TY - JOUR
T1 - Enhanced and sustained CD8+ T cell responses with an adenoviral vector-based hepatitis C virus vaccine encoding NS3 linked to the MHC class II chaperone protein invariant chain
AU - Mikkelsen, Marianne
AU - Holst, Peter Johannes
AU - Bukh, Jens
AU - Thomsen, Allan Randrup
AU - Christensen, Jan Pravsgaard
PY - 2011/2/15
Y1 - 2011/2/15
N2 - Potent and broad cellular immune responses against the nonstructural (NS) proteins of hepatitis C virus (HCV) are associated with spontaneous viral clearance. In this study, we have improved the immunogenicity of an adenovirus (Ad)-based HCV vaccine by fusing NS3 from HCV (Strain J4; Genotype 1b) to the MHC class II chaperone protein invariant chain (Ii). We found that, after a single vaccination of C57BL/6 or BALB/c mice with Ad-IiNS3, the HCV NS3-specific CD8+ T cell responses were significantly enhanced, accelerated, and prolonged compared with the vaccine encoding NS3 alone. The AdIiNS3 vaccination induced polyfunctional CD8+ T cells characterized by coproduction of IFN-γ, TNF-α and IL-2, and this cell phenotype is associated with good viral control. The memory CD8+ T cells also expressed high levels of CD27 and CD127, which are markers of long-term survival and maintenance of T cell memory. Functionally, the AdIiNS3-vaccinated mice had a significantly increased cytotoxic capacity compared with the AdNS3 group. The AdIiNS3-induced CD8+ T cells protected mice from infection with recombinant vaccinia virus expressing HCV NS3 of heterologous 1b strains, and studies in knockout mice demonstrated that this protection was mediated primarily through IFN-γ production. On the basis of these promising results, we suggest that this vaccination technology should be evaluated further in the chimpanzee HCV challenge model.
AB - Potent and broad cellular immune responses against the nonstructural (NS) proteins of hepatitis C virus (HCV) are associated with spontaneous viral clearance. In this study, we have improved the immunogenicity of an adenovirus (Ad)-based HCV vaccine by fusing NS3 from HCV (Strain J4; Genotype 1b) to the MHC class II chaperone protein invariant chain (Ii). We found that, after a single vaccination of C57BL/6 or BALB/c mice with Ad-IiNS3, the HCV NS3-specific CD8+ T cell responses were significantly enhanced, accelerated, and prolonged compared with the vaccine encoding NS3 alone. The AdIiNS3 vaccination induced polyfunctional CD8+ T cells characterized by coproduction of IFN-γ, TNF-α and IL-2, and this cell phenotype is associated with good viral control. The memory CD8+ T cells also expressed high levels of CD27 and CD127, which are markers of long-term survival and maintenance of T cell memory. Functionally, the AdIiNS3-vaccinated mice had a significantly increased cytotoxic capacity compared with the AdNS3 group. The AdIiNS3-induced CD8+ T cells protected mice from infection with recombinant vaccinia virus expressing HCV NS3 of heterologous 1b strains, and studies in knockout mice demonstrated that this protection was mediated primarily through IFN-γ production. On the basis of these promising results, we suggest that this vaccination technology should be evaluated further in the chimpanzee HCV challenge model.
KW - Adenoviridae
KW - Animals
KW - Antigens, CD27
KW - Antigens, Differentiation, B-Lymphocyte
KW - CD8-Positive T-Lymphocytes
KW - Cell Survival
KW - Cytotoxicity Tests, Immunologic
KW - Disease Models, Animal
KW - Epitopes, T-Lymphocyte
KW - Female
KW - Genetic Vectors
KW - Hepacivirus
KW - Hepatitis C
KW - Histocompatibility Antigens Class II
KW - Immunologic Memory
KW - Immunophenotyping
KW - Interleukin-7 Receptor alpha Subunit
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Recombinant Fusion Proteins
KW - Vaccinia virus
KW - Viral Hepatitis Vaccines
KW - Viral Nonstructural Proteins
U2 - 10.4049/jimmunol.1001877
DO - 10.4049/jimmunol.1001877
M3 - Journal article
C2 - 21257961
SN - 0022-1767
VL - 186
SP - 2355
EP - 2364
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -
