The vaccine candidate Vibrio cholerae 638 is protective against cholera in healthy volunteers.
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.
García
Luis
L
Centro Nacional de Investigaciones Científicas, P.O. Box 6412, Avenida 25, Esquina a 158, Ciudad de La Habana, Cuba.
Jidy
Manuel Díaz
MD
García
Hilda
H
Rodríguez
Boris L
BL
Fernández
Roberto
R
Año
Gemma
G
Cedré
Bárbara
B
Valmaseda
Tania
T
Suzarte
Edith
E
Ramírez
Margarita
M
Pino
Yadira
Y
Campos
Javier
J
Menéndez
Jorge
J
Valera
Rodrigo
R
González
Daniel
D
González
Irma
I
Pérez
Oliver
O
Serrano
Teresita
T
Lastre
Miriam
M
Miralles
Fernando
F
Del Campo
Judith
J
Maestre
Jorge Luis
JL
Pérez
José Luis
JL
Talavera
Arturo
A
Pérez
Antonio
A
Marrero
Karen
K
Ledón
Talena
T
Fando
Rafael
R
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
D000907:Antibodies, Bacterial; D022121:Cholera Vaccines; D006388:Hemagglutinins; D014613:Vaccines, Attenuated; D002480:Cellulase; D010447:Peptide Hydrolases