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Infection and Immunity, March 2000, p. 1034-1039, Vol. 68, No. 3
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 (
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

virG), does not produce enterotoxin (
sen
and
set), and has limited proliferation in vivo
(
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.
Present address: Clinical Development, Pasteur Mérieux
Connaught, Swiftwater, PA 18370-0187.
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