title: Safety and immunogenicity of escalating dosages of a single oral administration of peru-15 pCTB, a candidate live, attenuated vaccine against enterotoxigenic Escherichia coli and Vibrio cholerae.
abstract: Enterotoxigenic Escherichia coli (ETEC) organisms are a leading cause of infectious diarrhea in developing countries. A live, attenuated cholera strain that expresses high levels of the nontoxic B subunit of cholera toxin, which might also serve as an ETEC protective antigen, was evaluated for safety, excretion, and immunogenicity in healthy volunteers. We enrolled four inpatient dose-escalation cohorts of 15 to 16 eligible subjects to randomly (3:1) receive a single oral dose of vaccine or placebo (buffer alone), evaluating 1 ×10(7), 1 ×10(8), 1 ×10(9), and 1 ×10(10) CFU of the vaccine. The vaccine was well tolerated, although some subjects experienced moderate diarrhea. The serum Inaba vibriocidal antibody response appeared to display a dose-response relationship with increasing dosages of vaccine, plateauing at the 10(9)-CFU dosage. The serum antitoxin (cholera toxin and heat-labile enterotoxin) antibody seroconversion rate (4-fold increase over baseline) also appeared to display a dose-response relationship. The vaccine strain was excreted in stool cultures, displaying a dose-response relationship. A single oral dose of Peru-15 pCTB at dosages up to 1 ×10(10) CFU was safe and immunogenic in this first-in-human trial. These encouraging data support the ongoing clinical development of this candidate combined cholera and ETEC vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT00654108.).
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Wilbur H
authors.initials: WH
authors.lastname: Chen
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Garza
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Choquette
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hawkins
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Hoeper
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA mitchell.cohen@cchmc.org.
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Cohen
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood; D000992:Antitoxins / Q000097:blood; D022121:Cholera Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D003967:Diarrhea / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D054307:Enterotoxigenic Escherichia coli / Q000276:immunology*; D022361:Escherichia coli Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D016896:Treatment Outcome; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D014734:Vibrio cholerae / Q000276:immunology*; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial; D000992:Antitoxins; D022121:Cholera Vaccines; D022361:Escherichia coli Vaccines; C497037:Peru 15; D010919:Placebos; D014613:Vaccines, Attenuated