Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes - PubMed (original) (raw)

Clinical Trial

. 2006 May;80(10):4717-28.

doi: 10.1128/JVI.80.10.4717-4728.2006.

Stephen Moore, Len Dally, Nicola Winstone, Inese Cebere, Abdul Mahmoud, Susana Pinheiro, Geraldine Gillespie, Denise Brown, Vanessa Loach, Joanna Roberts, Ana Guimaraes-Walker, Peter Hayes, Kelley Loughran, Carole Smith, Jan De Bont, Carl Verlinde, Danii Vooijs, Claudia Schmidt, Mark Boaz, Jill Gilmour, Pat Fast, Lucy Dorrell, Tomas Hanke, Andrew J McMichael

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Clinical Trial

Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes

Nilu Goonetilleke et al. J Virol. 2006 May.

Abstract

A double-blind randomized phase I trial was conducted in human immunodeficiency virus type 1 (HIV-1)-negative subjects receiving vaccines vectored by plasmid DNA and modified vaccinia virus Ankara (MVA) expressing HIV-1 p24/p17 gag linked to a string of CD8(+) T-cell epitopes. The trial had two groups. One group received either two doses of MVA.HIVA (2x MVA.HIVA) (n=8) or two doses of placebo (2x placebo) (n=4). The second group received 2x pTHr.HIVA followed by one dose of MVA.HIVA (n=8) or 3x placebo (n=4). In the pTHr.HIVA-MVA.HIVA group, HIV-1-specific T-cell responses peaked 1 week after MVA.HIVA vaccination in both ex vivo gamma interferon (IFN-gamma) ELISPOT (group mean, 210 spot-forming cells/10(6) cells) and proliferation (group mean stimulation index, 37), with assays detecting positive responses in four out of eight and five out of eight subjects, respectively. No HIV-1-specific T-cell responses were detected in either assay in the 2x MVA.HIVA group or subjects receiving placebo. Using a highly sensitive and reproducible cultured IFN-gamma ELISPOT assay, positive responses mainly mediated by CD4(+) T cells were detected in eight out of eight vaccinees in the pTHr.HIVA-MVA.HIVA group and four out of eight vaccinees in the 2x MVA.HIVA group. Importantly, no false-positive responses were detected in the eight subjects receiving placebo. Of the 12 responders, 11 developed responses to previously identified immunodominant CD4(+) T-cell epitopes, with 6 volunteers having responses to more than one epitope. Five out of 12 responders also developed CD8(+) T-cell responses to the epitope string. Induced T cells produced a variety of anti-viral cytokines, including tumor necrosis factor alpha and macrophage inflammatory protein 1 beta. These data demonstrate that prime-boost vaccination with recombinant DNA and MVA vectors can induce multifunctional HIV-1-specific T cells in the majority of vaccinees.

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Figures

FIG. 1.

FIG. 1.

MVA.HIVA boosts pTHr.HIVA-induced T-cell responses measured in ex vivo IFN-γ ELISPOT. Subjects (eight per group) were vaccinated with pTHr.HIVA-MVA.HIVA (black circles), MVA.HIVA alone (open circle), or saline placebo (dashed line). Mean background-subtracted responses are shown for ex vivo IFN-γ ELISPOT (A) and IL-7-IL-15-supplemented ex vivo IFN-γ ELISPOT (B). Arrows indicate vaccinations in the pTHr.HIVA-MVA.HIVA group of pTHr.HIVA (open arrow) and MVA.HIVA (closed arrow). *, P < 0.05; **, P < 0.01 by ANOVA (Kruskal-Wallis test). SCR, bleed taken at screening visit.

FIG. 2.

FIG. 2.

MVA.HIVA boosts pTHr.HIVA-induced HIVA-specific proliferative responses. Subjects (eight per group) were vaccinated with either pTHr.HIVA-MVA (black circles), MVA.HIVA alone (open circle), or saline placebo (dashed line). Mean SI per group are shown in the[3H]thymidine proliferation assays (A). A positive proliferation index (PI) as measured by CFSE staining was observed in subject 1 from the pTHr.HIVA-MVA group 1 week after receiving MVA.HIVA (B). Arrows indicate vaccinations in the pTHr.HIVA-MVA group of pTHr.HIVA (open arrow) and MVA.HIVA (closed arrow). *, P < 0.05 by ANOVA (Kruskal-Wallis test). SCR, bleed taken at screening visit.

FIG. 3.

FIG. 3.

MVA.HIVA boosts pTHr.HIVA-induced T-cell responses measured in WB-ICS assays. Subjects (eight per group) were vaccinated with pTHr.HIVA-MVA.HIVA (black circles), MVA.HIVA alone (open circle), or saline placebo (dashed line). (A) The mean percentages of background-subtracted events in the CD3/CD4 or CD8/CD69/IFN-γ gate are shown for IFN-γ WB-ICS. (B) Despite significant differences in response following vaccination between groups, only subject 1 from the pTHr.HIVA-MVA.HIVA group produced a positive response 1 week after the MVA.HIVA boost (Table 2). Arrows indicate vaccinations in the pTHr.HIVA-MVA group of pTHr.HIVA (open arrow) and MVA.HIVA (closed arrow). *, P < 0.05; **, P < 0.01 by ANOVA (Kruskal-Wallis test). SCR, bleed taken at screening visit.

FIG. 4.

FIG. 4.

MVA.HIVA boosts pTHr.HIVA-induced T-cell responses measured in cultured IFN-γ ELISPOT. Subjects (eight per group) were vaccinated with pTHr.HIVA-MVA.HIVA (black circles), MVA.HIVA alone (open circle), or saline placebo (dashed line). Mean background-subtracted responses per group are shown for pool 90 STCL (A) and pool 9 STCL (B). Arrows indicate vaccinations in the pTHr.HIVA-MVA.HIVA group of pTHr.HIVA (open arrow) and MVA.HIVA (closed arrow). *, P < 0.05 by ANOVA (Kruskal-Wallis test). SCR, bleed taken at screening visit.

FIG. 5.

FIG. 5.

HIVA-specific cells expanded in culture secrete multiple cytokines. Culture supernatants from pool 90 and pool 9 STCL derived from week 10 bleeds after stimulation with mock, pool 90 or pool 9, or SEB. The average mock-subtracted cytokine concentrations in supernatants from the pool 90 STCL for subjects in the pTHr.HIVA-MVA.HIVA group (n = 7) are shown in panel A, and cytokine concentrations in supernatants from the pool 9 STCL for subject 1 from the pTHr.HIVA-MVA group are shown in panel B. *, P < 0.05 (Spearman's nonparametric correlation coefficient corrected for multiple comparisons).

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