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Journal of Virology, May 2006, p. 4717-4728, Vol. 80, No. 10
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.10.4717-4728.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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{dagger}

Nilu Goonetilleke,1* Stephen Moore,1 Len Dally,2 Nicola Winstone,1 Inese Cebere,1 Abdul Mahmoud,1 Susana Pinheiro,1 Geraldine Gillespie,3 Denise Brown,1 Vanessa Loach,1 Joanna Roberts,1 Ana Guimaraes-Walker,1 Peter Hayes,4 Kelley Loughran,2 Carole Smith,2 Jan De Bont,5 Carl Verlinde,5 Danii Vooijs,5 Claudia Schmidt,5 Mark Boaz,5 Jill Gilmour,5 Pat Fast,5 Lucy Dorrell,1 Tomas Hanke,3 and Andrew J. McMichael1,3

Centre for Clinical Vaccinology and Tropical Medicine,1 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford,3 IAVI Core Laboratory, Imperial College, London, United Kingdom,4 The EMMES Corporation, Rockville, Maryland,2 International AIDS Vaccine Initiative, New York, New York5

Received 22 November 2005/ Accepted 2 March 2006

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/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 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 1ß. 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.

* Corresponding author. Mailing address: Oxford University, CCVTM, Old Road, Churchill Hospital, Oxford OX3 7LJ, United Kingdom. Phone: 44-1865-222-145. Fax: 44-1865-222-502. E-mail: nilu.goonetilleke{at}ndm.ox.ac.uk.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org.

Journal of Virology, May 2006, p. 4717-4728, Vol. 80, No. 10
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.10.4717-4728.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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