The therapeutic HIV Env C5/gp41 vaccine candidate Vacc-C5 induces specific T cell regulation in a phase I/II clinical study

Kristin Brekke, Maja Sommerfelt, Mats Ökvist, Anne Margarita Dyrhol-Riise, Dag Kvale, Kristin Brekke, Maja Sommerfelt, Mats Ökvist, Anne Margarita Dyrhol-Riise, Dag Kvale

Abstract

Background: Levels of non-neutralising antibodies (AB) to the C5 domain of HIV Env gp120 are inversely related to progression of HIV infection. In this phase I/II clinical study we investigated safety of Vacc-C5, a peptide-based therapeutic vaccine candidate corresponding to C5/gp41732-744 as well as the effects on pre-existing AB levels to C5/gp41732-744, immune activation and T cell responses including exploratory assessments of Vacc-C5-induced T cell regulation. Our hypothesis was that exposure of the C5 peptide motif may have detrimental effects due to several of its HLA-like features and that enhancement of non-neutralising anti-C5 AB by vaccination could reduce C5 exposure and thereby chronic immune activation.

Methods: Thirty-six HIV patients on effective antiretroviral therapy were randomised to one of three dose levels of Vacc-C5 administered intramuscularly with Alhydrogel or intradermally with GM-CSF as adjuvant through initial immunisation and two booster periods over 26 weeks. Vacc-C5-specific AB were measured by ELISA and T cell responses by both IFN-γ ELISPOT and proliferative assays analysed by flow cytometry. Immune regulation was assessed by functional blockade of the two inhibitory cytokines IL-10 and TGF-β in parallel cultures. Non-parametric statistical tests were applied.

Results: Vacc-C5 was found safe and well tolerated in all patients. Only marginal changes in humoral and cellular responses were induced, without any effect on immune activation. Overall, anti-Vacc-C5 AB levels seemed to decrease compared to pre-existing levels. Whereas Vacc-C5-specific CD8+ T cell proliferative responses increased after the first booster period (p = 0.020; CD4+, p = 0.057), they were reduced after the second. In contrast, Vacc-C5-induced T cell regulation increased after completed vaccination (p ≤ 0.027) and was lower at baseline in the few AB responders identified (p = 0.027).

Conclusions: The therapeutic HIV vaccine candidate Vacc-C5 safely induced only marginal immune responses, whereas Vacc-C5-induced T cell regulation markedly increased. Our data support further attention on immune regulation during therapeutic HIV vaccination studies.

Trial registration: NCT01627678 .

Keywords: Antibodies; HIV; Immune activation; Immune regulation; T cell; Therapeutic vaccine.

Figures

Fig. 1
Fig. 1
The CONSORT diagram. Patients were randomised to low (LD, 100 μg), medium (MD, 300 μg) or high dose (HD, 900 μg) with GM-CSF or Alhydrogel as adjuvant
Fig. 2
Fig. 2
Anti-Vacc-C5-specific antibodies (AB) in serum. a AB levels for the total cohort at week 1 (baseline), 6 (after initial immunisation), 15 (after1st boost) and 26 (after 2nd boost, end of study). Data are given as medians, interquartile and overall ranges. The change from baseline to end of study is indicated (Wilcoxon matched pairs test). b AB levels for the three dose groups at week 1, 6, 15 and 26. LD = low, MD = median and HD = high dose. Data are given as medians, interquartile and overall ranges. Changes within each dose group with p-values less than 0.10 are indicated (Wilcoxon matched pairs test)
Fig. 3
Fig. 3
Vacc-C5-specific IFN-γ responses. a IFN-γ responses for the total cohort at week 1 (baseline), 6 (after initial immunisation), 15 (after1st boost) and 26 (after 2nd boost, end of study). Data are given as medians, interquartile and overall ranges. Changes with p-values less than 0.10 are indicated (Wilcoxon matched pairs test). b IFN-γ responses for the three dose groups at week 1, 6, 15 and 26. LD = low, MD = median and HD = high dose. Data are given as medians, interquartile and overall ranges. Significant changes within each dose group are indicated (Wilcoxon matched pairs test)
Fig. 4
Fig. 4
Vacc-C5-specific proliferative T cell responses. a Responses at week 1, 6, 15 and 26 in CD8+ (upper panel) and CD4+ (lower panel) T cell subsets. Data are given as medians, interquartile and overall ranges. Changes with p-values 0.10 or less are indicated. b Individual responses at week 1 (baseline), 6 (after initial immunisation), 15 (after1st boost) and 26 (after 2nd boost, end of study) in CD8+ (upper panel) and CD4+ (lower panel) T cell subsets
Fig. 5
Fig. 5
Vacc-C5-specific proliferative T cell responses without and with blockade of IL-10 and TGF-β in CD8+ (upper panel) and CD4+ (lower panel) T cell subsets at week 1 (baseline) (left panel) and week 26 (end of study) (right panel). Significant differences are indicated (Wilcoxon matched pairs test)
Fig. 6
Fig. 6
Vacc-C5-induced T cell regulation. a Net regulation at week 1 (baseline), 6 (after initial immunisation), 15 (after1st boost) and 26 (after 2nd boost, end of study) in CD8+ (upper panel) and CD4+ (lower panel) T cell subsets. The change from baseline to end of study is indicated (Wilcoxon matched pairs test). b Net regulation as fold increase at week 1 and 26. The change from baseline to end of study is indicated (Wilcoxon matched pairs test)

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