Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial

In a placebo-controlled trial of the peptide-based therapeutic HIV-1 p24Gag vaccine candidate Vacc-4x, participants on combination antiretroviral therapy (cART) received six immunizations over 18weeks, followed by analytical treatment interruption (ATI) between weeks 28 and 52. Cell-mediated immune...

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Veröffentlicht in:EBioMedicine 2017-10, Vol.24 (C), p.195-204
Hauptverfasser: Huang, Yunda, Pantaleo, Giuseppe, Tapia, Gonzalo, Sanchez, Brittany, Zhang, Lily, Trondsen, Monica, Hovden, Arnt-Ove, Pollard, Richard, Rockstroh, Jürgen, Ökvist, Mats, Sommerfelt, Maja A.
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Sprache:eng
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Zusammenfassung:In a placebo-controlled trial of the peptide-based therapeutic HIV-1 p24Gag vaccine candidate Vacc-4x, participants on combination antiretroviral therapy (cART) received six immunizations over 18weeks, followed by analytical treatment interruption (ATI) between weeks 28 and 52. Cell-mediated immune responses were investigated as predictors of Vacc-4x effect (VE) on viral load (VL) and CD4 count during ATI. All analyses of week 28 responses and fold-changes relative to baseline considered per-protocol participants (Vacc-4x:placebo=72:32) resuming cART after week 40. Linear regression models with interaction tests were used. VE was estimated as the Vacc-4x–placebo difference in log10-transformed VL (VEVL) or CD4 count (VECD4). A lower fold-change of CD4+ T-cell proliferation was associated with VECD4 at week 48 (p=0.036, multiplicity adjusted q=0.036) and week 52 (p=0.040, q=0.080). A higher fold-change of IFN-γ in proliferation supernatants was associated with VEVL at week 44 (p=0.047, q=0.07). A higher fold-change of TNF-α was associated with VEVL at week 44 (p=0.045, q=0.070), week 48 (p=0.028, q=0.070), and week 52 (p=0.037, q=0.074). A higher fold-change of IL-6 was associated with VEVL at week 48 (p=0.017, q=0.036). TNF-α levels (>median) were associated with VECD4 at week 48 (p=0.009, q=0.009). These exploratory analyses highlight the potential value of investigating biomarkers in T-cell proliferation supernatants for VE in clinical studies. •Ex vivo CD4+ T-cell proliferation was predictive of Vacc-4x effect.•IFN-γ, TNF-α and IL-6 secretion in T-cell proliferation supernatants were predictive of Vacc-4x effect.•Such immune predictors could be utilized to mitigate risks associated with cART interruption towards HIV cure. No immune correlates or predictors of therapeutic vaccine effect (i.e. a reduction in viral load compared to placebo on treatment interruption) for human immunodeficiency virus (HIV)-1 are known. We investigated a broad array of cytokines/chemokines produced in T-cell proliferation supernatants from a placebo-controlled clinical study of a therapeutic HIV vaccine. Although such supernatants do not provide cell type-specific readouts, the cytokines/chemokines studied included T-helper (Th)1, Th2, growth factor, immuno-modulatory and pro-inflammatory functions. Specifically, we found that, IFN-γ, TNF-α and IL-6 secretion correlated with vaccine effect, suggesting such supernatants could represent important sample material not previously
ISSN:2352-3964
2352-3964
DOI:10.1016/j.ebiom.2017.09.028