17 research outputs found
Towards a Functional Cure for HIV Infection: The Potential Contribution of Therapeutic Vaccination
Towards Eradication of HIV-1: Therapeutic Vaccination with the Peptide-Based Candidate Vacc-4x, 2014
Human immunodeficiency virus (HIV)-1 infection continues to threaten global health with approximately 34 million adults and children living with HIV infection worldwide in 2010. Antiretroviral therapy (ART) has made a significant impact on HIV infection, however, since it cannot eradicate HIV, ART must be taken daily for life, thereby conferring a significant financial burden on healthcare services worldwide. The aim of this study was to test a cure against HIV by using Vacc-4x, a peptide-based therapeutic HIV vaccine. The study is registered at www.clinicaltrials.gov. For further information about "Towards Eradication of HIV-1: Therapeutic Vaccination with the Peptide-Based Candidate Vacc-4x, 2014", please contact the principal investigator
The endogenous langur type D retrovirus PO-1-Lu and its exogenous counterparts in macaque and langur monkeys
A novel peptide-based vaccine candidate with protective efficacy against influenza A in a mouse model
Current influenza vaccines mainly induce antibody responses to the variable hemagglutinin proteins of the virus strains included in the vaccine. Instead, a broadly protective influenza vaccine should aim at inducing antibody and/or cell -mediated immunity against conserved viral proteins. Vacc-FLU is a peptide based vaccine combining conserved B and T cell epitopes. Peptide selection was done using a proprietary peptide design platform technology focusing on responses to human leukocyte antigen (HLA)-restricted epitopes. Immunization of wild -type mice and mice transgenic for HLA-A2.1 with the peptide mix successfully induced both humoral and cell mediated immune responses. Partial protection from severe weight loss upon challenge was observed in both mouse strains but was stronger and observed at lower vaccine doses in transgenic mice. Our results show that the Vacc-FLU peptide mix is capable of inducing IFNy-producing T cells and antibody-producing B cells which can protect from severe disease symptoms upon infection
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Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial.
BackgroundIn 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.MethodsAll 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).FindingsA 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).InterpretationThese exploratory analyses highlight the potential value of investigating biomarkers in T-cell proliferation supernatants for VE in clinical studies
A novel peptide-based vaccine candidate with protective efficacy against influenza A in a mouse model
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Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial.
BackgroundPresent combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1.MethodsBetween July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789.Findings174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23,100 copies per mL Vacc-4x vs 71,800 copies per mL placebo; p=0·025) and week 52 (median 19,550 copies per mL vs 51,000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations.InterpretationThe proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies.FundingNorwegian Research Council GLOBVAC Program and Bionor Pharma ASA
HIV-specific T cell responses were preserved during romidepsin treatment.
<p>Flow cytometric characterization of HIV-gag-specific CD8<sup>+</sup> and CD4<sup>+</sup> T cells within the memory subsets at baseline (Base, <i>n</i> = 6), on treatment (ROMI, <i>n</i> = 5) and at follow-up (Post, <i>n</i> = 6). Proportion of EM (<b>A</b>) and TD (<b>B</b>) CD8<sup>+</sup> T cells producing only IFNγ or both IFNγ and TNFα. Horizontal bars show median values. <b>(C, D)</b> Median fluorescence intensity (MFI) for IFNγ and TNFα for HIV-specific EM CD8<sup>+</sup> T cells and <b>(E, F)</b> TD CD8<sup>+</sup> T cells identified in Panels A-B. <b>(G)</b>, Proportion of polyfunctional memory EM CD4<sup>+</sup> T cells producing IFNγ, TNFα and IL-2. <b>(H)</b> Expression levels (MFI) for each cytokine (i.e. IL-2, TNFα and IFNγ) examined on the polyfunctional HIV-specific EM CD4<sup>+</sup> T cells identified in panel <b>(G)</b> TD, terminally differentiated; EM, effector memory. Statistical comparisons were performed using Wilcoxon matched-pairs signed-ranks test, Asterisk indicate p<0.05.</p