Early CD4+ T Cell Responses Are Associated with Subsequent CD8+ T Cell Responses to an rAd5-Based Prophylactic Prime-Boost HIV Vaccine Strategy

Abstract

Introduction: Initial evaluation of a candidate vaccine against HIV includes an assessment of the vaccine's ability to generate immune responses. However, the dynamics of vaccine-induced immune responses are unclear. We hypothesized that the IFN-γ producing cytotoxic CD8+ (CD8+ IFN-γ+) T cell responses could be predicted by early IL-2 producing CD4+ (CD4+ IL-2+) helper T cell responses, and we evaluated this hypothesis using data from a phase I/II prophylactic HIV vaccine trial. The objective was to assess the dynamics and correlations between CD4+ IL-2+ T cell and CD8+ IFN-γ+ T cell responses after vaccination with a recombinant adenoviral serotype 5 (rAd5) HIV vaccine.

Methods: We analyzed data from the HVTN 068 HIV vaccine trial, which evaluated the immunogenicity of two different strategies for prime and boost vaccination (rAd5-rAd5 vaccine versus DNA-rAd5) in 66 healthy volunteers. Spearman correlations between immunogenicity markers across time-points were calculated. CD8+ IFN-γ+ T cell response in the rAd5-rAd5 arm was modeled as a function of CD4+ IL-2+ T cell response and time using mixed effects regression models.

Results: Moderate to high correlations (r = 0.48-0.76) were observed in the rAd5-rAd5 arm between the CD4+ IL-2+ T cell response at week 2 and later CD8+ IFN-γ+ T cell responses (weeks 2-52). Regression models confirmed this relationship with a significant association between the two markers: for a 1.0% increase in CD4+ IL-2+ T cells at week 2 post-prime, a 0.3% increase in CD8+ IFN-γ+ T cell responses across subsequent time points, including post-boost time points, was observed (p<0.01).

Conclusion: These results suggest an early and leading role of CD4+ T cells in the cellular response to the rAd5-rAd5 vaccine and in particular the stimulation of cytotoxic CD8+ T cell responses. These results could inform better timing of CD4+ T cell measurements in future clinical trials.

Fig 1. HVTN 068 trial design with repeated immunogenicity measurements–cellular and antibody responses—during the 52 weeks of follow-up.

Fig 2. Kinetics of IL-2 producing CD4+ helper T cells (CD4+ IL-2+ T cells) and IFN-γ producing cytotoxic CD8+ T (CD8+ IFN-γ+ T cells) responses over time after Env ex-vivo stimulation of PBMC in the rAd5-rAd5 and DNA-rAd5 groups respectively, HVTN 068 trial.

(A) CD4+ IL-2+ T cells responses in the rAd5-rAd5 group. (B) CD8+ IFN-γ+ T cells responses in the rAd5-rAd5 group. (C) CD4+ IL-2+ T cells responses in the DNA-rAd5 group. (D) CD8+ IFN-γ+ T cells responses in the DNA-rAd5 group.

Fig 3. Heat map of Spearman correlation coefficients (r) between IL-2 producing CD4+ helper T cells (CD4+ IL-2+ T cells) and IFN-γ producing cytotoxic CD8+ T cells (CD8+ IFN-γ+ T cells) in the rAd5-rAd5 group (Env ex-vivo stimulation of PBMC), HVTN 068 trial.