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Infection and Immunity, May 2005, p. 3018-3024, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.3018-3024.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Luis García,^1, Manuel Díaz Jidy,^2, Hilda García,¹ Boris L. Rodríguez,³ Roberto Fernández,² Gemma Año,¹ Bárbara Cedré,¹ Tania Valmaseda,¹ Edith Suzarte,³ Margarita Ramírez,² Yadira Pino,¹ Javier Campos,³ Jorge Menéndez,¹ Rodrigo Valera,¹ Daniel González,² Irma González,¹ Oliver Pérez,¹ Teresita Serrano,² Miriam Lastre,¹ Fernando Miralles,² Judith del Campo,¹ Jorge Luis Maestre,² José Luis Pérez,¹ Arturo Talavera,¹ Antonio Pérez,² Karen Marrero,³ Talena Ledón,³ and Rafael Fando^3*

Instituto Finlay de Sueros y Vacunas, P.O. Box 16017, La Lisa, Ciudad de La Habana, Cuba,¹ Instituto de Medicina Tropical Pedro Kouri, P.O. Box 601, La Lisa, Ciudad de La Habana, Cuba,² Centro Nacional de Investigaciones Científicas, P.O. Box 6412, Playa, Ciudad de La Habana, Cuba³

Received 2 September 2004/ Returned for modification 19 November 2004/ Accepted 17 January 2005

Vibrio cholerae 638 is a living candidate cholera vaccine strain attenuated by deletion of the CTX 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 CTX 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.

Editor: V. J. DiRita

Luis García and Manuel Díaz Jidy contributed equally to the results presented in this article.

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