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250 Concomitant Administration of Two Facilitated DNA Plasmid Vaccines Containing HIV-1 Env/Rev and Gag/Pol Genes in HIV-Infected Patients on HAART: Safety, Immune Testing, and Plasma Virus Levels
R. MacGregor*1, J. Boyer1, R. Ginsberg2, T. Higgins2, R. Ciccarelli2, J. Eldridge2, and D. Weiner1
1Univ. of Pennsylvania, Philadelphia, USA and 2Wyeth-Lederle Vaccines, Pearl River, NY, USA
Background: HIV-infected patients with viremia suppressed by antiretroviral therapy (HAART) may have capacity to mount effective immune responses to HIV vaccines, thereby controlling subsequent HIV production. We gave 2 HIV DNA plasmid constructs expressing env/rev and gag/pol genes to well-controlled HIV-positive patients to determine safety and immune and viral responses.
Methods: This was a randomized double-blind dose-ranging study of 100, 300, or 1,000 mug vaccine doses in patients with viral load (VL) <1,000/ml on HAART and CD4 cells >400. They were randomized 5:2 to vaccine:placebo and received 3 I.M. injections at 4-week intervals with a booster at 24 weeks. Monitoring included tests for safety, flow cytometry, cell-mediated immune responses, and plasma viral levels.
Results: Minor local and no systemic clinical toxicity occurred. CBC, urinalysis, and serum chemistries remained less than grade 2 ACTG adverse experience criteria, and none developed ANA or discontinued study for toxicity. Mean entry CD4 count was 660 and showed no clear trend after vaccination. Lymphocytes were stimulated with gp160, rev, or p24 antigens in parallel. Positive responses (a stimulation index [SI] > 5 above media controls) were seen in similar numbers and with a similar range of SI in both vaccinees and controls. SI > 5 were seen more than twice as often to p24 and rev (34 and 32%) than to gp160 (13%). CD8 MHC class I-restricted responses to env, gag, and RT were assayed in 13 vaccinees and 2 controls: 8/13 vaccinees responded at week 10 or 26 vs. 0/2 controls. VL measured throughout the study was <400 copies/ml in 20/21 subjects on entry. Over the 52 weeks of study, 3/5 placebo recipients developed detectable VL compared with 1/14 vaccine recipients originally undetectable (p < 0.044).
Conclusions: The HIV DNA constructs had no significant toxicity in well-controlled HIV-positive patients. Rev and p24 were more effective antigens for LPA induction than gp160. Anti-HIV CD8 responses developed more often in vaccinees than controls, and vaccinees had significantly fewer viral relapses, suggesting enhanced antiviral control.
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