title: Recombinant adenoviral vector expressing HCV NS4 induces protective immune responses in a mouse model of Vaccinia-HCV virus infection: a dose and route conundrum.
abstract: Hepatitis C virus (HCV) leads to chronic infection in the majority of infected patients presumably due to failure or inefficiency of the immune responses generated. Both antibody and cellular immune responses have been suggested to be important in viral clearance. Non-replicative adenoviral vectors expressing antigens of interest are considered as attractive vaccine vectors for a number of pathogens. In this study, we sought to evaluate cellular and humoral immune responses against HCV NS4 protein using recombinant adenovirus as a vaccine vector expressing NS4 antigen. We have also measured the effect of antigen doses and routes of immunization on the quality and extent of the immune responses, especially their role in viral load reduction, in a recombinant Vaccinia-HCV (Vac-HCV) infection mouse model. Our results show that an optimum dose of adenovirus vector (2×10(7)pfu/mouse) administered intramuscularly (i.m.) induces high T cell proliferation, granzyme B-expressing CD8(+) T cells, pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-2 and IL-6, and antibody responses that can significantly reduce the Vac-HCV viral load in the ovaries of female C57BL/6 mice. Our results demonstrate that recombinant adenovirus vector can induce both humoral and cellular protective immunity against HCV-NS4 antigen, and that immunity is intricately controlled by route and dose of immunizing vector.
authors.affiliation: Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Shakti
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Satish
authors.initials: S
authors.lastname: Vedi
authors.affiliation: Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Subodh Kumar
authors.initials: SK
authors.lastname: Samrat
authors.affiliation: Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. Electronic address: bagrawal@ualberta.ca.
authors.forename: Babita
authors.initials: B
authors.lastname: Agrawal
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D016207:Cytokines / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D016174:Hepacivirus / Q000276:immunology; D006526:Hepatitis C / Q000517:prevention & control*; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007114:Immunization / Q000379:methods*; D007156:Immunologic Memory; D007273:Injections, Intramuscular; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology; D014761:Viral Hepatitis Vaccines / Q000276:immunology*; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D016207:Cytokines; C093542:NS4 protein, hepatitis C virus; D014614:Vaccines, Synthetic; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins
keywords: Adenoviral vector; Dose; Hepatitis C virus; Immune responses; Immunization; NS4; Route; Vaccinia-HCV challenge