Phase I Safety and Immunogenicity Vaccine Trial Against HIV/AIDS

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

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.

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.