A Phase I/II, Randomized, Double-Blind Study to Evaluate the Safety, Tolerability, and Immunogenicity of LC002, a DermaVir Vaccine, in HIV-1-Infected Subjects Currently Under Treatment With Highly Active Antiretroviral Therapy (HAART)

Brief Summary

Detailed Description

The use of highly active antiretroviral therapy (HAART) has dramatically improved the rates of survival, morbidity, and mortality among HIV-infected people throughout the world. However, the costs, long-term toxicity, and problems with adherence associated with HAART regimens make such treatment plans less than optimal for individuals seeking treatment for HIV infection. Also, because viral reservoirs cannot be eradicated, HIV-infected people must usually be on HAART indefinitely in order to keep their infection under control. While the mechanism is still unclear, the immune system weakens as HIV disease progresses. A therapeutic HIV vaccine given to HIV infected people may help to promote better immune responses. LC002 is a novel HIV therapeutic vaccine containing a DNA plasmid that codes for most of HIV-1's proteins. LC002 is a unique vaccine in that it is given through topical administration; this allows for Langerhans cells (immune cells located under the surface of the skin) to pick up the vaccine and deliver it to the lymph nodes, causing an immune reaction. This study evaluated the safety, tolerability, and immunogenicity of LC002 in HIV-infected adults currently receiving HAART. There were three cohorts in this study which were enrolled sequentially. Participants in a given cohort were randomly assigned to receive either LC002 (6 participants) or placebo (2 participants). * In Cohort 1, participants received three separate low-dose vaccinations of LC002 (Arm A: 0.1 mg DNA/participant, 0.8 ml total, administered over two skin sites of 80 cm\^2 each, 0.4 ml/site) or 3 separate vaccinations of placebo (Arm B: 0.8 ml total, administered over two skin sites of 80 cm\^2 each, 0.4 ml/site). Vaccinations were given over two skin sites on the left and right upper back. Participants received vaccinations at weeks 1, 7, and 13. * In Cohort 2, participants received three separate high-dose vaccinations of LC002 (Arm C: 0.4 mg DNA/participant, 3.2 ml total, administered over four skin sites of 80 cm\^2 each, 0.8 ml/site) or three separate vaccinations of placebo (Arm D: 3.2 ml total, administered over four skin sites of 80 cm\^2 each, 0.8 ml/site). Vaccinations were given over four skin sites on the left and right upper back and left and right upper ventral thigh. Participants received vaccinations at weeks 1, 7, and 13. * In Cohort 3, participants received six separate high-dose vaccinations of LC002 (Arm E: 0.4 mg DNA/participant, 3.2 ml total, administered over four skin sites of 80 cm\^2 each, 0.8 ml/site) or six vaccinations of placebo (Arm F: 3.2 ml total, administered over four skin sites of 80 cm\^2 each, 0.8 ml/site). Vaccinations were given over four skin sites on the left and right upper back and left and right upper ventral thigh. Participants received vaccinations at study entry and weeks 1, 6, 7, 12, and 13. The decision to open the next cohort was made when all participants in the current cohort have remained on study for \>=14 days after the second vaccination or prematurely discontinued from study or had a primary safety endpoint (see primary outcome measure definition). Dose escalation required no primary safety endpoint and on-study follow-up for \>=6 participants in the previous cohort(s). Prior to receiving the vaccine, the chosen vaccine administration site on the back or thigh was disinfected and exfoliated. A skin patch was applied to the site, and the vaccine solution was placed on the skin underneath the patch with a needleless syringe. Participants were allowed to remove the skin patch 3 hours post vaccination. For the first and second vaccinations, participants were required to remain at the clinic for 3 hours post-vaccination so study staff can assess for side effects. If no side effects occurred after the first two vaccinations, participants were required to stay at the clinic for only 30 minutes after receiving later vaccinations. At the start of the study, participants were asked to keep a diary and record daily any side effects or skin irritation they may have experienced following vaccination. Participants were required to bring their diaries with them to their next clinic visit. Two days after vaccination, participants were followed-up by phone and were asked about any side effects they may have experienced. Participants who experienced side effects were asked to return to the clinic for examination. There were 13 study visits; they occurred at study entry and Weeks 1, 3, 6, 7, 9, 12, 13, 15, 17, 24, 37, and 61. Study visits included medication history, a physical exam, and collection of diaries. Blood and urine collection occurred at selected visits. HAART was not be provided by the study.

Primary Outcomes

Secondary Outcomes

• Time-averaged Area Under the Curve (AUC) of CD4+ T-cell Count in PBMCs(From start of study vaccination to week 61)
• Time-averaged AUC of the Magnitude of HIV-specific Immune Response, as Determined by the Number of Spot-forming Cells/10^6 PBMCs Observed in Each PHPC Assay for IFN-gamma Production for Gag p17, Gag p24, Gag p15 and Tat/Rev.(From start of study vaccination to week 37)
• Time-averaged AUC of the Magnitude of HIV-specific Immune Response, as Determined by Taking the Mean of the Number of Spot-forming Cells/10^6 PBMCs Observed in Each ELISPOT Assay for IFN-gamma Production for Gag p17, Gag p24, Gag p15 and Tat/Rev.(From start of study vaccination to week 37)
• Time-averaged AUC of CD8+ T-cell Count in PBMCs(From start of study vaccination to week 61)
• Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to p24 Protein, Gag/Pol/Env and Tat/Rev.(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Anti-CD3(From start of study vaccination to week 24)
• Time-averaged AUC of the Magnitude of HIV-specific Immune Response, as Determined by Taking the Mean of the Number of Spot-forming Cells/10^6 PBMCs Observed in Each PHPC Assay for IFN-gamma Production for Gag p17, Gag p24, Gag p15 and Tat/Rev.(From start of study vaccination to week 37)
• Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Whole HIV-1 Antigen(From start of study vaccination to week 24)
• Time-averaged AUC of the Magnitude of HIV-specific Immune Response, as Determined by the Number of Spot-forming Cells/10^6 PBMCs Observed in Each ELISPOT Assay for IFN-gamma Production for Gag p17, Gag p24, Gag p15 and Tat/Rev.(From start of study vaccination to week 37)
• Anti-dsDNA Antibody Response(From start of study vaccination to week 61)
• Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to p24 Protein, Gag/Pol/Env and Tat/Rev(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Percent of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to p24 Protein, Gag/Pol/Env, Tat/Rev and Whole HIV-1 Antigen.(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IFN-gamma-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IL-2-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens(From start of study vaccination to week 24)
• Lymphocyte Proliferation Stimulation Index (SI) in Response to Whole HIV-1 Antigen, p24 Antigen, and Pooled HIV-1 Peptide Antigens(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Count of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Anti-CD3(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IFN-gamma-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Count of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IFN-gamma-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Percent of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IL-2-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Whole HIV-1 Antigen(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Count of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Anti-CD3(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Percent of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to Anti-CD3(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Percent of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IFN-gamma-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Count of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IL-2-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Count of HIV-1-specific CD8+ T-cell Subsets, Based on Flow Cytometry With CFSE Staining to Detect Antigen-specific Lymphocyte Proliferation Responding to p24 Protein, Gag/Pol/Env, Tat/Rev and Whole HIV-1 Antigen.(From start of study vaccination to week 24)
• Time-averaged AUC of T-cell Percent of HIV-1-specific CD4+ T-cell Subsets, Based on Flow Cytometry to Detect Antigen-specific IL-2-producing Cells Responding to Whole Zn-finger Inactivated Virus Stimulation and Various HIV-1 Peptide Antigens(From start of study vaccination to week 24)