = PGT121 + vesatolimod treatment; ‘Vax’ or ‘Ad26/MVA + VES’ = Ad26/MVA + vesatolimod treatment; and ‘bNAb + Vax’ or ‘Ad26/MVA + PGT121 + VES’ = Ad26/MVA, PGT121, + vesatolimod treatment. *p < 0.05 (in a, from left to right, p = 0.184 and 0.0339 for Sham; in c, p = 0.0465 in Clade C and 0.0489 in Mosaic M), **p < 0.01 (in a, from left to right, p = 0.0072 and 0.0016 for Sham, 0.0024 and 0.0068 for bNAb, and 0.002 for bNAb + Vax; in c, p = 0.0013), ***p < 0.001 (in a, from left to right, p = 0.005 for Sham, 0.0005 for all Vax, and 0.001 for bNAb + Vax from weeks 28 to 50; in c, p = 0.0008), ****p < 0.0001.

Fig. 3. The combination of vesatolimod, Ad26/MVA, and PGT121 treatment resulted in the fewest viremic animals post-ART cessation.

Plasma SHIV viral loads from the cessation of ART to day 168 with the median viral load of each group indicated by a red line. The number and percentage of animals in each group that rebounded are indicated below the group label, and the number of animals in the group with a negative viral load at the end of the surveillance period is indicated in the lower right corner of each graph.

Fig. 4. All treatment interventions reduced post-treatment interruption viral loads.

a Treatment interventions induced significantly lower setpoint viral loads as compared to sham (left). There was no association of virologic control with pre-ART peak viral loads in the Ad26/MVA vaccinated animals (right). Two-sided Mann–Whitney tests used to determine significance. b PGT121 treatment significantly delayed viral rebound. The Kaplan–Meier plot shows the significant difference between the PGT121 groups and sham group, determined via the Mantel-Cox log-rank test (PGT121, χ² = 14.37, p = 0.0001; Ad26/MVA + PGT121, χ² = 14.85, p = 0.0001). The dot-plot visualizes the days to rebound (median indicated in red). Two-sided Mann–Whitney tests used to determine significance. Sham = sham treatment; PGT121 + VES = PGT121 + vesatolimod treatment; Ad26/MVA + VES = Ad26/MVA + vesatolimod treatment; and Ad26/MVA + PGT121 + VES = Ad26/MVA, PGT121, + vesatolimod treatment. Horizontal red lines indicate median values. ***p < 0.001 (in a, p = 0.0008; in b, p = 0.0002), ****p < 0.0001.