| Summary: | Over the last 30 years, HIV-1 has transformed from an untreatable fatal infection to a chronic condition susceptible to over thirty antiretroviral agents. Although the overall incidence of HIV has declined during the last decade, HIV prevention and treatment still remain key public health priorities worldwide. A vaccine could address both HIV prevention and be utilised therapeutically. This MD(Res) thesis hypothesizes that, in both HIV negative and HIV infected individuals, the quality of HIV-specific T cell immunity induced by the GTU® MultiHIV-B Clade DNA vaccine is influenced by the route of vaccination, and has antiviral function in both cohorts. The phenotypical T cell response is presented using IFN-ɣ ELISpot assays on frozen peripheral blood mononuclear cells (PBMCS) stimulated by peptide pools matched to the vaccine to show magnitude, breadth and duration of response, and the functional response is presented using an in vitro viral inhibition assay (VIA) as a marker of CD8+ cytolytic activity. In the first trial, 30 HIV uninfected volunteers were randomised to receive DNA vaccination administered either intradermally (ID), or transcutaneously (TC) in combination with intramuscular delivery (IM), or with electroporation (EP) following IM vaccination. Results showed in the EP+IM group the magnitude, breadth and duration of response was significantly greater than in other groups. In the VIA, all groups showed viral inhibitory activity to at least one virus, with the greatest number of participants with detectable HIV-specific CD8+ cells inhibiting virus in the EP+IM group. In the second cohort the trial design was modified based on results from the first trial, and 30 HIV infected volunteers on ART were randomised to receive the same vaccine either TC+IM or EP+IM with a further randomisation to receive the vaccine or placebo. The results from T cell ELISpots showed pre-existing immunity to peptide pools in most participants at baseline, but no significant differences either between or within groups or at the primary end point. The VIA was substantially modified for this HIV-infected cohort and showed high levels of pre-vaccination inhibition suggesting some preservation of immune function in these volunteers, although there was little change in viral inhibition at the primary end point. To summarise, this data indicates that in an HIV uninfected cohort DNA vaccination induced HIV-specific T cell responses particularly using electroporation to enhance IM injection. However, IFN-ɣ alone could not predict the function of CD8+ cells and inhibition was seen in all 3 groups. In the HIV positive cohort, this DNA vaccine was unable to induce detectable HIV-specific immunity to the vaccine delivered by either route. The VIA indicates some preservation of immune function in this cohort with the ability to inhibit virus at the pre-vaccination time point. Importantly, the vaccine was found to be clinically safe in both trials.
|
|---|
