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HIV-1 TAT VACCINES: CLINICAL STUDIES |
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 The successful 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 this study the Tat protein would be evaluated in humans for safety and immunogenicity. |
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| The HIV Tat vaccine development platform included the following key activities: |
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- Good Manufacturing Practice (GMP) Tat vaccine production. It was necessary to identify a validated facility adequate to sustain Phase I trials. A GMP facility was not available in Italy. A contractor in the United Kingdom produced and released the Tat vaccine according to current European Union (EU) regulations. 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 two years at -80°C.
- Regulatory approval by the National agency within the European Union (EU). According to established guidelines and laws issued by European and Italian regulatory authorities, a dossier ("Expert Report") was submitted to the "Committee for evaluation of safety and quality of new drugs" to the ISS and to the Italian Ministry of Health. The Expert Report contained the required information on the quality, safety, immunogenicity and efficacy of the Tat vaccine in preclinical studies. It also included the clinical protocols. Upon approval of the study by the regulatory agencies, enrollment of volunteers started at each clinical site (four sites, three in Rome and one in Milan were involved) for both the preventive and therapeutic Phase I trials.
- 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 behavioral 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.
- 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 counseled and communicated with the volunteers.
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Study protocol details |
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| 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.
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| 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.
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Study design: |
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- 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.
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| 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). |
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Study Results: |
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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 |
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| A review of the history of the Tat-based vaccine, from basic science to preclinical studies and to completion of Phase I trials, has recently 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). |
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