Phase 1 safety and immunogenicity evaluation of ADMVA, a multigenic, modified vaccinia Ankara-HIV-1 B'/C candidate vaccine

Abstract

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

Methodology/principal findings: ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1x10(7) (low), 5x10(7) (mid), or 2.5x10(8) pfu (high)] volunteers were randomized in a 3:1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNgamma ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA. ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNgamma ELISpot response rate to any HIV antigen was 0/12 (0%) in the placebo group, 3/12 (25%) in the low dosage group, 6/12 (50%) in the mid dosage group, and 8/13 (62%) in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%), 8/13 (62%), 6/12 (50%) and 10/13 (77%) in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement with the ability to neutralize HIV-1 SF162 in vitro. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses.

Conclusions/significance: ADMVA was well-tolerated and elicited durable humoral and cellular immune responses.

Trial registration: Clinicaltrials.gov NCT00252148.

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. There is evidence of increased moderate/severe local reactions with increasing dose (two-tailed Cochran-Armitage trend test: p = 0.015). A similar comparison of systemic reactogenicity was not statistically significant (p = 0.129).

Figure 3. Graphs depict the anti-vaccinia binding antibody titer after each vaccination (arrows) by dose group, expressed as geometric mean titer.

Error bars represent SEM. Arrows indicate vaccination time points. As predicted, anti-vaccinia antibody titers increased after each vaccination and with increasing doses of ADMVA.