Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys

Abstract

Preclinical studies of viral vector-based HIV-1 vaccine candidates have previously shown partial protection against neutralization-resistant virus challenges in rhesus monkeys. In this study, we evaluated the protective efficacy of adenovirus serotype 26 (Ad26) vector priming followed by purified envelope (Env) glycoprotein boosting. Rhesus monkeys primed with Ad26 vectors expressing SIVsmE543 Env, Gag, and Pol and boosted with AS01B-adjuvanted SIVmac32H Env gp140 demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIVmac251 challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. These data demonstrate robust protection by Ad/Env vaccines against acquisition of neutralization-resistant virus challenges in rhesus monkeys.

Figure 1. Humoral immune responses elicited by the Ad26/Env SIV vaccine

(A) SIVmac239 Env-specific ELISA titers at weeks 0, 4, 28, 64, and 96. Mean log endpoint ELISA titers are shown. (B–G) Multi-dimensional systems serology analysis integrating 150 antibody Fc parameters per animal demonstrates differences in antibody Fc profiles. (B) Principal component analysis (PCA) of antibody Fc profiles from animals immunized with Ad/Env (red) or Ad Alone (blue) vaccines. (C) Loadings plot mirrors the multidimensional space in the PCA but shows the distribution of all measured Fc features, demonstrating the features that drove the separation of antibody profiles (red arrows). (D) Partial least squares discriminant analysis (PLSDA) of antibody profiles from Ad/Env and Ad Alone vaccinees. (E) Univariate analyses of antibody functions identified in (D). A composite (F) dot plot and (G) pie chart show the overall functionality of antibody responses elicited by the Ad/Env and the Ad Alone vaccines. Error bars reflect s.e.m. P-values reflect Mann-Whitney tests.

Figure 2. Protective efficacy of the Ad26/Env SIV vaccine against repetitive, intrarectal SIVmac251 challenges

(A) Number of challenges required for acquisition of infection in each vaccine group. (B) Statistical analyses include the hazard ratio with 95% confidence interval and the per exposure reduction of acquisition risk in each group, with P-values reflecting Cox proportional hazard models and log-rank tests. Additional statistical analyses include the percentage of completely protected animals at the end of the challenge series, with P-values reflecting chi-square tests and Fisher’s exact tests. (C) Correlation of log ELISA titers and antibody Fc polyfunctionality at week 64 with the number of challenges required to establish infection. The plotted data reflect only vaccinated animals and do not include the sham controls. Values plotted as >6 challenges reflect animals that remained uninfected. P-values reflect Spearman rank-correlation tests. (D) Plasma SIV RNA copies/ml over time in infected and protected animals in each vaccine group. Red asterisks indicate elite controllers. + indicates mortality.

Figure 2. Protective efficacy of the Ad26/Env SIV vaccine against repetitive, intrarectal SIVmac251 challenges

(A) Number of challenges required for acquisition of infection in each vaccine group. (B) Statistical analyses include the hazard ratio with 95% confidence interval and the per exposure reduction of acquisition risk in each group, with P-values reflecting Cox proportional hazard models and log-rank tests. Additional statistical analyses include the percentage of completely protected animals at the end of the challenge series, with P-values reflecting chi-square tests and Fisher’s exact tests. (C) Correlation of log ELISA titers and antibody Fc polyfunctionality at week 64 with the number of challenges required to establish infection. The plotted data reflect only vaccinated animals and do not include the sham controls. Values plotted as >6 challenges reflect animals that remained uninfected. P-values reflect Spearman rank-correlation tests. (D) Plasma SIV RNA copies/ml over time in infected and protected animals in each vaccine group. Red asterisks indicate elite controllers. + indicates mortality.

Figure 3. Tissue analyses and adoptive transfer studies in SIVmac251 challenged animals

(A) Ultrasensitive SIV DNA and SIV RNA assays in multiple tissues from one elite controller (red) and the 8 apparently completely protected monkeys (black) following necropsy. SIV copies/10⁸ cell equivalents are shown. (B) Plasma SIV RNA copies/ml in previously naïve recipient monkeys following adoptive transfer of 60 million peripheral blood and lymph node mononuclear cells from the 2 elite controllers (red) or the 8 apparently completely protected monkeys (black). Only one week of follow-up was available for one of the protected animals.

Figure 4. Protective efficacy of the Ad/Env HIV-1 vaccine against repetitive, intrarectal SHIV-SF162P3 challenges

(A) Number of challenges required for acquisition of infection in each vaccine group. (B) Statistical analyses include the hazard ratio with 95% confidence interval and the per exposure reduction of acquisition risk in each group, with P-values reflecting Cox proportional hazard models and log-rank tests. Additional statistical analyses include the percentage of completely protected animals at the end of the challenge series, with P-values reflecting chi-square tests and Fisher’s exact tests.