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Vaccines and Antiviral Agents | Spotlight

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, 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
Nilu Goonetilleke
1Centre for Clinical Vaccinology and Tropical Medicine
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  • For correspondence: nilu.goonetilleke@ndm.ox.ac.uk
Stephen Moore
1Centre for Clinical Vaccinology and Tropical Medicine
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Len Dally
2The EMMES Corporation, Rockville, Maryland
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Nicola Winstone
1Centre for Clinical Vaccinology and Tropical Medicine
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Inese Cebere
1Centre for Clinical Vaccinology and Tropical Medicine
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Abdul Mahmoud
1Centre for Clinical Vaccinology and Tropical Medicine
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Susana Pinheiro
1Centre for Clinical Vaccinology and Tropical Medicine
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Geraldine Gillespie
3MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford
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Denise Brown
1Centre for Clinical Vaccinology and Tropical Medicine
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Vanessa Loach
1Centre for Clinical Vaccinology and Tropical Medicine
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Joanna Roberts
1Centre for Clinical Vaccinology and Tropical Medicine
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Ana Guimaraes-Walker
1Centre for Clinical Vaccinology and Tropical Medicine
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Peter Hayes
4IAVI Core Laboratory, Imperial College, London, United Kingdom
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Kelley Loughran
2The EMMES Corporation, Rockville, Maryland
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Carole Smith
2The EMMES Corporation, Rockville, Maryland
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Jan De Bont
5International AIDS Vaccine Initiative, New York, New York
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Carl Verlinde
5International AIDS Vaccine Initiative, New York, New York
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Danii Vooijs
5International AIDS Vaccine Initiative, New York, New York
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Claudia Schmidt
5International AIDS Vaccine Initiative, New York, New York
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Mark Boaz
5International AIDS Vaccine Initiative, New York, New York
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Jill Gilmour
5International AIDS Vaccine Initiative, New York, New York
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Pat Fast
5International AIDS Vaccine Initiative, New York, New York
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Lucy Dorrell
1Centre for Clinical Vaccinology and Tropical Medicine
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Tomas Hanke
3MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford
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Andrew J. McMichael
1Centre for Clinical Vaccinology and Tropical Medicine
3MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford
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DOI: 10.1128/JVI.80.10.4717-4728.2006
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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 (2× MVA.HIVA) (n = 8) or two doses of placebo (2× placebo) (n = 4). The second group received 2× pTHr.HIVA followed by one dose of MVA.HIVA (n = 8) or 3× 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-γ) ELISPOT (group mean, 210 spot-forming cells/106 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 2× MVA.HIVA group or subjects receiving placebo. Using a highly sensitive and reproducible cultured IFN-γ 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 2× 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 1β. 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.

  • Copyright © 2006 American Society for Microbiology
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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, 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
Journal of Virology Apr 2006, 80 (10) 4717-4728; DOI: 10.1128/JVI.80.10.4717-4728.2006

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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 Couple…
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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, 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
Journal of Virology Apr 2006, 80 (10) 4717-4728; DOI: 10.1128/JVI.80.10.4717-4728.2006
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KEYWORDS

AIDS Vaccines
CD8-Positive T-Lymphocytes
cell proliferation
Epitopes, T-Lymphocyte
Gene Products, gag
Immunization, Secondary
Lymphocyte Activation
Vaccines, DNA

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