Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial
| Autor: | Maja A. Sommerfelt, Gonzalo Tapia, Yunda Huang, Arnt-Ove Hovden, Mats Ökvist, Richard B. Pollard, Brittany Sanchez, Giuseppe Pantaleo, Lily Zhang, Jürgen K. Rockstroh, Monica Trondsen |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology CD4-Positive T-Lymphocytes Male lcsh:Medicine HIV Infections 0302 clinical medicine Viral load 030212 general & internal medicine Young adult AIDS Vaccines Immunity Cellular lcsh:R5-920 General Medicine Middle Aged Treatment Outcome Infectious Diseases 6.1 Pharmaceuticals Public Health and Health Services HIV/AIDS Female lcsh:Medicine (General) Research Paper Cart Adult medicine.medical_specialty Clinical Trials and Supportive Activities Clinical Sciences General Biochemistry Genetics and Molecular Biology AIDS Vaccines/administration & dosage AIDS Vaccines/pharmacology CD4 Lymphocyte Count CD4-Positive T-Lymphocytes/cytology CD4-Positive T-Lymphocytes/drug effects Cell Proliferation/drug effects HIV Infections/drug therapy HIV Infections/immunology HIV-1/immunology HIV-1/physiology Humans Interleukin-6/metabolism Tumor Necrosis Factor-alpha/metabolism Viral Load/drug effects Young Adult Analytical treatment interruption (ATI) CD4 HIV Immune predictors Therapeutic vaccine Vaccine Related 03 medical and health sciences Immune system Clinical Research Internal medicine medicine Cell Proliferation business.industry Tumor Necrosis Factor-alpha Interleukin-6 Hiv 1 vaccine lcsh:R Immunity Evaluation of treatments and therapeutic interventions Analytical treatment interruption Cell mediated immunity Clinical trial 030104 developmental biology Good Health and Well Being Treatment interruption Immunology HIV-1 Immunization Cellular business |
| Zdroj: | EBioMedicine, Vol 24, Iss C, Pp 195-204 (2017) EBioMedicine, vol. 24, pp. 195-204 EBioMedicine |
| ISSN: | 2352-3964 |
| Popis: | Background 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 18 weeks, 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. Methods 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). Findings 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). Interpretation These exploratory analyses highlight the potential value of investigating biomarkers in T-cell proliferation supernatants for VE in clinical studies. Highlights • 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 considered for the identification of immune markers of vaccine effect. |
| Databáze: | OpenAIRE |
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