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Construction and preclinical evaluation of mmCT, a novel mutant cholera toxin adjuvant that can be efficiently produced in genetically manipulated Vibrio cholerae

Journal article
Authors Michael Lebens
Manuela Terrinoni
Stefan L. Karlsson
Maximilian Larena
Tobias Gustafsson-Hedberg
Susanne Källgård
Erik Nygren
Jan Holmgren
Published in Vaccine
Volume 34
Issue 18
Pages 2121-2128
ISSN 0264-410X
Publication year 2016
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Pages 2121-2128
Language en
Links dx.doi.org/10.1016/j.vaccine.2016.0...
Keywords Adjuvant, Cholera toxin, Mucosal immunity, Mucosal vaccine, enterotoxigenic escherichia-coli, b-subunit, vaccine development, recent, progress, dmlt adjuvant, etec vaccine, t-cells, immunogenicity, generation, antibodies, Immunology, Research & Experimental Medicine, lorenzo v, 1994, bacterial pathogenesis, pt a, v235, p386
Subject categories Microbiology in the medical area

Abstract

There is an urgent need for new adjuvants that are effective with mucosally administered vaccines. Cholera toxin (CT) is the most powerful known mucosal adjuvant but is much too toxic for human use. In an effort to develop a useful mucosal adjuvant we have generated a novel non-toxic mutant CT molecule that retains much of the adjuvant activity of native CT. This was achieved by making the enzymatically active A subunit (CTA) recalcitrant to the site-specific proteolytic cleavage ("nicking") required for toxicity, which was found to require mutations not only in the two residues rendering the molecule resistant to trypsin but also in neighboring sites protecting against cleavage by Vibrio cholerae proteases. This multiple-mutated CT (mmCT) adjuvant protein could be efficiently produced in and purified from the extracellular medium of CT-deleted V. cholerae. The mmCT completely lacked detectable enterotoxicity in an infant mouse model and had >1000-fold reduced cAMP inducing activity compared to native CT in a sensitive mammalian target cell system. It nonetheless proved to have potent adjuvant activity on mucosal and systemic antibody as well as cellular immune responses to mucosally co-administered antigens including oral cholera and intranasal influenza vaccines. We conclude that mmCT is an attractive novel non-toxic mucosal adjuvant for enhancing immune responses to co-administered mucosal vaccines. (C) 2016 Elsevier Ltd. All rights reserved.

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