title: The vaccine candidate Vibrio cholerae 638 is protective against cholera in healthy volunteers.
abstract: Vibrio cholerae 638 is a living candidate cholera vaccine strain attenuated by deletion of the CTXPhi prophage from C7258 (O1, El Tor Ogawa) and by insertion of the Clostridium thermocellum endoglucanase A gene into the hemagglutinin/protease coding sequence. This vaccine candidate was previously found to be well tolerated and immunogenic in volunteers. This article reports a randomized, double-blind, placebo-controlled trial conducted to test short-term protection conferred by 638 against subsequent V. cholerae infection and disease in volunteers in Cuba. A total of 45 subjects were enrolled and assigned to receive vaccine or placebo. The vaccine contained 10(9) CFU of freshly harvested 638 buffered with 1.3% NaHCO(3), while the placebo was buffer alone. After vaccine but not after placebo intake, 96% of volunteers had at least a fourfold increase in vibriocidal antibody titers, and 50% showed a doubling of at least the lipopolysaccharide-specific immunoglobulin A titers in serum. At 1 month after vaccination, five volunteers from the vaccine group and five from the placebo group underwent an exploratory challenge study with 10(9) CFU of DeltaCTXPhi attenuated mutant strain V. cholerae 81. Only two volunteers from the vaccine group shed strain 81 in their feces, but none of them experienced diarrhea; in the placebo group, all volunteers excreted the challenge strain, and three had reactogenic diarrhea. An additional 12 vaccinees and 9 placebo recipients underwent challenge with 7 x 10(5) CFU of virulent strain V. cholerae 3008 freshly harvested from a brain heart infusion agar plate and buffered with 1.3% NaHCO(3). Three volunteers (25%) from the vaccine group and all from the placebo group shed the challenge agent in their feces. None of the 12 vaccinees but 7 volunteers from the placebo group had diarrhea, and 2 of the latter exhibited severe cholera (>5,000 g of diarrheal stool). These results indicate that at 1 month after ingestion of a single oral dose (10(9) CFU) of strain 638, volunteers remained protected against cholera infection and disease provoked by the wild-type challenge agent V. cholerae 3008. We recommend that additional vaccine lots of 638 be prepared under good manufacturing practices for further evaluation.
authors.affiliation: Centro Nacional de Investigaciones Científicas, P.O. Box 6412, Avenida 25, Esquina a 158, Ciudad de La Habana, Cuba.
authors.forename: Luis
authors.initials: L
authors.lastname: García
authors.forename: Manuel Díaz
authors.initials: MD
authors.lastname: Jidy
authors.forename: Hilda
authors.initials: H
authors.lastname: García
authors.forename: Boris L
authors.initials: BL
authors.lastname: Rodríguez
authors.forename: Roberto
authors.initials: R
authors.lastname: Fernández
authors.forename: Gemma
authors.initials: G
authors.lastname: Año
authors.forename: Bárbara
authors.initials: B
authors.lastname: Cedré
authors.forename: Tania
authors.initials: T
authors.lastname: Valmaseda
authors.forename: Edith
authors.initials: E
authors.lastname: Suzarte
authors.forename: Margarita
authors.initials: M
authors.lastname: Ramírez
authors.forename: Yadira
authors.initials: Y
authors.lastname: Pino
authors.forename: Javier
authors.initials: J
authors.lastname: Campos
authors.forename: Jorge
authors.initials: J
authors.lastname: Menéndez
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Valera
authors.forename: Daniel
authors.initials: D
authors.lastname: González
authors.forename: Irma
authors.initials: I
authors.lastname: González
authors.forename: Oliver
authors.initials: O
authors.lastname: Pérez
authors.forename: Teresita
authors.initials: T
authors.lastname: Serrano
authors.forename: Miriam
authors.initials: M
authors.lastname: Lastre
authors.forename: Fernando
authors.initials: F
authors.lastname: Miralles
authors.forename: Judith
authors.initials: J
authors.lastname: Del Campo
authors.forename: Jorge Luis
authors.initials: JL
authors.lastname: Maestre
authors.forename: José Luis
authors.initials: JL
authors.lastname: Pérez
authors.forename: Arturo
authors.initials: A
authors.lastname: Talavera
authors.forename: Antonio
authors.initials: A
authors.lastname: Pérez
authors.forename: Karen
authors.initials: K
authors.lastname: Marrero
authors.forename: Talena
authors.initials: T
authors.lastname: Ledón
authors.forename: Rafael
authors.initials: R
authors.lastname: Fando
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood; D001435:Bacteriophages / Q000235:genetics; D002480:Cellulase / Q000235:genetics; D002771:Cholera / Q000517:prevention & control*; D022121:Cholera Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D048013:Acetivibrio thermocellus; D004311:Double-Blind Method; D005243:Feces / Q000382:microbiology; D017353:Gene Deletion; D006388:Hemagglutinins / Q000235:genetics; D006801:Humans; D008297:Male; D010447:Peptide Hydrolases / Q000235:genetics; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014734:Vibrio cholerae / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity / Q000821:virology
chemical_list: D000907:Antibodies, Bacterial; D022121:Cholera Vaccines; D006388:Hemagglutinins; D014613:Vaccines, Attenuated; D002480:Cellulase; D010447:Peptide Hydrolases