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-¿, TNF-a 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-¿ 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-¿, TNF-a 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-¿ 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

VL - 186

SP - 2355

EP - 2364

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 4

ER -