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* Institute of International Health, Immunology and Microbiology, The Panum Institute, Copenhagen, Denmark; and
Institute of Medical Anatomy, The Panum Institute, Copenhagen, Denmark
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by the Novo Nordisk Foundation, the Danish Cancer Society, the Lundbeck Foundation, the Sophus C. E. Friis Foundation, the Foundation for the Advancement of Medical Sciences, Aase and Ejnar Danielsen Foundation, The Hede Nielsen Family Foundation, The Leo Nielsen Foundation, Merchant Foght’s Foundation, the Christian and Ellen Larsen Foundation, and The Leo Pharma Research Foundation. P.J.H. and M.R.S. are the recipients of Research Fellowships from the Faculty of Health Science, University of Copenhagen.
2 Address correspondence and reprint requests to Dr. Allan Randrup Thomsen, Institute of International Health, Immunology, and Microbiology. The Panum Institute, Building 22.5.18, Blegdamsvej 3c, DK-2200 Copenhagen, Denmark. E-mail address: a.r.thomsen{at}immi.ku.dk
3 Abbreviations used in this paper: HCV, hepatitis C virus; Ii, invariant chain; LCMV, lymphocytic choriomeningitis virus; NP, nucleoprotein; WT, wild type; DC, dendritic cell; BMDC, bone marrow-derived DC; MOI, multiplicity of infection; i.c., intracerebral(ly).
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  M. Grujic, P. J. Holst, J. P. Christensen, and A. R. Thomsen Fusion of a viral antigen to invariant chain leads to augmented T-cell immunity and improved protection in gene-gun DNA-vaccinated mice J. Gen. Virol., February 1, 2009; 90(2): 414 - 422. [Abstract] [Full Text] [PDF]
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