HIV vaccine mimicking the RV144 regimen tightly controls and ablates SHIV BaL.P4 infection in rhesus macaques

Abstract

Abstract The RV144 human HIV-1 vaccine trial provided the first and only immunologic signal to define a correlate of reduced risk. This sole independent correlate of reduced risk of HIV infection among the >150 variables studied, was the level of antibodies (Abs) reactive with the V1V2 region of HIV-1 Envelope protein. We designed vaccine/challenge experiments designed to mimic the RV144 vaccine trial to study the protective effects of vaccine-elicited immune responses in rhesus macaques (RM). Nine RM were co-immunized at weeks 0, 4, 12 and 20 intradermally with gp160 92TH023 and SIV gag DNA via gene gun together with gp120 A244 and MN proteins formulated in Adjuplex. Two weeks after the final immunization, all RM and naïve controls were challenged intrarectally with SHIVBaL.P4. Blood and mucosal secretions were collected weekly. Plasma viral load (PVL) and PBMC-associated VL were significantly different between controls and immunized RM (p=0.0091, p=0.0045, respectively). Time to infection was greater in immunized NHP (p=0.0235, Kaplan Meier). PVL in 5 RM were either undetectable or transient at 102–103 copies/ml. Midpoint titers of anti-V2 plasma binding antibodies (Abs) were ~1 Log10 lower compared to titers against cognate and heterologous gp140 and gp120. The vaccine regimen induced strong Ab responses with neutralizing activity that inversely correlated with VL to tightly control or ablate SHIV infection in 5 of the 9 immunized macaques. At necropsy no virus was detectable in lymphoid tissues. Efficacy based on this outcome is 55%, representing a milestone in pre-clinical vaccine protection. This study provides a strong basis to investigate mechanisms associated with tight viremia control, including antibody Fc-mediated activities.