title: Development of pathogenicity-driven definitions of outcomes for a field trial of a killed oral vaccine against enterotoxigenic Escherichia coli in Egypt: application of an evidence-based method.
abstract: BACKGROUND
  To design an efficacy trial of a killed oral vaccine against enterotoxigenic Escherichia coli (ETEC) diarrhea in Egyptian children, we derived for ETEC diarrhea an empirical definition that increased the probability that diarrhea associated with excretion of ETEC was caused by the detected ETEC.
  
  
  METHODS
  We conducted a cohort study of 397 Egyptian children <24 months old and monitored them until they were 3 years old. Vaccine-preventable (VP) ETEC was defined as ETEC expressing >/=1 of the toxin- (heat-labile [LT] toxin) and colonization-factor antigens (CFA I, II, and IV) in the vaccine.
  
  
  RESULTS
  Although fecal excretion of VP-ETEC was highly associated with diarrhea, excretion of LT-ETEC per se was not related to diarrhea (adjusted odds ratio [OR(A)], 1.16 [95% confidence interval [CI], 0.90-1.49]). The fecal excretion of antigenic types of VP-ETEC other than LT-ETEC (non-LT VP-ETEC) was highly associated with diarrheal symptoms (OR(A), 3.91 [95% CI, 2.78-5.49]; P<.001), and this association was greater for nonbloody than for bloody diarrhea.
  
  
  CONCLUSIONS
  Because the vaccine had been anticipated to protect primarily against symptomatic ETEC diarrhea, these results indicate that the primary-outcome definition of ETEC diarrhea for the trial should be restricted to nonbloody diarrheal episodes associated with fecal excretion of non-LT VP-ETEC.
authors.affiliation: International Vaccine Institute, Seoul, Korea. jclemens@ivi.int.
authors.forename: John
authors.initials: J
authors.lastname: Clemens
authors.forename: Stephen
authors.initials: S
authors.lastname: Savarino
authors.forename: Remon
authors.initials: R
authors.lastname: Abu-Elyazeed
authors.forename: Mohammad
authors.initials: M
authors.lastname: Safwat
authors.forename: Malla
authors.initials: M
authors.lastname: Rao
authors.forename: Thomas
authors.initials: T
authors.lastname: Wierzba
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Svennerholm
authors.forename: Jan
authors.initials: J
authors.lastname: Holmgren
authors.forename: Robert
authors.initials: R
authors.lastname: Frenck
authors.forename: Eunsik
authors.initials: E
authors.lastname: Park
authors.forename: Abdollah
authors.initials: A
authors.lastname: Naficy
mesh_terms: D001427:Bacterial Toxins / Q000378:metabolism; D002675:Child, Preschool; D002986:Clinical Trials as Topic / Q000379:methods*; D003967:Diarrhea / Q000382:microbiology / Q000517:prevention & control; D004534:Egypt; D004768:Enterotoxins / Q000378:metabolism; D004926:Escherichia coli / Q000302:isolation & purification / Q000378:metabolism / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000382:microbiology / Q000517:prevention & control*; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines / Q000008:administration & dosage* / Q000627:therapeutic use; D019317:Evidence-Based Medicine; D005243:Feces / Q000382:microbiology; D036781:Fimbriae Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D012107:Research Design; D016896:Treatment Outcome; D015164:Vaccines, Inactivated / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines; D015164:Vaccines, Inactivated; C022924:colonization factor antigens; D036781:Fimbriae Proteins; C027538:heat-labile enterotoxin, E coli