Phase I Safety and Immunogenicity Preventative Vaccine Trial Based on Recombinant Tat Protein

A Phase I Safety and Immunogenicity Trial of Recombinant HIV-1 Tat Protein in HIV-1 Uninfected Adult Volunteers

This Phase I study is directed at evaluating the safety profile (as a primary end-point) and the immunogenicity (as a secondary end-point) of the recombinant HIV-1 Tat vaccine in healthy, immunologically competent adult subjects without identifiable risk of HIV-1 infection.

The development of a vaccine against HIV/AIDS has been primary focused on the structural proteins (Env, Gag) of HIV-1 with the aim of inducing sterilizing immunity by blocking virus entry. Alternative approaches are focused on new vaccine strategies aimed at modifying the virus-host dynamic favouring the establishment of a long-term non-progressing disease status. Such strategies target regulatory proteins that are the first to be expressed after infection and are essential for viral replication, infectivity and pathogenesis. Thus, this approach may be effective for both preventive and therapeutic vaccination strategies.

Being a very early viral regulatory protein necessary for viral gene expression, cell-to-cell virus transmission and disease progression, Tat represents a key target protein for the host immune response and an optimal candidate for such a vaccination strategy.

Preclinical studies demonstrated that vaccination with a biologically active Tat protein is safe, elicits a broad and specific immune response and induces a long-term protection against infection. Cross-sectional and longitudinal studies in natural infection suggest that the presence of an anti-Tat humoral immune response correlates with asymptomatic infection and with a slower disease progression while the presence of CD8+ T cell responses to Tat correlate with early virus control both in humans and monkeys. Since the immunogenic regions of Tat are well conserved among the HIV-1 M group, a vaccine based on Tat may be used in different geographic areas of the world.

The subjects were stratified in two Arms according to the administration route to receive 5 intradermal or subcutaneous immunizations at 4 weeks intervals.

Inclusion Criteria:

• Negative pregnancy test for women of childbearing potential within 3 days prior to baseline evaluation and use of an acceptable means of contraception (condom, hormonal or mechanical method) for one month prior to immunization and for all the duration of the study;
• Complete blood count and differential defined as:
• Hematocrit >=30% for women, >= 38% for men
• Hemoglobin >= 9.5 g/dL
• White cell counts >= 4,000 and <= 9,500 cells/mm3
• Total lymphocyte count >=1000 cells/mm3
• CD4+ T cell count > 500 cells/microL based on 2 separate determinations (Hannet, 1992)
• Platelets (100,000-550,000/ mm3)
• Differential within institutional normal limits or approval of site physician;
• Normal ALT (as defined by the range of the clinical site laboratory) and Creatinine (< 1.6 mg/dl);
• Normal urine dipstick with esterase and nitrite;
• Normal thyroid function;
• Negative ELISA for HIV-1/HIV-2 and HIV-1 viral load (plasma viremia) < 50 copies/mL within 1 month of immunization;
• Availability for follow-up for planned duration of at least 12 months and willing to have further brief evaluations at 24 and 36 months;
• Signed informed consent.

Exclusion Criteria:

• Identifiable high-risk behavior for HIV-1 infection, including a history of injection drug use within 12 months prior to enrollment or higher-risk sexual behavior;
• History of neoplastic diseases, encephalopathy, neuropathy or unstable CNS pathology, immunodeficiency, autoimmune disease, angina or cardiac arrhythmias, or any other clinically significant medical problems;
• Chest radiography showing evidence of active or acute cardiac or pulmonary disease;
• History of anaphylaxis or serious adverse reactions to vaccines as well as serum IgE levels exceeding 1000 U.I./ml;
• History of serious allergic reaction to any substance, requiring hospitalization or emergent medical care (e.g. Steven-Johnson syndrome, bronchospasm, or hypotension);
• Active syphilis [NOTE. If the serology is documented to be a false positive or due to an adequately treated infection, the volunteer is eligible];
• Active tuberculosis [NOTE: Volunteers with a positive PPD and a normal chest X-ray showing no evidence of TB and not requiring isoniazid (INH) therapy are eligible];
• Medical or psychiatric condition or occupational responsibilities which preclude subject compliance with the protocol. Specifically excluded are persons with psychotic disorders, major affective disorders, suicidal ideation;
• Current use of psychotropic drugs;
• Participation in another experimental protocol within six months prior to pre-study screening;
• Current or prior therapy with immunomodulators or immunosuppressive drugs and anticoagulant drugs within 30 days prior to study medication administration;
• Any unstable cardiovascular disease (e.g. unstable hypersensitive disease needing modification or introduction of an anti-hypersensitive treatment);
• Live attenuated vaccines within 60 days of study [NOTE: Medically indicated sub-unit or killed vaccines (e.g., influenza, pneumococcal, hepatitis A and B) are not exclusionary, but should be given at least 4 weeks away from HIV immunizations];
• Use of investigational agents within 90 days prior to study;
• Receipt of blood products or immunoglobulin in the past 6 months;
• Prior receipt of HIV-1 vaccine in a previous HIV vaccine trial;
• Positivity for HBV antigens (HBs Ag, HBe Ag), and HCV, HTLV-I and HTLV-II antibodies;
• Pregnant or lactating women.