title: The oral, live attenuated enterotoxigenic Escherichia coli vaccine ACE527 reduces the incidence and severity of diarrhea in a human challenge model of diarrheal disease.
abstract: An oral, live attenuated, three-strain recombinant bacterial vaccine, ACE527, was demonstrated to generate strong immune responses to colonization factor and toxin antigens of enterotoxigenic Escherichia coli (ETEC) in human volunteers. The vaccine was safe and well tolerated at doses of up to 10(11) CFU, administered in each of two doses given 21 days apart. These observations have now been extended in a phase 2b study with a total of 70 subjects. Fifty-six of these subjects were challenged 28 days after the second dose of vaccine with the highly virulent ETEC strain H10407 to obtain preliminary indicators of efficacy against disease and to support further development of the vaccine for both travelers and infants in countries where ETEC is endemic. The vaccine had a significant impact on intestinal colonization by the challenge strain, as measured by quantitative fecal culture 2 days after challenge, demonstrating the induction of a functional immune response to the CFA/I antigen. The incidence and severity of diarrhea were also reduced in vaccinees as measured by a number of secondary and ad hoc endpoints, although the 27% reduction seen in the primary endpoint, moderate to severe diarrhea, was not statistically significant. Together, these observations support the hypothesis that the ACE527 vaccine has a dual mode of action, targeting both colonization factors and the heat-labile enterotoxin (LT), and suggest that it should be further developed for more advanced trials to evaluate its impact on the burden of ETEC disease in field settings.
authors.affiliation: TD Vaccines A/S, Skorping, Denmark. mjd@mdbiologic.co.uk
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Darsley
authors.forename: Subhra
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Barbara
authors.initials: B
authors.lastname: DeNearing
authors.forename: David A
authors.initials: DA
authors.lastname: Sack
authors.forename: Andrea
authors.initials: A
authors.lastname: Feller
authors.forename: Charlotte
authors.initials: C
authors.lastname: Buchwaldt
authors.forename: A Louis
authors.initials: AL
authors.lastname: Bourgeois
authors.forename: Richard
authors.initials: R
authors.lastname: Walker
authors.forename: Clayton D
authors.initials: CD
authors.lastname: Harro
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D058491:Bacterial Load; D003967:Diarrhea / Q000382:microbiology / Q000473:pathology* / Q000517:prevention & control*; D054307:Enterotoxigenic Escherichia coli / Q000276:immunology*; D004927:Escherichia coli Infections / Q000382:microbiology / Q000473:pathology* / Q000517:prevention & control*; D022361:Escherichia coli Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D005243:Feces / Q000382:microbiology; D006805:Human Experimentation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D014611:Vaccination / Q000379:methods; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D055815:Young Adult
chemical_list: D022361:Escherichia coli Vaccines; D014613:Vaccines, Attenuated