title: Targeting the antigen encoded by adenoviral vectors to the DEC205 receptor modulates the cellular and humoral immune response.
abstract: Replication-defective adenoviral vectors have emerged as promising vaccine candidates for diseases relying on strong CD8(+) T-cell responses for protection. In this study, we modified a non-replicative adenoviral vector to selectively deliver, in situ, an encoded ovalbumin (OVA) model antigen to dendritic cells (DCs). Efficient uptake and presentation of OVA was achieved through fusion of the antigen to a single-chain antibody directed against DEC205, an endocytic receptor expressed on DCs. The immunogenicity of the vaccine was thereby enhanced as demonstrated by elevated antibody levels and increased T-cell responses after low-dose vaccination with 10(7) viral particles compared with a non-targeted control. Nevertheless, after immunization with higher doses of the targeted vaccine, the capacity of vaccine-induced CD8(+) T cells to produce the cytokine IL-2 was diminished and the CD8(+) T-cell response was dominated by an effector memory phenotype (CD62L(-)/CD127(+)) in contrast to the effector phenotype (CD62L(-)/CD127(-)) observed after non-targeted antigen delivery. Interestingly, the protective capacity of the non-targeted vaccine was superior to that of the targeted vaccine in an antigen-specific vaccinia virus infection as well as in a tumor challenge model. In the latter, the low dose of the DC-targeted vaccine also conferred partial protection from tumor growth, demonstrating dose-dependent effects of the DC-targeting on the quality of the vaccine-induced immune response. Significant differences could be observed in regard to the antibody pattern, the functional and phenotypic T-cell repertoire, and to the protective capacity.
authors.affiliation: Department of Molecular and Medical Virology, Ruhr-Universität Bochum, Germany. matthias.tenbusch@rub.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Tenbusch
authors.forename: Godwin
authors.initials: G
authors.lastname: Nchinda
authors.forename: Michael
authors.initials: M
authors.lastname: Storcksdieck genannt Bonsmann
authors.forename: Vladimir
authors.initials: V
authors.lastname: Temchura
authors.forename: Klaus
authors.initials: K
authors.lastname: Überla
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000917:Antibody Formation; D017951:Antigen Presentation; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D058990:Molecular Targeted Therapy; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C093569:DEC-205 receptor; D007376:Interleukin-2; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D057127:Single-Chain Antibodies; D010047:Ovalbumin