In vivo electroporation enhances the immunogenicity of an HIV-1 DNA vaccine candidate in healthy volunteers

Abstract

Background: DNA-based vaccines have been safe but weakly immunogenic in humans to date.

Methods and findings: We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines.

Conclusions: This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate.

Trial registration: ClinicalTrials.gov NCT00545987.

Figure 1. Participant Flow Diagram.

Figure 2. Tolerability and Acceptability of Electroporation.

Volunteers randomized to receive ADVAX or placebo via EP completed a questionnaire to rate the tolerability of the procedure on a 5 point pain scale at three different time points during and after EP (Panel A), and the acceptability of the procedure for future vaccination (Panel B). Results represent a total of 75 responses from 32 volunteers.

Figure 3. Cellular Immune Response.

Panel A depicts the fold increase over the HD-IM response in the mean of all IFNγ ELISpot responses to each antigen at Week 10, coinciding with the peak cellular immune response. Panel B depicts the sum of all mean ELISpot counts for each peptide pool at each study time point for all ADVAX dose groups, color coded by antigen. SFU  =  spot forming units.

Figure 4. Individual IFNγ ELISpot Responses.

All individual background-subtracted IFNγ ELISpot counts to each antigen at study Week 10, the peak response after the second administration. Horizontal lines indicate median values for each group. P-values indicate pair-wise comparisons of the three EP responses with HD-IM responses using the non-parametric Wilcoxon 2-sample test (t approximation). Significance is set at p<0.017, since there are 3 tests per antigen. Significant p values are depicted. SFU  =  spot forming units.