title: MHC class II-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines.
abstract: The ideal vaccine induces a potent protective immune response, which should be rapidly induced, long-standing, and of broad specificity. Recombinant adenoviral vectors induce potent Ab and CD8+ T cell responses against transgenic Ags within weeks of administration, and they are among the most potent and versatile Ag delivery vehicles available. However, the impact of chronic infections like HIV and hepatitis C virus underscore the need for further improvements. In this study, we show that the protective immune response to an adenovirus-encoded vaccine Ag can be accelerated, enhanced, broadened, and prolonged by tethering of the rAg to the MHC class II-associated invariant chain (Ii). Thus, adenovirus-vectored vaccines expressing lymphocytic choriomeningitis virus (LCMV)-derived glycoprotein linked to Ii increased the CD4+ and CD8+ T cell stimulatory capacity in vitro and in vivo. Furthermore, mice vaccinated with a single dose of adenovirus-expressing LCMV-derived glycoprotein linked to Ii were protected against lethal virus-induced choriomeningitis, lethal challenge with strains mutated in immunodominant T cell epitopes, and systemic infection with a highly invasive strain. In therapeutic tumor vaccination, the vaccine was as efficient as live LCMV. In comparison, animals vaccinated with a conventional adenovirus vaccine expressing unmodified glycoprotein were protected against systemic infection, but only temporarily against lethal choriomeningitis, and this vaccine was less efficient in tumor therapy.
authors.affiliation: Institute of International Health, Immunology and Microbiology, The Panum Institute, Copenhagen, Denmark.
authors.forename: Peter Johannes
authors.initials: PJ
authors.lastname: Holst
authors.forename: Maria Rathmann
authors.initials: MR
authors.lastname: Sorensen
authors.forename: Camilla Maria
authors.initials: CM
authors.lastname: Mandrup Jensen
authors.forename: Cathrine
authors.initials: C
authors.lastname: Orskov
authors.forename: Allan Randrup
authors.initials: AR
authors.lastname: Thomsen
authors.forename: Jan Pravsgaard
authors.initials: JP
authors.lastname: Christensen
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005822:Genetic Vectors; D000949:Histocompatibility Antigens Class II / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D007111:Immunity, Cellular / Q000235:genetics; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019590:Nucleocapsid Proteins / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D019496:Cancer Vaccines; D000949:Histocompatibility Antigens Class II; D052118:Lysosomal-Associated Membrane Protein 1; D019590:Nucleocapsid Proteins; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; C045084:invariant chain