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Cholera toxin

Vaxjo ID 11
Vaccine Adjuvant Name Cholera toxin
Adjuvant VO ID VO_0000143
Description Cholera toxin (CT) given perorally is a powerful mucosal immunogen and adjuvant. Information that explains the adjuvant effect of CT may be used for the development of more effective oral vaccines and might also contribute to our understanding of the mechanisms involved in regulating mucosal immunity (Hörnquist and Lycke, 1993).
Stage of Development Research
Preparation Cholera toxin was biotinylated following dialysis in 0.1 M sodium bicarbonate buffer (pH 8.3) using a Slide Dialyzer (10-kDa m.w. cutoff) (van et al., 2000).
Dosage Purified CT purchased from List Biological Laboratories Inc. was administered per-orally at 10 µg/dose, according to a study (Vajdy and Lycke, 1992).
Function The mechanism for the powerful adjuvant activity of CT is unknown although many immunomodulating effects of this molecule have been described. It has been reported that CT increases gut permeability and uptake of luminal antigens, enhances Ag presentation and promotes B cell isotype-switch differentiation. In contrast, mostly inhibitory effects on T cells in vitro have been reported. Several studies have documented blocking effects of CT on T cell signal transduction and IL-2 production. Moreover, [Munoz et al. [14] demonstrated that Thl clones were more susceptible to CT inhibition as compared to Th2 clones, suggesting that CT may affect subsets of T cells differently: despite the aforementioned, both the holotoxin and its B subunit (CTB) function as very strong immunogens in vivo, efficiently stimulating CT specific T cells [15-17](Hörnquist and Lycke, 1993).
Safety Cholera toxin (CT), produced by Vibrio cholerae, and Escherichia coli heat-labile enterotoxin (LT) whose sequence shows 80% similarity with that of CT are the causative agents of cholera and one of the causative agents of traveller’s diarrhea, respectively [1, 2. T.K. Sixmaa, S.E. Pronk, K.W. Kalk, E.S. Wartna, B.A.M. van Zanten, B. Witholt and W.G.J. Hol]. (Hagiwara et al., 1999).
Although cholera toxin functions as a mucosal adjuvant, its usage as an adjuvant of mucosal vaccine in humans is not feasible owing to its toxicity. In addition, these toxins have another potential drawback, possibly inducing IgE antibody (Ab) responses to bystander antigens, as well as the toxins [7 and 8]. These two problems, which impinge on the safety, toxicity and allergenicity of these toxins, should be considered when these toxins are used as a mucosal vaccine adjuvant in humans. One approach being explored to resolve the problems is to use the nontoxic B subunits (CTB or LTB) alone [9], or B subunits coupled chemically or by gene fusion technology to vaccines [10, 11, 12 and 13]. Another approach is to use the B subunits containing a trace amount of the toxin, because the B subunit and a trace amount of the holotoxin act synergistically as an adjuvant for the mucosal immune responses to the vaccine [14, 15 and 16] (Hagiwara et al., 1999).
Related Vaccine(s)
Hagiwara et al., 1999: Hagiwara Y, Komase K, Chen Z, Matsuo K, Suzuki Y, Aizawa C, Kurata T, Tamura S. Mutants of cholera toxin as an effective and safe adjuvant for nasal influenza vaccine. Vaccine. 1999; 17(22); 2918-2926. [PubMed: 10438064].
Hörnquist and Lycke, 1993: Hörnquist E, Lycke N. Cholera toxin adjuvant greatly promotes antigen priming of T cells. European journal of immunology. 1993; 23(9); 2136-2143. [PubMed: 8370397].
Vajdy and Lycke, 1992: Vajdy M, Lycke NY. Cholera toxin adjuvant promotes long-term immunological memory in the gut mucosa to unrelated immunogens after oral immunization. Immunology. 1992; 75(3); 488-492. [PubMed: 1572696].
van et al., 2000: van Ginkel FW, Jackson RJ, Yuki Y, McGhee JR. Cutting edge: the mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues. Journal of immunology (Baltimore, Md. : 1950). 2000; 165(9); 4778-4782. [PubMed: 11045998].