Mucosal vaccines: non toxic derivatives of LT and CT as mucosal adjuvants

Clostridium difficileToxin A Carboxyl-Terminus Peptide Lacking ADP-Ribosyltransferase Activity Acts as a Mucosal Adjuvant

“…However, the development of effective mucosal vaccines is still jeopardized by the poor immunological properties of nonreplicating antigens and the lack of efficient delivery systems and mucosal adjuvants (14). To date the most effective mucosal adjuvants are CT and LT and their genetically detoxified mutant versions, which are used as vaccine carriers and immunomodulators (38). Here we report that a recombinant peptide, the nontoxic carboxy-terminus domain of C. difficile toxin A, demonstrates robust adjuvant properties when coadministered with poor antigens via mucosal routes.…”

“…CT and LT, as well as mistletoe lectins, possess a catalytic domain and a carbohydrate recognition domain able to bind simultaneously several specific membrane receptors. Recent studies aimed at developing new effective mucosal adjuvants have generated nontoxic mutant CT and LT retaining mucosal immunogenicity and adjuvant activity (38). Thus, it is now evident that the enzymatic ADP ribosylation activity in CT and LT is not absolutely required to exert the adjuvant activity whereas the carbohydrate-binding domain can act as a mucosal adjuvant per se (38).…”

“…This is quite interesting since oral adjuvants have to survive the harsh gastric environment and avoid destruction from pancreatic proteases. Accordingly, bacterial toxins are generally more effective mucosal adjuvants following nasotracheal administration than following oral administration (38,54) (Fig. 3 to 5).…”

“…The paucity of adjuvants for human mucosal vaccines, because the toxicity of CT and LT limits their clinical application (38), prompted us to investigate whether the nontoxic receptor binding domain of C. difficile toxin A displayed any adjuvant activity against antigens coadministered via the oral or nasotracheal route. The hypothesis behind this study was that the carboxyl-terminal region of toxin A, consisting of identical repeat units, presents a striking structural homology with the most powerful mucosal adjuvants known.…”

Development of Vaccine Adjuvants: A Historical Perspective

“…LT also has toxicity associated with its A subunit, but mutants with signifi cantly lower toxicity have been generated [175,176]. The mutants LTK63 and LTR72 have been shown to have potent activity in the generation of mucosal antibody in preclinical models against a variety of antigens when administered by oral, nasal [177], or transdermal routes [178] and appear ready for clinical testing [177].…”