502
HIV-1 pGA2/JS2 Plasmid DNA Priming Vector Vaccine Is Safe and Well Tolerated in HIV-1-uninfected Adults
M Mulligan1, C Celum2, M Allen3, J Kahn4, A Rubin2, E Noonan2, D Montefiori5, K Weinhold5, J Smith6, R Amara6, Harriet Robinson*6, and for the NIH/NIAID/DAIDS HIV Vaccine Trials Network
1Univ of Alabama at Birmingham, USA; 2Fred Hutchinson Cancer Res Ctr, Seattle, WA, USA; 3NIAID, Bethesda, MD, USA; 4Univ of California, San Francisco, USA; 5Duke Univ Med Ctr, Durham, NC, USA; and 6Emory Univ, Atlanta, GA, USA
Background: Long-term control of a pathogenic SHIV-89.6P
challenge in rhesus macaques has been achieved with a Gag-Pol-Env SHIV-89.6 DNA/MVA vaccine. Based on these preclinical data, a
clade-B DNA HIV vaccine termed
pGA2/JS2 was developed for use as a priming vector for a DNA/MVA combination vaccine in humans. This 9.5-kb DNA uses a cytomegalovirus (CMV) promoter and a
bovine growth hormone polyadenylation sequence to express a single transcript
that undergoes Rev-dependent subgenomic splicing and frame-shifting to express
Gag, Pr, RT, Env, Tat, Rev, and Vpu.
Methods: A phase I multi-center, randomized,
placebo-controlled, double-blind trial was conducted in 30 HIV-uninfected
volunteers aged 18 to 40 years. The
initial group of volunteers received 0.3 mg of DNA
(n = 12) or placebo (n = 3) delivered intramuscularly in 1 mL of saline to the
upper deltoid at times 0 and 2 months and a second group of volunteers was
vaccinated with 3 mg of JS2 DNA (n
= 12) or placebo (n = 3) at similar time points. Safety assessments were
compared among groups using the Kruksal Wallis test and immunogenicity, using
the Fisher exact test.
Results: Tolerability was excellent. No significant
adverse local or systemic events were documented at either dose. No significant
differences were noted between the control, 0.3-mg, or 3-mg groups in clinical
or laboratory findings through 12 months of post-vaccination follow-up. A
validated ELISpot assay performed on frozen samples in the HVTN Central
Laboratory did not detect any interferon-γ (INF-γ )-producing T cells
in any of the 0.3- or 3-mg recipients, nor were HIV-1-specific neutralizing
antibodies detected. Fresh PBMC, assayed at Emory University
using Gag peptide stimulations and intracellular cytokine staining,
demonstrated transient low frequencies of anti-Gag INF-γ-producing CD4 and
CD8 T cells that were detected only at the peak vaccine response. One of 12
volunteers receiving 0.3 mg of DNA
scored for low-frequency CD8 and CD4 T-cell responses and a second scored for a
low-frequency CD8 T-cell response to Gag. Of 12 volunteers, 4 who received 3 mg
of DNA exhibited anti-Gag CD4 T-cell
frequencies of 0.01 to 0.1% at 2 weeks after the second dose. None of the
recipients of placebo scored for responding T cells, as measured by INF-γ.
Conclusions: This initial human trial of the pGA2/JS2
plasmid DNA HIV vaccine indicated
that 2 priming doses of either 0.3 or 3.0 mg of the plasmid DNA are safe and well tolerated in healthy
HIV-1-uninfected individuals.
Keywords: vaccine; DNA/MVA; T cells
