title: A novel adjuvanted capsule based strategy for oral vaccination against infectious diarrhoeal pathogens.
abstract: Diarrhoeal infections are a major cause of morbidity and mortality with enterotoxigenic Escherichia coli (ETEC) and cholera imposing a significant global burden. There is currently no licensed vaccine for ETEC. Development of new nonliving oral vaccines has proven difficult due to the physicochemical and immunological challenges associated with the oral route. This demands innovative delivery solutions to protect antigens, control their release and build in immune-stimulatory activity. We describe the Single Multiple Pill® (SmPill®) vaccine formulation which combines the benefits of enteric polymer coating to protect against low gastric pH, a dispersed phase to control release and aid the solubility of non-polar components and an optimized combination of adjuvant and antigen to promote mucosal immunity. We demonstrate the effectiveness of this system with whole cell killed E. coli overexpressing colonization factor antigen I (CFA/I), JT-49. Alpha-galactosylceramide was identified as a potent adjuvant within SmPill® that enhanced the immunogenicity of JT-49. The bacteria associated with the dispersed phase were retained within the capsules at gastric pH but released at intestinal pH. Vaccination with an optimized SmPill® formulation promoted CFA/I-specific immunoglobulin A (IgA) responses in the intestinal mucosa in addition to serum IgG and a solubilized adjuvant was indispensable for efficacy.
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Davitt
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Edel A
authors.initials: EA
authors.lastname: McNeela
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Longet
authors.affiliation: University of Gothenburg Vaccine Research Institute (GUVAX), Dept. of Microbiology and Immunology, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden.
authors.forename: Joshua
authors.initials: J
authors.lastname: Tobias
authors.affiliation: Sigmoid Pharma Limited, Dublin City University, The Invent Centre, DCU, Glasnevin, Dublin 9, Ireland.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Aversa
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Craig P
authors.initials: CP
authors.lastname: McEntee
authors.affiliation: Sigmoid Pharma Limited, Dublin City University, The Invent Centre, DCU, Glasnevin, Dublin 9, Ireland.
authors.forename: Monica
authors.initials: M
authors.lastname: Rosa
authors.affiliation: Sigmoid Pharma Limited, Dublin City University, The Invent Centre, DCU, Glasnevin, Dublin 9, Ireland.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Coulter
authors.affiliation: University of Gothenburg Vaccine Research Institute (GUVAX), Dept. of Microbiology and Immunology, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Holmgren
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland; Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN); Advanced Materials Bio-Engineering Research Centre (AMBER), Trinity College Dublin, Dublin 2, D02 PN40, Ireland. Electronic address: lavellee@tcd.ie.
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000284:Administration, Oral; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology*; D002214:Capsules; D003967:Diarrhea / Q000517:prevention & control; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000517:prevention & control; D022361:Escherichia coli Vaccines / Q000008:administration & dosage*; D005260:Female; D036781:Fimbriae Proteins / Q000276:immunology*; D005699:Galactosylceramides / Q000008:administration & dosage*; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007422:Intestines / Q000276:immunology; D008807:Mice, Inbred BALB C; D014611:Vaccination / Q000379:methods
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D002214:Capsules; D022361:Escherichia coli Vaccines; D005699:Galactosylceramides; D007070:Immunoglobulin A; D007074:Immunoglobulin G; C493154:alpha-galactosylceramide; C022924:colonization factor antigens; D036781:Fimbriae Proteins
keywords: Adjuvant; Alpha-galactosylceramide (KRN 7000) (PubChem CID: 2826713); Capsule; Enteric; Eudragit L30D 55 (Alcogum) (PubChem CID: 107665); Kolliphor HS 15 (Solutol® HS 15) (PubChem CID: 71311956); Oral delivery; Sorbitol (PubChem CID: 5780); Traveller's diarrhoea; Vaccine