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Göteborgs universitets publikationer

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

Författare och institution:
Michael Lebens (Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi); Manuela Terrinoni (Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi); Stefan L. Karlsson (Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi); Maximilian Larena (Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi); Tobias Gustafsson-Hedberg (Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi); Susanne Källgård (Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi); Erik Nygren (Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi); Jan Holmgren (Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi)
Publicerad i:
Vaccine, 34 ( 18 ) s. 2121-2128
ISSN:
0264-410X
Publikationstyp:
Artikel, refereegranskad vetenskaplig
Publiceringsår:
2016
Språk:
engelska
Fulltextlänk:
Sammanfattning (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.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP ->
Medicinska grundvetenskaper ->
Mikrobiologi inom det medicinska området
Nyckelord:
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
Postens nummer:
237448
Posten skapad:
2016-06-08 14:08

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