169
Randomized, Placebo-controlled, Phase1/2a Evaluation of the Safety, Biological Activity and Antiretroviral Properties of an Avipox Virus Vaccine Expressing HIV gag-pol and Interferon-gamma in HIV-1 Infected Subjects
D Cooper*1,10, C Workman1,2, R Puls1,2, M Bloch3, D Baker4, N Bodsworth5, J Anderson6, S Crowe7, M French8, J Hoy9, A Kelleher1, A Aichelberg1, L Ward11, M Law1, and S Emery1
1Natl. Ctr. in HIV Epidemiology and Clin. Res., Sydney, Australia; 2Ground Zero Med. Ctr., Sydney, Australia; 3Holdsworth House Gen. Practice, Sydney, Australia; 4407 Doctors, Sydney, Australia; 5Taylor Square Clin., Sydney, Australia; 6Carlton Clin., Melbourne, Australia; 7Macfarlane Burnet Ctr., Melbourne, Australia; 8Royal Perth Hosp., Australia; 9The Alfred Hosp., Melbourne, Australia; 10St. Vincent's Hosp., Sydney, Australia; and 11Viral Immunotherapeutics Pty. Ltd., Melbourne, Australia
Background:
A
multi-centre, randomized, double-blind, placebo-controlled trial examined the
safety, immunogenicity and biological activity of candidate HIV vaccines using
recombinant fowlpox virus (rFPV) vectors.
Methods: HIV-infected
patients who commenced combination antiretroviral therapy (ART) at primary HIV infection and maintained
control of virus replication (plasma HIV RNA, pVL<400 copies/mL) were
recruited. Eligible subjects were randomised to diluent alone (placebo, n=12),
rFPV expressing HIV gag/pol (partial construct PC, n = 11) or rFPV expressing HIV gag/pol and IFN-γ (full
construct FC, n = 12). The study was
conducted in 2 parts. In part 1, intramuscular injection of vaccines (5 x 107pfu/mL)
occurred at weeks 0, 4, and 12. Combination ART
was maintained until week 52. Primary endpoints included time-weighted mean
change in CD8+ effector function by IFN- γ ELISpot. In part 2,
consenting subjects received a fourth vaccination and discontinued ART 7 days later. The primary endpoint was
time-weighted mean change from baseline pVL. Secondary endpoints were time to
detectable pVL, median time to re-initiation of ART
and T-cell count changes. Efficacy analyses were performed using intention to
treat methods.
Results: All immunizations were well-tolerated. In part
1 (n = 35), there was no significant
difference between the combined PC and FC groups compared with placebo for
anti-HIV gag ELISpot responses (time-weighted mean change from baseline; mean
difference = -56 sfu/106 PBMC; p
= 0.062). For patients entering part 2 (n
= 25, 71%) (placebo = 7; PC = 8; FC = 10), the time-weighted mean (ąsd) change from baseline pVL was 1.80 (0.72),
1.78 (0.91), and 0.96 (0.91) log10 copies/mL for placebo, PC and FC
respectively (p = 0.253, comparing FC
and PC recipients with placebo; p =
0.077 comparing PC with FC recipients). Compared to placebo, FC and PC
recipients had similar times to detectable pVL after ceasing ART (hazard ratio 1.21, 95%CI: 0.40 to 2.97, p = 0.682). ART was
re-introduced in 7 patients (placebo = 3; PC = 3; FC = 1) and time to re-initiation was not significantly different in FC and PC
recipients compared to placebo (hazard ratio = 2.08, 95%CI: 0.49 to 9.31, p = 0.338). Time-weighted mean (ąsd) change from baseline CD4+
cell count was -91 (210), 2 (166), and 3 (161) cells/mL for placebo, PC, and FC respectively (p = 0.238, comparing FC and PC recipients to placebo).
Conclusions: Although safe, neither of the candidate
vaccine constructs appeared to possess detectable T-cell mediated anti-HIV
immunogenic properties, as measured by standard assays in part 1. Following a
fourth immunization and treatment interruption, FC recipients experienced 0.8
log reduction in pVL compared with recipients of PC or placebo. Other measures
of pVL change also suggest a superior but statistically non-significant viral
load outcome for recipients of FC, compared to either or both PC and placebo.
Keywords: vaccine; therapeutic; clinical trial
