title: Nonintegrating lentivector vaccines stimulate prolonged T-cell and antibody responses and are effective in tumor therapy.
abstract: Lentiviral vectors (lentivectors) are effective for stimulation of cell-mediated and humoral immunity following subcutaneous and intramuscular immunization. However, lentivector genome integration carries a risk of perturbation of host gene expression. Here, we demonstrate that lentivectors with multiple mutations that prevent integration are also effective immunogens. First, systemic CD8(+) T-cell responses to the model antigen ovalbumin were detected following subcutaneous injection of nonintegrating lentivectors. Transfer of transgenic OT1 T cells demonstrated that antigen presentation persisted for at least 30 days. Furthermore, an enhanced CD8(+) T-cell response, peaking at 7 days, was stimulated by coexpression of p38 MAP kinase or an NF-kappaB activator from the same vector. Second, we demonstrated systemic CD8(+) T-cell and antibody responses to the secreted hepatitis B virus (HBV) surface antigen expressed from a nonintegrating lentivector injected intramuscularly. The induction, specificity, and kinetics of antibody production closely mimicked those of natural HBV infection. In this case, both the vector genome and the immune response were maintained for at least 2 months. Together, our data indicate that nonintegrating lentivectors can be employed to generate effective vaccines.
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Karwacz
authors.forename: Sayandip
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Luis
authors.initials: L
authors.lastname: Apolonia
authors.forename: Michael P
authors.initials: MP
authors.lastname: Blundell
authors.forename: Gerben
authors.initials: G
authors.lastname: Bouma
authors.forename: David
authors.initials: D
authors.lastname: Escors
authors.forename: Mary K
authors.initials: MK
authors.lastname: Collins
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood*; D019496:Cancer Vaccines / Q000276:immunology*; D005822:Genetic Vectors; D017325:Hepatitis B Vaccines / Q000276:immunology*; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009369:Neoplasms / Q000473:pathology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology*; D016662:Virus Integration
chemical_list: D000912:Antibodies, Neoplasm; D000914:Antibodies, Viral; D019496:Cancer Vaccines; D017325:Hepatitis B Vaccines