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CTA1-DD-Immune Stimulating Complexes: a Novel, Rationally Designed Combined Mucosal Vaccine Adjuvant Effective with Nanogram Doses of Antigen¹

Allan M. I. Mowat^2,*, Anne M. Donachie^*, Sara Jägewall, Karin Schön, Björn Löwenadler, Kristian Dalsgaard, Peter Kaastrup and Nils Lycke

^* Department of Immunology and Bacteriology, University of Glasgow, Western Infirmary, Glasgow, Scotland; Department of Clinical Immunology, University of Göteborg, Göteborg, Sweden; AstraZeneca R&D, Mölndal, Sweden; and Department of Microbiology and Immunology, Panum Institute, University of Copenhagen, Copenhagen, Denmark

Mucosally active vaccine adjuvants that will prime a full range of local and systemic immune responses against defined antigenic epitopes are much needed. Cholera toxin and lipophilic immune stimulating complexes (ISCOMS) containing Quil A can both act as adjuvants for orally administered Ags, possibly by targeting different APCs. Recently, we have been successful in separating the adjuvant and toxic effects of cholera toxin by constructing a gene fusion protein, CTA1-DD, that combines the enzymatically active CTA1-subunit with a B cell-targeting moiety, D, derived from Staphylococcus aureus protein A. Here we have extended this work by combining CTA1-DD with ISCOMS, which normally target dendritic cells and/or macrophages. ISCOMS containing a fusion protein comprising the OVA_323–339 peptide epitope linked to CTA1-DD were highly immunogenic when given in nanogram doses by the s.c., oral, or nasal routes, inducing a wide range of T cell-dependent immune responses. In contrast, ISCOMS containing the enzymatically inactive CTA1-R7K-DD mutant protein were much less effective, indicating that at least part of the activity of the combined vector requires the ADP-ribosylating property of CTA1. No toxicity was observed by any route. To our knowledge, this is the first report on the successful combination of two mechanistically different principles of adjuvant action. We conclude that rationally designed vectors consisting of CTA1-DD and ISCOMS may provide a novel strategy for the generation of potent and safe mucosal vaccines.

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				C. S. Andersen, J. Dietrich, E. M. Agger, N. Y. Lycke, K. Lovgren, and P. Andersen The Combined CTA1-DD/ISCOMs Vector Is an Effective Intranasal Adjuvant for Boosting Prior Mycobacterium bovis BCG Immunity to Mycobacterium tuberculosis Infect. Immun., January 1, 2007; 75(1): 408 - 416. [Abstract] [Full Text] [PDF]

				A. Helgeby, N. C. Robson, A. M. Donachie, H. Beackock-Sharp, K. Lovgren, K. Schon, A. Mowat, and N. Y. Lycke The Combined CTA1-DD/ISCOM Adjuvant Vector Promotes Priming of Mucosal and Systemic Immunity to Incorporated Antigens by Specific Targeting of B Cells J. Immunol., March 15, 2006; 176(6): 3697 - 3706. [Abstract] [Full Text] [PDF]