Vaccine Candidate Vibrio cholerae 638 Is Protective against Cholera in Healthy Volunteers

• Published in: Infection and Immunity Vol. 73; no. 5; pp. 3018 - 3024
• Main Authors: García, Luis, Jidy, Manuel Díaz, García, Hilda, Rodríguez, Boris L, Fernández, Roberto, Año, Gemma, Cedré, Bárbara, Valmaseda, Tania, Suzarte, Edith, Ramírez, Margarita, Pino, Yadira, Campos, Javier, Menéndez, Jorge, Valera, Rodrigo, González, Daniel, González, Irma, Pérez, Oliver, Serrano, Teresita, Lastre, Miriam, Miralles, Fernando, del Campo, Judith, Maestre, Jorge Luis, Pérez, José Luis, Talavera, Arturo, Pérez, Antonio, Marrero, Karen, Ledón, Talena, Fando, Rafael
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.05.2005
• Subjects: administration & dosage; Administration, Oral; Adolescent; Adult; Antibodies, Bacterial; Antibodies, Bacterial - blood; Applied microbiology; Bacterial diseases; Bacteriology; Bacteriophages; Bacteriophages - genetics; Biological and medical sciences; blood; blood serum; Cellulase; Cellulase - genetics; Cholera; Cholera - prevention & control; Cholera Vaccines; Cholera Vaccines - administration & dosage; Cholera Vaccines - genetics; Cholera Vaccines - immunology; Clostridium thermocellum; diarrhea; Double-Blind Method; endo-1,4-beta-glucanase; feces; Feces - microbiology; Fundamental and applied biological sciences. Psychology; Gene Deletion; genes; genetics; hemagglutinins; Hemagglutinins - genetics; Human bacterial diseases; Humans; immunoglobulins; immunology; Infectious diseases; ingestion; Male; Medical sciences; Microbial Immunity and Vaccines; Microbiology; Miscellaneous; mutants; pathogenicity; Peptide Hydrolases; Peptide Hydrolases - genetics; prevention & control; proteinases; Tropical bacterial diseases; Vaccination; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Vaccines, Attenuated; Vaccines, Attenuated - administration & dosage; Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Vibrio cholerae; Vibrio cholerae - genetics; Vibrio cholerae - immunology; Vibrio cholerae - pathogenicity; Vibrio cholerae - virology; virology; virulent strains; Infection; Microbiology; Vibrio cholerae; Bacteriosis; Bacteria; Vibrionaceae; Cholera; Vaccine; Immunity
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.73.5.3018-3024.2005

Vibrio cholerae 638 is a living candidate cholera vaccine strain attenuated by deletion of the CTX[Phi] 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 10⁹ CFU of freshly harvested 638 buffered with 1.3% NaHCO₃, 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 10⁹ CFU of [Delta]CTX[Phi] 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 10⁵ CFU of virulent strain V. cholerae 3008 freshly harvested from a brain heart infusion agar plate and buffered with 1.3% NaHCO₃. 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 (10⁹ 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.