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  HIV and AIDS
    What is "AIDS"
    Routes of infection
    First symptoms
    Having AIDS
    Can AIDS be cured?
  The Need for Vaccines
    AIDS in the World
    AIDS in Africa
  HIV-1 Tat:
    Scientific Background & Rationale
    HIV-1 Tat Protein
    Pre-clinical Studies
    Clinical Studies
    International Collaborations
    1st. Gen.: Tat alone
    2nd Gen.: Tat+Microparticles
    2nd Gen.: Tat+Env
    Discovery Phase Leads
HIV-1 TAT VACCINES CLINICAL STUDIES The promising results obtained with the biologically-active Tat protein in monkeys encouraged the Italian National Institute of Health (ISS) to sponsor Phase I clinical trials in Italy. In these studies the Tat protein has been evaluated in humans for safety and immunogenicity. The successful completion of phase I studies allowed to advance the clinical development of the Tat vaccine to phase II studies both in Italy and in South Africa.
The HIV Tat vaccine development platform included the following key activities:
  1. Good Manufacturing Practice (GMP) Tat vaccine production.A GMP facility in the United Kingdom produced and released the Tat vaccine for the phase I trials, while an Italian GMP authorized facility manufactured the vaccine for all the following clinical trials, according to the current regulations on the investigational medicinal products for human use. Comparability studies with the research-grade product confirmed that specifications of the GMP product matched those of the research-grade product. The GMP product was also subjected to amino-acidic terminal sequencing and mass spectrometry. Stability tests confirmed that the GMP-manufactured clinical lot retained full biological activity up to 3 years at -80°C in the dark.

  2. Regulatory approval by the Competent National Agencies. According to the current laws and guidelines, regulatory and technical-scientific documentation for the conduction of clinical trials, including information on the quality, safety, immunogenicity and efficacy of the Tat vaccine, were submitted to the competent National Agencies in Italy and South Africa, respectively. Upon approval, enrolment of volunteers started at each involved clinical site for both preventive and therapeutic trials.

  3. Establishment of clinical, laboratory and social-behavioral platforms. Care was taken to ensure comparable read-outs for clinical trials conducted in a multicenter context. All clinical and laboratory activities, as well as psychosocial and behavioural assessments, were harmonized among the participants along common Good Clinical Practice (GCP) procedures. This was done by establishing specific and integrated (clinical, laboratory and psychological) platforms.

  4. Involvment of Community Advisory Board (CAB). A CAB was established for these studies. It was comprised of the most representative Italian non-governmental organizations (NGOs) involved in all issues relating to HIV/AIDS. The CAB has provided a communication network among communities, scientists, community-care providers and the study sponsor. The CAB helped to establish the methodology for ethical information, and it counselled and communicated with the volunteers.
1. Phase I preventive (ISS P-001) and therapeutic (ISS T-001) clinical trials with Tat (conducted in Italy, completed)
Enrollment of Volunteers :
  • Healthy HIV-uninfected adults at low risk of infection (preventive protocol)
  • HIV-1 infected, asymptomatic adult volunteers naïve (never having received) to therapy (therapeutic protocol). Volunteers had CD4+ T cell counts equal or above 400/µl of blood and viral loads equal or lower than 50,000 copies/ml.
End-points (key parameters) in both healthy and HIV-infected individuals were:
  • To qualify the biologically active Tat protein as safe (primary end-point) AND
  • To qualify the Tat protein as immunogenic (secondary end-point) for its further evaluation in Phase II trials.

Study design:

  • Both studies were randomized, placebo-controlled, and double-blinded (neither the volunteers nor those who administered the vaccine knew which volunteers were receiving either the vaccine or the placebo).
  • Volunteers were randomized (divided by random choice ) to one of two treatment arms with different routes of administration. They were also blinded (not informed) to which dosage group they belonged (i.e., placebo vs. different vaccine doses).
  • In Treatment Arm A, volunteers received Tat subcutaneously (just under the skin) with alum as an adjuvant. A dose of 7.5, 15 or 30 µg was administered at weeks 0, 4, 8, 12, and 16. One group of volunteers received alum plus saline solution as a placebo (inactive "treatment").
  • In Treatment Arm B, volunteers received Tat intradermally (in the skin) without adjuvant. A dose of 7.5, 15 or 30 µg was administered at weeks 0, 4, 8, 12, and 16. One group of volunteers received saline (salt) solution as a placebo.
Clinical and laboratory safety was assessed at several time points during the study and was monitored by an independent "Committee for the evaluation of adverse events." In addition, clinical trial monitoring (i.e., initiation visits, routine monitoring visits and termination visits) and quality assurance (i.e., clinical site audits, database audits and clinical study report visits) was conducted by Parexel International, a highly experienced Contract Research Organization (CRO).

Study Results:

When the studies were completed, the independent Committee for the evaluation of adverse events certified the safety of the vaccine in both HIV-negative and HIV-positive individuals. This certification confirmed that the primary and secondary end-points were fully achieved for both the preventive and therapeutic trials. All the reports were submitted to Regulatory Bodies.

The successful completion if this Phase I study has encouraged and supported the launch of Phase II trials to test the immunogenic capacity of Tat in a larger number of volunteers
A review of the history of the Tat-based vaccine, from basic science to preclinical studies and to completion of Phase I trials, has been published in an editorial of the "AIDS" journal (Barbara Ensoli, Valeria Fiorelli, Fabrizio Ensoli, Aurelio Cafaro, Fausto Titti, Stefano Butto`, Paolo Monini, Mauro Magnani, Antonella Caputo and Enrico Garaci - AIDS 2006, 20:2245-2261).
2. Phase I Extended follow up: ISS OBS P-001 and ISS OBS T-001 (conducted in Italy, completed)
These studies were aimed at extending the follow-up of the volunteers who participated to the preventive and therapeutic phase I clinical trials with Tat, respectively, for additional 3 years to evaluate the persistence of the anti-Tat humoral and cellular immune response, and, for the therapeutic trial, to monitor the progression of HIV-1 infection ( ID NCT01024764 and NCT01024595).
3. ISS OBS T-002 (conducted in Italy, completed)
A 3-years prospective observational study ( NCT01024556) was conducted in 128 adult individuals under successful cART in Italy. Study results indicate that the presence of anti-Tat Abs is significantly associated with a more effective recovery of CD4+ and CD8+ T cells under cART, suggesting that the induction of anti-Tat immune responses may help intensify ART efficacy toward immunologic restoration in treated individuals.
4. ISS OBS T-003 (conducted in Italy, completed)
A 3-years prospective observational study ( NCT01029548) was conducted in 61 asymptomatic drug naïve HIV-infected adults (CD4+ T cells counts ≥400/μl and plasma viremia ≤100,000 copies/ml) in Italy. Study results show a significant association between the presence of anti-Tat Abs and the containment of CD4+ T cell loss and of viral load, with a slower progression to disease (prolonged time to HAART initiation). Thus, the induction of anti-Tat immunity may help delay, and possibly block, HIV disease progression and ART implementation (S. Bellino et al., submitted).
5. ISS OBS T-004 (conducted in South Africa, completed)
An observational, cross-sectional study ( NCT01359800) conducted in South Africa on 531 HIV infected individuals naive or on cART, in the frame of an Italy-South Africa governmental bilateral programme, to determine the extent of anti-Tat immune responses and HIV co-infections, in preparation for the conduction of the phase II clinical trial of the Tat vaccine in South Africa. No difference in the pattern of anti-Tat humoral response was observed in naive versus treated subjects. Moreover, cART showed no impact on the prevalence of HBV and HPV infections. Prevalence of syphilis was high, more so in the ART treated group.
6. ISS T-002 (conducted in Italy, completed)
A phase II, randomized open-label therapeutic clinical trial ( NCT00751595) with the Tat vaccine administered intradermally at 7.5 µg or 30 µg, for 3 or 5 times monthly, was completed in 168 anti-Tat negative HAART-treated individuals in 11 clinical centers in Italy. The results, up to three years after Tat immunization, confirmed those observed at the 48-weeks interim analysis [Ensoli, PLoS ONE 2010] and indicated that immunization with Tat is safe, highly immunogenic, and capable of inducing a durable restoration of CD4+ and CD8+ T cell number with a recovery of key functional T cell subsets and of B and NK cells, while reducing immune activation. Remarkably, Tat induced a significant reduction of blood HIV-1 DNA load. Effects were greatest with Tat 30 µg, given 3 times and under Protease Inhibitors (PI)-based regimens, with a predicted 70% HIV-1 DNA decay after 3 years from vaccination and a half-life of 88 weeks. HIV-1 DNA decay was associated with anti-Tat Abs and neutralization of Tat-mediated Env entry in target cells, which predicted HIV-1 DNA decay. These effects were not observed in a reference group of HIV+ subjects under effective HAART enrolled in a parallel observational study at the same centers (ISS OBS T-002) (F.Ensoli et al, submitted).

These results indicate that Tat is a key virulence factor, which plays a pivotal role in virus spreading and persistence, and that the induction of anti-Tat immune responses represents a pathogenetic intervention to intensify HAART efficacy and to attack the HAART-resistant virus reservoir (Ensoli, submitted).
7. ISS T-002 EF-UP (conducted in Italy, ongoing)
This study is aimed at extending the follow-up of the volunteers who participated to the therapeutic phase II ISS T-002 trial for additional 3 years to evaluate the persistence of the immunological and virological effects of Tat immunization. The study is ongoing in 8 clinical centers in Italy.
8. ISS T-003 (conducted in South Africa, treatment phase completed – follow-up ongoing)
A phase II, randomized, double blinded, placebo controlled, therapeutic trial ( NCT01029548) with Tat immunization, given 3 times at 30 µg dose conducted in South Africa in 200 successfully ARV-treated subjects having CD4+ T cells equal or above 200 cells/µl. The treatment phase has been completed and the follow-up will be completed by mid-2014.
9. ISS P-002 (conducted in Italy, completed)
Randomized, open label preventive vaccine trial ( NCT01441193) with clade B Tat and clade C Env recombinant proteins in association, as compared to vaccination with the single proteins, conducted in 11 healthy adults also at risk of infection in Italy. Volunteers enrolment was prematurely interrupted because of the expiration date of one vaccine component (Env protein, produced by Novartis). Thus, this component was not further available for the conduction of clinical studies. The study has been completed at the beginning of 2014. Results indicated that this vaccine candidate is safe and immunogenic.


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