Phase I Safety and Immunogenicity Vaccine Trial Against HIV/AIDS

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.

This Phase I study was 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 HIV-1 infected adult volunteers with mild immune deficiency (Clinical category A according to CDC), CD4+ T cell counts 400/mL and levels of plasma viremia < 50,000 copies/mL.

Study Design: Randomized, Double Blind, Placebo Controlled, Safety/Immunogenicity Study.

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 the duration of the study;
• Clinically asymptomatic HIV-1 infected individuals (CDC Clinical category A), as determined by two positive Enzyme-linked immunosorbent assay (ELISA) and a confirmatory Western Blot;
• Mean CD4+ T cell count >= 400 cells/microL based on 2 separate determinations, at least 2 weeks apart, within the four weeks pre-study screening period. [Note: If one of the two values is < 400 the patient will be excluded. Patients ever having had a value of CD4+ T cell number < 250 will be excluded];
• Plasma HIV-1 viremia levels <= 50,000 copies/mL;
• Complete blood count and differential defined as:
• Hematocrit >= 30% for women, >= 38% for men
• Hemoglobin >= 9.5 g/dL
• White cell counts >= 4,000 cells/mm3
• Total lymphocyte count >= 1000 cells/mm3
• Platelets >= 100,000/mm3
• Differential within institutional normal limits or approval of site physician
• Normal ALT (as defined by the range of the clinical site laboratories) and Creatinine (<= 1.6 mg/dL);
• Normal urine dipstick with esterase and nitrite;
• Normal thyroid function;
• 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

• History of AIDS-related opportunistic or neoplastic disease;
• History of encephalopathy, neuropathy, or unstable CNS pathology (HIV or non-HIV related);
• History of non-HIV related neoplastic diseases, autoimmune diseases, angina or cardiac arthymias, 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 psychotrophic drugs;
• Use of antiretroviral therapy within 3 months of pre-study screening.
• Use of any experimental HIV therapy or participation in another experimental protocol within three (3) months of 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 cardio-vascular disease (e.g unstable hypertensive disease needing modification or introduction of an anti-hypertensive 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];
• Receipt of blood products or immunoglobulin in the past year;
• 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;
• Positivity for HHV-8 antibodies and plasmaviremia (volunteers will be screened for anti-HHV-8 antibodies and positivity confirmed by PCR, only the individuals confirmed positive by PCR will be excluded);
• Pregnant or lactating women.