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

Marianne Mikkelsen; Peter Johannes Holst; Jens Bukh; Allan Randrup Thomsen; Jan Pravsgaard Christensen

doi:10.4049/jimmunol.1001877

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

Marianne Mikkelsen, Peter Johannes Holst, Jens Bukh, Allan Randrup Thomsen, Jan Pravsgaard Christensen

Department of Immunology and Microbiology

47 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Immunology
Volume	186
Issue number	4
Pages (from-to)	2355-64
Number of pages	10
ISSN	0022-1767
DOIs	https://doi.org/10.4049/jimmunol.1001877
Publication status	Published - 15 Feb 2011

Keywords

Adenoviridae
Animals
Antigens, CD27
Antigens, Differentiation, B-Lymphocyte
CD8-Positive T-Lymphocytes
Cell Survival
Cytotoxicity Tests, Immunologic
Disease Models, Animal
Epitopes, T-Lymphocyte
Female
Genetic Vectors
Hepacivirus
Hepatitis C
Histocompatibility Antigens Class II
Immunologic Memory
Immunophenotyping
Interleukin-7 Receptor alpha Subunit
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Recombinant Fusion Proteins
Vaccinia virus
Viral Hepatitis Vaccines
Viral Nonstructural Proteins

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.4049/jimmunol.1001877

http://www.jimmunol.org/content/186/4/2355.full.pdf

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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. / Mikkelsen, Marianne; Holst, Peter Johannes ; Bukh, Jens et al.
In: Journal of Immunology, Vol. 186, No. 4, 15.02.2011, p. 2355-64.

Research output: Contribution to journal › Journal article › Research › peer-review

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abstract = "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.",

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AU - Holst, Peter Johannes

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AU - Thomsen, Allan Randrup

AU - Christensen, Jan Pravsgaard

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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.

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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 -

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

Abstract

Keywords

UN SDGs

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