The central premise of our program is that durable control of HIV in the absence of antiretroviral therapy ("remission") will require the generation of de novo potent and sustained HIV-specific CD8+ cell responses that target evolutionarily conserved epitopes. Our program is inspired by the recent success of VGX-3100 (Inovio), a DNA therapeutic vaccine for HPV that leads to histopathologic regression of pre-malignant lesions in people and is associated with a potent, sustained boost to HPV-specific CD8+ T cell populations. A closely related multi-clade gag/pol/env DNA vaccine administered with an IL-12 DNA plasmid (PENNVAX, Inovio) has been studied for HIV prevention and is known to be both safe and highly immunogenic. In a randomized placebo-controlled study we will compare the immunogenicity and anti-reservoir activities of gag/pol DNA versus gag/pol/env DNA (both administered with IL-12). We will determine for the first time in established HIV disease whether presence of env in a DNA vaccine blunts T cell responses to more conserved Gag-specific and Pol-specific epitopes. We will also determine if Env-specific responses (which will presumably be mediated by antibodies and antibody-dependent cellular cytotoxicity, or ADCC) have a measurable effect on reservoir.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
56
PENNVAX®-GP is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag, Pol and Env proteins.
INO-6145 is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag and Pol proteins.
The IL-12 DNA adjuvant (INO-9012) consists of a single plasmid containing a dual promoter system for expression of both the IL-12 p35 and p40 genes necessary for production of the active heterodimeric (p70) IL-12 protein.
Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.
University of California, Los Angeles
Los Angeles, California, United States
Zuckerberg San Francisco General Hospital (ZSFG)
San Francisco, California, United States
The Percentage of Participants With Grade 3 or Higher Treatment-related Adverse Events
Counts and percentages of adverse events will be presented in frequency tables and characterized for each arm with 95% Clopper-Pearson Confidence Intervals. We will use the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1
Time frame: Week 64
The Change in the Magnitude of T Cell Responses Will be Evaluated by the IFN-γ Enzyme-linked Immunospot (ELISpot) Assay
The magnitude of Gag-specific responses was characterized in detail via matrix mapping using vaccine-matched peptides, while pools of 15 overlapping peptides will used to evaluate the magnitude of T cell response to Pol and Env, as well as Nef (internal control). In addition, ELISpot responses to pools of Gag, Pol, Env, and Nef peptides (n=50 peptides/pool) that have been derived from circulating HIV viruses (potential T cell epitope peptides, PTE; NIH AIDS Reagent Program) were evaluated in parallel. All measures were performed on two baseline PBMC samples. The primary outcome in terms of the magnitude of the response was calculated as the fold-change (ratio) in the number of spot-forming units per million peripheral blood mononuclear cells between week 14 and baseline (pre-vaccine).
Time frame: Baseline to Week 14
HIV Reservoir Size
The frequency of circulating CD4+ T cells harboring replication-competent HIV as measured using multiplex digital droplet PCR assay to quantify the total number of intact proviruses (IPDA). The frequency of cells harboring an intact genome per million CD4+ T cells was calculated. Values were log10 transformed. The mean log10 change from baseline to Week 64 was calculated.
Time frame: Baseline and Week 64
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