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.
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.
Goonetilleke
Nilu
N
Centre for Clinical Vaccinology and Tropical Medicine and MRC Human Immunology Unit, University of Oxford, Oxford OX3 7LJ, United Kingdom. nilu.goonetilleke@ndm.ox.ac.uk
Moore
Stephen
S
Dally
Len
L
Winstone
Nicola
N
Cebere
Inese
I
Mahmoud
Abdul
A
Pinheiro
Susana
S
Gillespie
Geraldine
G
Brown
Denise
D
Loach
Vanessa
V
Roberts
Joanna
J
Guimaraes-Walker
Ana
A
Hayes
Peter
P
Loughran
Kelley
K
Smith
Carole
C
De Bont
Jan
J
Verlinde
Carl
C
Vooijs
Danii
D
Schmidt
Claudia
C
Boaz
Mark
M
Gilmour
Jill
J
Fast
Pat
P
Dorrell
Lucy
L
Hanke
Tomas
T
McMichael
Andrew J
AJ
D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004311:Double-Blind Method; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D015683:Gene Products, gag / Q000276:immunology* / Q000378:metabolism; D005822:Genetic Vectors; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007117:Immunization, Secondary; D008213:Lymphocyte Activation / Q000276:immunology*; D008969:Molecular Sequence Data; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology
D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic