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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.


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