title: Genetically modified enterotoxigenic Escherichia coli vaccines induce mucosal immune responses without inflammation.
abstract: OBJECTIVE
  Enterotoxigenic Escherichia coli (ETEC) is a major cause of acute diarrhoea in children in the developing world, in travellers and in the military. Safe, effective vaccines could reduce morbidity and mortality. As immunity to ETEC is strain specific, the ability to create vaccines in vitro which express multiple antigens would be desirable. It was hypothesised that three genetically attenuated ETEC strains, one with a genetic addition, would be immunogenic and safe, and they were evaluated in the first licensed UK release of genetically modified oral vaccines.
  
  
  METHODS
  Phase 1 studies of safety and immunogenicity were carried out at a Teaching Hospital in London. Varying oral doses of any of three oral vaccines, or placebo, were administered to volunteers of both sexes (n = 98). Peripheral blood responses were measured as serum antibodies (IgG or IgA) by ELISA, antibody-secreting cell (ASC) responses by enzyme-linked immunospot (ELISPOT), and antibody in lymphocyte supernatant (ALS) by ELISA. Mucosal antibody secretion was measured by ELISA for specific IgG and IgA in whole gut lavage fluids (WGLFs).
  
  
  RESULTS
  Significant mucosal IgA responses were obtained to colonisation factors CFA/I, CS1, CS2 and CS3, both when naturally expressed and when genetically inserted. Dose-response relationships were most clearly evident in the mucosal IgA in WGLF. Vaccines were well tolerated and did not elicit interleukin (IL) 8 or IL6 secretion in WGLF.
  
  
  CONCLUSIONS
  Genetically modified ETEC vaccines are safe and induce significant mucosal IgA responses to important colonisation factors. Mucosal IgA responses were clearly seen in WGLF, which is useful for evaluating oral vaccines.
authors.affiliation: Centre for Adult & Paediatric Gastroenterology, Institute of Cell and Molecular Science, Barts & The London School of Medicine, Turner Street, London E1 2AD, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Daley
authors.forename: Roger
authors.initials: R
authors.lastname: Randall
authors.forename: Michael
authors.initials: M
authors.lastname: Darsley
authors.forename: Naheed
authors.initials: N
authors.lastname: Choudhry
authors.forename: Nicola
authors.initials: N
authors.lastname: Thomas
authors.forename: Ian R
authors.initials: IR
authors.lastname: Sanderson
authors.forename: Nick M
authors.initials: NM
authors.lastname: Croft
authors.forename: Paul
authors.initials: P
authors.lastname: Kelly
mesh_terms: D000293:Adolescent; D000328:Adult; D004306:Dose-Response Relationship, Immunologic; D054307:Enterotoxigenic Escherichia coli / Q000276:immunology; D022361:Escherichia coli Vaccines / Q000276:immunology*; D005260:Female; D005751:Gastric Lavage; D005759:Gastroenteritis / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology*; D008297:Male; D008875:Middle Aged
chemical_list: D022361:Escherichia coli Vaccines