title: Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin a.
abstract: Subunit intranasal vaccines offer the prospect of inducing combined systemic-mucosal immunity against mucosally transmitted infections such as human immunodeficiency virus. However, although human studies have demonstrated the induction of active immunity, secretory immunoglobulin A (sIgA) responses are variable, and no study has demonstrated protection by accepted vaccine-licensing criteria as measured by direct toxin-neutralizing activity. Using the genetically inactivated mutant diphtheria toxoid CRM(197) in a bioadhesive polycationic polysaccharide chitosan delivery system, we found that a single nasal immunization was well tolerated and boosted antitoxin neutralizing activity in healthy volunteers, which could be further boosted by a second immunization. The neutralizing activity far exceeded accepted protective levels and was equivalent to that induced by standard intramuscular vaccine and significantly greater than intranasal immunization with CRM(197) in the absence of chitosan. A striking but unexpected observation was that although unilateral intranasal immunization induced circulating antitoxin antibody-secreting cells, a nasal antitoxin sIgA response was seen only after the second immunization and only in the vaccinated nostril. If these data are reproduced in larger studies, an intranasal diphtheria vaccine based on CRM(197)-chitosan could be rapidly licensed for human use. However, a restricted sIgA response suggests that care must be taken in the priming-boosting strategy and clinical sampling techniques when evaluating such vaccines for the induction of local mucosal immunity.
authors.affiliation: Immune Regulation Research Group, Department of Biochemistry, Trinity College, Dublin 2, Ireland.
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
authors.forename: Catherine
authors.initials: C
authors.lastname: Cosgrove
authors.forename: Edel A
authors.initials: EA
authors.lastname: McNeela
authors.forename: Amy
authors.initials: A
authors.lastname: Sexton
authors.forename: Rafaela
authors.initials: R
authors.lastname: Giemza
authors.forename: Inderjit
authors.initials: I
authors.lastname: Jabbal-Gill
authors.forename: Anne
authors.initials: A
authors.lastname: Church
authors.forename: Wu
authors.initials: W
authors.lastname: Lin
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Illum
authors.forename: Audino
authors.initials: A
authors.lastname: Podda
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Pizza
authors.forename: George E
authors.initials: GE
authors.lastname: Griffin
authors.forename: David J M
authors.initials: DJ
authors.lastname: Lewis
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood* / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D002686:Chitin / Q000031:analogs & derivatives*; D048271:Chitosan; D003353:Corynebacterium diphtheriae / Q000276:immunology; D004165:Diphtheria / Q000517:prevention & control*; D004167:Diphtheria Toxin / Q000276:immunology*; D004168:Diphtheria Toxoid / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D018928:Immunity, Mucosal; D007117:Immunization, Secondary; D007071:Immunoglobulin A, Secretory / Q000378:metabolism*; D008297:Male; D009500:Neutralization Tests; D014611:Vaccination
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D004167:Diphtheria Toxin; D004168:Diphtheria Toxoid; D007071:Immunoglobulin A, Secretory; C028581:CRM197 (non-toxic variant of diphtheria toxin); D002686:Chitin; D048271:Chitosan