title: Intranasal immunization with genetically detoxified diphtheria toxin induces T cell responses in humans: enhancement of Th2 responses and toxin-neutralizing antibodies by formulation with chitosan.
abstract: We previously reported that intranasal immunization with a non-toxic mutant cross-reacting material (CRM)197 of diphtheria toxin, formulated with chitosan, generated protective neutralizing antibodies in mice and guinea pigs. Furthermore, we demonstrated that intranasal delivery of a powder formulation of the CRM197-based vaccine was well tolerated and significantly boosted antibody responses in adult volunteers. Here we report that intranasal booster immunization with CRM197 alone or with chitosan induced systemic T cell responses. We addressed for the first time the induction of T cell subtypes following intranasal vaccination in humans. Intranasal vaccination with CRM197, like parenteral immunization with a conventional diphtheria toxoid vaccine, enhanced antigen-specific IFN-gamma production. However, formulation of the nasal diphtheria vaccine with chitosan significantly augmented Th2-type responses, which correlated with protective levels of toxin-neutralizing antibodies in intranasally boosted individuals. The results suggest that vaccines capable of inducing strong Th2-type responses, such as CRM197 formulated with chitosan, have potential for the development of a protective mucosal vaccine against diphtheria in humans. Furthermore, our findings demonstrate that mucosal subunit vaccines with appropriate delivery systems have considerable potential for booster immunization of adults.
authors.affiliation: Immune Regulation Research Group, Department of Biochemistry, Trinity College, Dublin 2, Ireland.
authors.forename: Edel A
authors.initials: EA
authors.lastname: McNeela
authors.forename: Inderjit
authors.initials: I
authors.lastname: Jabbal-Gill
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Illum
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Pizza
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Audino
authors.initials: A
authors.lastname: Podda
authors.forename: David J M
authors.initials: DJ
authors.lastname: Lewis
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood* / Q000276:immunology; D002626:Chemistry, Pharmaceutical; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry*; D048271:Chitosan; D004167:Diphtheria Toxin / Q000008:administration & dosage* / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D009297:Nasal Mucosa / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D004167:Diphtheria Toxin; D002686:Chitin; D048271:Chitosan