A Phase Il of a Therapeutic, Recombinant, Biologically Active HIV-1 Tat Protein Vaccine in HIV-Infected, Anti-Tat Negative, ARV-Treated Adult Volunteers
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 2

Summary: 
      Tat is a key HIV regulatory protein produced very early after infection, prior to virus
      integration, and necessary for viral gene expression, cell-to-cell virus transmission and
      disease progression. Previous studies in natural HIV infection, indicated that the presence
      of a Tat-specific immune response correlates with a lower incidence and reduced risk of
      progression to AIDS as compared to anti-Tat negative individuals suggesting that an immune
      response to Tat may exert a protective role and control the progression to AIDS in vivo.
      Moreover, Tat is conserved in its immunogenic regions (both B and T cell) among all subtypes.
      subtypes. Recent data, in fact, indicate an effective cross-clade recognition of clade B
      strain-derived (BH-10) Tat protein from the HTLV-IIIB lab-adapted virus strain (Buttò, 2003),
      which was isolated about 30 years ago (Ratner, 1985), by sera from individuals infected with
      viruses circulating at the present in Italy and in Africa, thus reflecting the high degree of
      conservation of the corresponding Tat regions and providing strong formal evidence that a
      Tat-based vaccine may indeed be used in the different geographic areas of the world, since it
      is capable of inducing a broad immune response against different virus clades. Based on this
      rationale and on the positive results of preclinical (Cafaro, Nat Med 1999) and phase I
      preventive and therapeutic clinical trials with Tat protein (ISS P-001 and ISS T-001,
      respectively) (Ensoli AIDS 2008, Vaccine 2009; Longo Vaccine 2009; Bellino RRCT, 2009) a
      phase II therapeutic, open label, clinical study with Tat protein (ISS T-002,
      ClinicalTrials.gov NCT00751595) was sponsored by ISS and activated in 11 clinical sites in
      Italy in HIV-infected HAART-treated subjects (Ensoli F, Retrovirology 2015).In this study,
      subjects are randomized into two arms to receive 3 or 5 vaccinations monthly; each arm is
      composed of two treatment groups, receiving 7, 5 or 30 µg of Tat, respectively.Results
      obtained in 168 individuals after trial completion (48 weeks), as well as after a follow-up
      of 144 weeks for a subgroup of vaccines, indicated that Tat vaccination is safe, immunogenic
      and capable of reducing the immune dysregulation which persists despite HAART in treated
      individuals (Ensoli et al,PLoS ONE 2010). Anti-Tat Abs were induced in most patients (79%),
      with the highest frequency and durability in the Tat 30 µg groups (89%) particularly when
      given 3 times (92%) (Ensoli B.,PLoS ONE 2010; Ensoli F., Retrovirology 2015). Moreover,
      vaccination promoted a durable and significant restoration of T, B, natural killer (NK)
      cells, and CD4+ and CD8+ central memory subsets. Moreover, a significant reduction of blood
      proviral DNA was seen after week 72, particularly under PI-based regimens and with Tat 30 µg
      given 3 times (30 μg, 3x), reaching a predicted 70% decay after 3 years from vaccination with
      a half-life of 88 weeks. This decay was significantly associated with anti-Tat IgM and IgG
      Abs and neutralization of Tat-mediated entry of oligomeric Env in dendritic cells, which
      predicted HIV-1 DNA decay. Finally, the 30 μg, 3x group was the only one showing significant
      increases of NK cells and CD38+HLA-DR+/CD8+ T cells, a phenotype associated with increased
      killing activity in elite controllers (Ensoli F., Retrovirology 2015). These data indicate
      that Tat immunization represents a promising pathogenesis-driven intervention to intensify
      HAART efficacy (Ensoli et al,PLoS ONE 2010).
    

Detailed description: 
      Based on this, the ISS T-003 study in South Africa was started; the study was a phase II,
      randomized, double-blinded, placebo controlled, clinical trial to evaluate the immunogenicity
      (as a primary end-point) and the safety (as a secondary end-point), of a therapeutic,
      recombinant, biologically active HIV-1 Tat vaccine in HIV-1 infected, anti-Tat antibody
      negative, ARV-treated adult volunteers with chronically suppressed HIV-1 infection as
      indicated by a HIV-1 plasma viraemia < 400 copies/ml, and a CD4+ T cell count ≥ 200 cells/μl,
      at screening and documented at least once during the 12 month period prior to screening,
      irrespective of the pre-ARV CD4 nadir.

      After a screening period of up to 21 days, the study duration will be 48 weeks, including an
      8 week treatment phase (during which 3 vaccinations will be administered at 4-week intervals)
      and a 40 week follow-up phase.

      This study will be conducted at 1 clinical site in South Africa. 200 Subjects were randomized
      in a 1:1 ratio to one of the two treatment groups (Tat 30 mcg or placebo administered
      intradermally, 3 times).
    

Intervention name(s): Tat; Placebo
Intervention type(s): Biological; Biological
Intervention description(s): Recombinant biologically active Tat 30 mcg in Phosphate saline buffer, pH 7.4, 1% sucrose, 1% Human Serum Albumin; Phosphate saline buffer, pH 7.4, 1% sucrose, 1% Human Serum Albumin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: HIV,; HAART-treated; participants; Tat protein,; Therapeutic immunization