Phase 1 safety and immunogenicity evaluation of ADVAX, a multigenic, DNA-based clade C/B' HIV-1 candidate vaccine

Abstract

Background: We conducted a Phase I dose escalation trial of ADVAX, a DNA-based candidate HIV-1 vaccine expressing Clade C/B' env, gag, pol, nef, and tat genes. Sequences were derived from a prevalent circulating recombinant form in Yunnan, China, an area of high HIV-1 incidence. The objective was to evaluate the safety and immunogenicity of ADVAX in human volunteers.

Methodology/principal findings: ADVAX or placebo was administered intramuscularly at months 0, 1 and 3 to 45 healthy volunteers not at high risk for HIV-1. Three dosage levels [0.2 mg (low), 1.0 mg (mid), and 4.0 mg (high)] were tested. Twelve volunteers in each dosage group were assigned to receive ADVAX and three to receive placebo in a double-blind design. Subjects were followed for local and systemic reactogenicity, adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA. Cellular immunogenicity was assessed by a validated IFNgamma ELISpot assay and intracellular cytokine staining. ADVAX was safe and well-tolerated, with no vaccine-related serious adverse events. Local and systemic reactogenicity events were reported by 64% and 42% of vaccine recipients, respectively. The majority of events were mild. The IFNgamma ELISpot response rates to any HIV antigen were 0/9 (0%) in the placebo group, 3/12 (25%) in the low-dosage group, 4/12 (33%) in the mid-dosage group, and 2/12 (17%) in the high-dosage group. Overall, responses were generally transient and occurred to each gene product, although volunteers responded to single antigens only. Binding antibodies to gp120 were not detected in any volunteers, and HIV seroconversion did not occur.

Conclusions/significance: ADVAX delivered intramuscularly is safe, well-tolerated, and elicits modest but transient cellular immune responses.

Trial registration: Clinicaltrials.gov NCT00249106.

Figure 1. Clinical Trial Participant Flow Diagram.

Figure 2. Local and Systemic Reactogenicity by Dosage Group.

Panels A and B depict the percentage of volunteers experiencing local or systemic reactogenicity, respectively, by severity and dosage group. Total responses and (percentage of responses) are depicted above each bar. The proportion of volunteers experiencing moderate or severe local reactogenicity increased with increasing dosage (two-tailed Cochran-Armitage trend test, p = 0.0040). A similar comparison of systemic reactogenicity was not statistically significant (p = 0.738).