Mucosal adjuvants

Stevceva, L. and Ferrari, M 2005. Mucosal adjuvants. Current Pharmaceutical Design 11(6), 801-811. 

Holmgren, J., N. Lycke, C. Czerkinsky, Cholera-Toxin and Cholera-B Subunit as Oral Mucosal Adjuvant and Antigen Vector Systems, Vaccine. 11, 1179, 1993. 

Mucosal adjuvants Bind to M cells and GMl ganglioside receptors on mucosal epithelium CT toxin... 

In a more recent study, Webster et al. (2006) report the expression and characterization of lettuce-derived measles vaccine. The MV-H protein expressed in lettuce was demonstrated to be immunogenic in mice following intraperitoneal injection in the absence of adjuvant in addition to intranasal inoculation in the presence of a mucosal adjuvant. The highest response was observed in mice primed first with MV-H DNA and then boosted with an oral formulation of freeze-dried MV-H lettuce in conjunction with a mucosal adjuvant. In addition to this, the type of immune response was found to depend largely on the manner in which MV-H is presented to the immune system. Secreted and soluble forms of MV-H were demonstrated to induce a Th2 type response, while membrane-bound MV-H protein was found to be associated with a Thl response. 

The most potent mucosal adjuvants have been shown to be the toxins derived from Vibrio cholerae or Escherichia coli, which should not be surprising since these organisms invade the body through the GI tract. Obviously too toxic for human use because they are the source of cholera or diarrhoea, heat labile enterotoxins have been tested in mice and shown to be potent adjuvants for orally or nasally administered influenza vaccine. The potency of heat-labile enterotoxin mutants may also be enhanced by formulation into bioadhesive particulate delivery systems, and this is an area under current exploration. 

Cardenas-Freytag, L., et al. 2002. Partial protection against experimental vaginal candidiasis after mucosal vaccination with heat-killed Candida albicans and the mucosal adjuvant LT(R192G). Med My col 40 291. 

Mucosal adjuvant and vaccine delivery system development is an area of importance for improving public health. Mucosal immunization can serve in the future in increasing mucosal immune function, induction of protective immunity against infections, and induction of tolerance or modifying autoimmune disorders, allergies, and autoimmune diseases. Development of oral vaccines would have large implications for rural and remote populations where access to trained medical staff to administer vaccines by injection can be lacking. 

The mucosal vaccines approved for human use include typhoid, cholera, adenovirus, Sabin oral polio, and rotavirus vaccines. New mucosal vaccine strategies are focused on development of non-replicating subunit vaccines, DNA, plant, and other types of recombinant vaccines as well as the use of mucosal adjuvants preferably inbuilt into the vaccine. The conjugation of lipids to peptide antigens is one approach which enables the production of highly... 

Munro P, Flatau G, Lemichez E (2007) Intranasal immunization with tetanus toxoid and CNF1 as a new mucosal adjuvant protects BALB/c mice against lethal challenge. Vaccine... 

Tritto E, Muzzi A, Pesce I, Monaci E, Nuti S, Galli G, Wack A, Rappuoli R, Hussell T, De Gregorio E (2007) The acquired immune response to the mucosal adjuvant LTK63 imprints the mouse lung with a protective signature. J Immunol 179(8) 5346-5357 Ulrich JT, Myers KR (1995) Monophosphoryl lipid A as an adjuvant. Past experiences and new directions. Pharm Biotechnol 6 495-524... 

Mineral Salts Immunostimulatory adjuvants Lipid particles Particulate adjuvants Mucosal adjuvants Aluminium hydroxide, aluminium phosphate, calcium phosphate Saponins (e.g., QS21), MDP derivatives, bacterial DNA (CpG oligos), LPS, MPL and synthetic derivatives, lipopeptides, cytokines (e.g., GM-CSF, IL-2, IL-12) Liposomes, virosomes, iscoms, cochleates, emulsions (e.g., Freunds adjuvant, SAF, MF59 ) Poloxamer particles, virus-like particles, PLG microparticles Cholera toxin (CT), mutant toxin (e.g., LTK63, LTR72), heat labile enterotoxin (LT), microparticles, polymerized liposomes, chitosan... 

Lemere CA, Spooner ET, Leveroiie JF, Mori C, Clements JD (2002) Indanasal immunotherapy for the treatment of Alzheimer s disease Escherichia coli LT and LT(R192G) as mucosal adjuvants. Neurobiol Aging 23 991—1000. 

Homquist, E. Lycke, N. Czerkinsky, C. Holmgren, J. Cholera toxin and cholera B subunit as oral-mucosal adjuvant and antigen carrier systems. In Novel Delivery Systems for Oral Vaccines O Hagan, D.T., Ed. CRC Press, Inc. Ann Arbor, MI, 1994 157-173. 

The current status of adjuvanted influenza vaccines has been reviewed (26). The authors concluded that the vaccine produces a higher titer of antibodies than non-adjuvanted or virosomal vaccines. Local reactions occur more often, but are mild and transient. The results of a trial with two doses of an intranasally administered inactivated virosome-formulated influenza vaccine containing Escherichia coli heat-labile toxin as a mucosal adjuvant in 106 volunteers aged 33-63 years have been reported (27). About 50% of vaccinees had local adverse reactions (44% after the first dose and 54% after the second dose) or systemic adverse reactions (48 and 46%) after administration of the vaccine. Rhinorrhea, sneezing, and headache were the most common reactions they were mild and transient and resolved within 24-48 hours. No febrile reactions were associated with immunization. Between 77 and 92% of vaccinees developed protective hemagglutination inhibition antibody titers against the two influenzae A strains of the vaccine, whereas protective antibody titers against the B strain of the vaccine were achieved in only 49-58%. 

Gluck R, Mischler R, Durrer P, Furer E, Lang AB, Herzog C, Cryz SJ Jr. Safety and immunogenicity of intranasally administered inactivated trivalent virosome-formulated influenza vaccine containing Escherichia coli heat-labile toxin as a mucosal adjuvant J Infect Dis 2000 181(3) 1129-32. 

Dertzbaugh MT, Elson CO, (1991) Cholera toxin as a mucosal adjuvant. In Topics in Vaccine Adjuvant Research, (Spriggs D, Koff W) CRC Press, Boca Raton, FL,119—132. 

Douce G, Turcotte C, Cropley I, etal. (1995) Mutants of Escherichia coli heat-labile toxin lacking ADP-ribosyltransferase activity act as nontoxic, mucosal adjuvants. In Proc. Natl. Acad. Sci. USA 92 1644-1648. 

Kende, M., Del Giudice, G., Rivera, N. and Hewetson, J. (2006) Enhancement of intranasal vaccination in mice with deglycosylated chain A ricin by LTR72, a novel mucosal adjuvant. Vaccine, 24, 2213-2221. 

LPS and lipid A derivatives EPS is a component of the membrane of Gram-negative bacteria, with lipid A, the central poly-acylated disaccharide, as the main active part. Since EPS is highly toxic, derivates with reduced toxicity have been developed, one of them is monophospholipid A (M PE), a mucosal adjuvant supporting humoral and cellular response [32]. 

Bacterial toxins As an example, cholera toxin is a strong mucosal adjuvant which can act as adjuvant. 

Mineral salts Immunostimulatory adjuvants Lipid particles Particulate adjuvants Mucosal adjuvants... 

Klinguer, C., Beck, A., De-Lys, P., Bussat, M.C., Blaecke, A., Derouet, F., Bormefoy, J.Y., Nguyen, T., Corvai a, N. and Velin, D., 2001, Lipophilic quaternary ammonium salt acts as mucosal adjuvant when co-administrated by nasal route with antigens. Vaccine 19 4236-4244. 

EdTx has been shown to act as a mucosal adjuvant, enhancing both systemic and mucosal antibody responses to ovalbumin (OVA) and inducing a mixed T helper (Th) 1/Th2 OVA-specific CD4 T response following intra-nasal co-administration, potentially related to its ability to induce AP-1 and C/EBP-P expression in murine macrophages. In contrast, EdTx inhibits murine CD4 T-cell proliferation and the production of IL-12 and tumour necrosis factor (TNF)-a by murine DC in response to B. anthracis spores. Additionally, both LeTx and EdTx have been shown to inhibit human neutrophil chemotaxis - and superoxide production. - ... 

Roberts M, Bacon A, Rappuoli R et al. A mutant pertussis toxin molecule that lacks AOP-ribosyltranslerase activity, PT-9K/129G, is an effective mucosal adjuvant for intranasally delivered proteins. Infect Immun 1995 63(6) 2100-2108. 

Millar DG, Hirst TR, Snider DP. Escherichia coli heat-labile enterotoxin B subunit is a more potent mucosal adjuvant than its viosely related homologue, the B subunit of cholera toxin. Infect Immun 2001 69(5) 3476-3482. 

Maeyama J, Isaka M, Yasuda Y et al. Cytokine responses to recombinant cholera toxin B subunit produced by bacillus brevis as a mucosal adjuvant. Microbiol Immunol 2001 45(2) 111-117. 

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