title: Safety and efficacy of low dose Escherichia coli enterotoxin adjuvant for urease based oral immunisation against Helicobacter pylori in healthy volunteers.
abstract: OBJECTIVE
  Escherichia coli heat labile enterotoxin (LT) at doses of 5 micro g or 10 micro g has adjuvant activity for oral immunisation in humans infected with Helicobacter pylori, but causes severe diarrhoea. This study was undertaken to establish a safe and effective dose of LT, to confirm the safety of recombinant urease, and to compare the immunogenicity of orally compared with enterically delivered urease.
  
  
  METHODS
  42 healthy adults without present or past H pylori infection were randomised to receive 60 mg recombinant H pylori urease in soluble or in encapsulated form, given with doses of LT ranging from 0 micro g to 2.5 micro g. Four oral doses were administered at day 1, 8, 29, and 57. Specific IgG, IgA, and antibody secreting cells were measured as well as total alpha4beta7 integrin positive lymphocyte responses.
  
  
  RESULTS
  Enterically delivered urease was well tolerated and no serious adverse events occurred. Mild diarrhoea (one to four loose stools) occurred after the first immunisation in 50% (6 of 12) of the volunteers exposed to 2.5 micro g LT (p=0.06; paired t test, compared with baseline) but not in volunteers exposed to lower LT doses. Immune responses occurred in five (p=0.048; Fisher's exact test), one, two, and one of six subjects exposed to 2.5 micro g, 0.5 micro g, 0.1 micro g, and no LT, respectively. Significant CD4(+), CD69(+), and CD45RO(hi) responses occurred over time among alpha4beta7(hi) lymphocytes in volunteers receiving 2.5 micro g LT. Enterically delivered urease induced higher lymphocyte responses than soluble urease.
  
  
  CONCLUSIONS
  The safety of H pylori urease is confirmed. Oral LT may conserve its adjuvant activity at low doses with minimal side effects.
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Banerjee
authors.forename: A
authors.initials: A
authors.lastname: Medina-Fatimi
authors.forename: R
authors.initials: R
authors.lastname: Nichols
authors.forename: D
authors.initials: D
authors.lastname: Tendler
authors.forename: M
authors.initials: M
authors.lastname: Michetti
authors.forename: J
authors.initials: J
authors.lastname: Simon
authors.forename: C P
authors.initials: CP
authors.lastname: Kelly
authors.forename: T P
authors.initials: TP
authors.lastname: Monath
authors.forename: P
authors.initials: P
authors.lastname: Michetti
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D001427:Bacterial Toxins / Q000008:administration & dosage*; D003692:Delayed-Action Preparations; D003967:Diarrhea / Q000209:etiology; D004311:Double-Blind Method; D004768:Enterotoxins / Q000008:administration & dosage*; D029968:Escherichia coli Proteins; D005260:Female; D016481:Helicobacter Infections / Q000517:prevention & control*; D016480:Helicobacter pylori / Q000201:enzymology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology; D014510:Urease / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D003692:Delayed-Action Preparations; D004768:Enterotoxins; D029968:Escherichia coli Proteins; C027538:heat-labile enterotoxin, E coli; D014510:Urease