Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man.
Currently, no vaccine exists for hepatitis C virus (HCV), a major pathogen thought to infect 170 million people globally. Many studies suggest that host T cell responses are critical for spontaneous resolution of disease, and preclinical studies have indicated a requirement for T cells in protection against challenge. We aimed to elicit HCV-specific T cells with the potential for protection using a recombinant adenoviral vector strategy in a phase 1 study of healthy human volunteers. Two adenoviral vectors expressing NS proteins from HCV genotype 1B were constructed based on rare serotypes [human adenovirus 6 (Ad6) and chimpanzee adenovirus 3 (ChAd3)]. Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A). HCV-specific T cells consisted of both CD4+ and CD8+ T cell subsets; secreted interleukin-2, interferon-γ, and tumor necrosis factor-α; and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using major histocompatibility complex peptide tetramers revealed long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity. These data indicate that an adenoviral vector strategy can induce sustained T cell responses of a magnitude and quality associated with protective immunity and open the way for studies of prophylactic and therapeutic vaccines for HCV.
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
Eleanor
E
Barnes
Antonella
A
Folgori
Stefania
S
Capone
Leo
L
Swadling
Stephen
S
Aston
Ayako
A
Kurioka
Joel
J
Meyer
Rachel
R
Huddart
Kira
K
Smith
Rachel
R
Townsend
Anthony
A
Brown
Richard
R
Antrobus
Virginia
V
Ammendola
Mariarosaria
M
Naddeo
Geraldine
G
O'Hara
Chris
C
Willberg
Abby
A
Harrison
Fabiana
F
Grazioli
Maria Luisa
ML
Esposito
Loredana
L
Siani
Cinzia
C
Traboni
Ye
Y
Oo
David
D
Adams
Adrian
A
Hill
Stefano
S
Colloca
Alfredo
A
Nicosia
Riccardo
R
Cortese
Paul
P
Klenerman
D000256:Adenoviridae / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000821:virology; D049109:Cell Proliferation; D005838:Genotype; D057809:HEK293 Cells; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000166:cytology; D013601:T-Lymphocytes / Q000821:virology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014761:Viral Hepatitis Vaccines / Q000627:therapeutic use*
D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D014761:Viral Hepatitis Vaccines; D007371:Interferon-gamma