TY - JOUR

T1 - MHC class II-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines

AU - Holst, Peter Johannes

AU - Mandrup Jensen, Camilla Maria

AU - Orskov, Cathrine

AU - Thomsen, Allan Randrup

AU - Christensen, Jan Pravsgaard

AU - Sørensen, Maria Rathmann

N1 - Keywords: Adenoviridae; Animals; Antigens, Differentiation, B-Lymphocyte; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cells, Cultured; Coculture Techniques; Genetic Vectors; Histocompatibility Antigens Class II; Immunity, Cellular; Lymphocytic choriomeningitis virus; Lysosomal-Associated Membrane Protein 1; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nucleocapsid Proteins; Viral Envelope Proteins; Viral Vaccines

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

M3 - Journal article

C2 - 18292559

VL - 180

SP - 3339

EP - 3346

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -