This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kotloff, K. L.
Right arrow Articles by Levine, M. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kotloff, K. L.
Right arrow Articles by Levine, M. M.

 Previous Article  |  Next Article 

Infection and Immunity, March 2000, p. 1034-1039, Vol. 68, No. 3
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Shigella flexneri 2a Strain CVD 1207, with Specific Deletions in virG, sen, set, and guaBA, Is Highly Attenuated in Humans

Karen L. Kotloff,1,2,* Fernando R. Noriega,1,2,dagger Taraz Samandari,2 Marcelo B. Sztein,1,2 Genevieve A. Losonsky,1,2 James P. Nataro,1,2 William D. Picking,3 Eileen M. Barry,2 and Myron M. Levine1,2

Division of Infectious Diseases and Tropical Pediatrics, Department of Pediatrics,1 and Division of Geographic Medicine, Department of Medicine,2 Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland 21201, and Department of Biology, Saint Louis University, St. Louis, Missouri 63103-20103

Received 28 June 1999/Returned for modification 2 September 1999/Accepted 23 November 1999

A phase 1 clinical trial was conducted among 35 healthy adult volunteers to evaluate the safety, immunogenicity, and shedding of different doses of CVD 1207, a live attenuated Shigella flexneri 2a vaccine candidate with specific deletion mutations in virG, sen, set, and guaBA. CVD 1207 retains the ability to invade epithelial cells but cannot effectively spread intercellularly after invasion (Delta virG), does not produce enterotoxin (Delta sen and Delta set), and has limited proliferation in vivo (Delta guaBA). In a consecutive fashion, groups of three to seven subjects ingested a single oral dose of CVD 1207 at an inoculum of either 106, 107, 108, 109, or 1010 CFU. CVD 1207 was remarkably well-tolerated at inocula as high as 108 CFU. In comparison, one of 12 subjects who received 109 CFU experienced mild diarrhea and another experienced a single episode of emesis. One of five subjects who received 1010 CFU experienced watery diarrhea and emesis. All subjects who ingested doses of 108 to 1010 CFU excreted the vaccine; in 23 of 25, the duration of excretion was <= 3 days. A dose-related, immunoglobulin A antibody-secreting cell (ASC) response to S. flexneri 2a O-specific lipopolysaccharide was seen, with geometric mean peak values of 6.1 to 35.2 ASCs/106 peripheral blood mononuclear cells (PBMC) among recipients of 107 to 1010 CFU. The cytokine response to Shigella-specific antigens observed in volunteers' PBMC following vaccination suggested a Th1 pattern with stimulation of gamma interferon and absence of interleukin 4 (IL-4) or IL-5. CVD 1207 represents a Shigella live oral vaccine strain prepared from wild-type S. flexneri 2a by rational use of recombinant DNA technology that achieves a remarkable degree of attenuation compared with earlier recombinant strains, even when administered at high dosage.


* Corresponding author. Mailing address: Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore St., HSF 480, Baltimore, MD 21201. Phone: (410) 706-5328. Fax: (410) 706-6205. E-mail: kkotloff{at}medicine.umaryland.edu.

dagger Present address: Clinical Development, Pasteur Mérieux Connaught, Swiftwater, PA 18370-0187.


Infection and Immunity, March 2000, p. 1034-1039, Vol. 68, No. 3
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.



This article has been cited by other articles:

  • Coburn, B., Sekirov, I., Finlay, B. B. (2007). Type III Secretion Systems and Disease. Clin. Microbiol. Rev. 20: 535-549 [Abstract] [Full Text]  
  • Suzuki, T., Yoshikawa, Y., Ashida, H., Iwai, H., Toyotome, T., Matsui, H., Sasakawa, C. (2006). High Vaccine Efficacy against Shigellosis of Recombinant Noninvasive Shigella Mutant That Expresses Yersinia Invasin. J. Immunol. 177: 4709-4717 [Abstract] [Full Text]  
  • Ranallo, R. T., Fonseka, C. P., Cassels, F., Srinivasan, J., Venkatesan, M. M. (2005). Construction and Characterization of Bivalent Shigella flexneri 2a Vaccine Strains SC608(pCFAI) and SC608(pCFAI/LTB) That Express Antigens from Enterotoxigenic Escherichia coli. Infect. Immun. 73: 258-267 [Abstract] [Full Text]  
  • Kotton, C. N., Hohmann, E. L. (2004). Enteric Pathogens as Vaccine Vectors for Foreign Antigen Delivery. Infect. Immun. 72: 5535-5547 [Full Text]  
  • Katz, D. E., Coster, T. S., Wolf, M. K., Trespalacios, F. C., Cohen, D., Robins, G., Hartman, A. B., Venkatesan, M. M., Taylor, D. N., Hale, T. L. (2004). Two Studies Evaluating the Safety and Immunogenicity of a Live, Attenuated Shigella flexneri 2a Vaccine (SC602) and Excretion of Vaccine Organisms in North American Volunteers. Infect. Immun. 72: 923-930 [Abstract] [Full Text]  
  • Cersini, A., Martino, M. C., Martini, I., Rossi, G., Bernardini, M. L. (2003). Analysis of Virulence and Inflammatory Potential of Shigella flexneri Purine Biosynthesis Mutants. Infect. Immun. 71: 7002-7013 [Abstract] [Full Text]  
  • Wei, J., Goldberg, M. B., Burland, V., Venkatesan, M. M., Deng, W., Fournier, G., Mayhew, G. F., Plunkett, G. III, Rose, D. J., Darling, A., Mau, B., Perna, N. T., Payne, S. M., Runyen-Janecky, L. J., Zhou, S., Schwartz, D. C., Blattner, F. R. (2003). Complete Genome Sequence and Comparative Genomics of Shigella flexneri Serotype 2a Strain 2457T. Infect. Immun. 71: 2775-2786 [Abstract] [Full Text]  
  • Dougan, G., Huett, A., Clare, S. (2002). Vaccines against human enteric bacterial pathogens. Br Med Bull 62: 113-123 [Abstract] [Full Text]  
  • Kotloff, K. L., Taylor, D. N., Sztein, M. B., Wasserman, S. S., Losonsky, G. A., Nataro, J. P., Venkatesan, M., Hartman, A., Picking, W. D., Katz, D. E., Campbell, J. D., Levine, M. M., Hale, T. L. (2002). Phase I Evaluation of {Delta}virG Shigella sonnei Live, Attenuated, Oral Vaccine Strain WRSS1 in Healthy Adults. Infect. Immun. 70: 2016-2021 [Abstract] [Full Text]  
  • Altboum, Z., Barry, E. M., Losonsky, G., Galen, J. E., Levine, M. M. (2001). Attenuated Shigella flexneri 2a {Delta}guaBA Strain CVD 1204 Expressing Enterotoxigenic Escherichia coli (ETEC) CS2 and CS3 Fimbriae as a Live Mucosal Vaccine against Shigella and ETEC Infection. Infect. Immun. 69: 3150-3158 [Abstract] [Full Text]  
  • Sanchez, D. O., Zandomeni, R. O., Cravero, S., Verdun, R. E., Pierrou, E., Faccio, P., Diaz, G., Lanzavecchia, S., Aguero, F., Frasch, A. C. C., Andersson, S. G. E., Rossetti, O. L., Grau, O., Ugalde, R. A. (2001). Gene Discovery through Genomic Sequencing of Brucella abortus. Infect. Immun. 69: 865-868 [Abstract] [Full Text]  
  • Bernardini, M. L., Arondel, J., Martini, I., Aidara, A., Sansonetti, P. J. (2001). Parameters Underlying Successful Protection with Live Attenuated Mutants in Experimental Shigellosis. Infect. Immun. 69: 1072-1083 [Abstract] [Full Text]  
  • Koprowski, H. II, Levine, M. M., Anderson, R. J., Losonsky, G., Pizza, M., Barry, E. M. (2000). Attenuated Shigella flexneri 2a Vaccine Strain CVD 1204 Expressing Colonization Factor Antigen I and Mutant Heat-Labile Enterotoxin of Enterotoxigenic Escherichia coli. Infect. Immun. 68: 4884-4892 [Abstract] [Full Text]