Deletion in the Shigella Enterotoxin Genes Further Attenuates Shigella flexneri 2a Bearing Guanine Auxotrophy in a Phase 1 Trial of CVD 1204 and CVD 1208.
Kotloff, Karen L. 1,2; Pasetti, Marcela F. 1; Barry, Eileen M. 2; Nataro, James P. 1,2; Wasserman, Steven S. 2; Sztein, Marcelo B. 1; Picking, William D. 3; Levine, Myron M. 1,2
[Article]
Journal of Infectious Diseases.
190(10):1745-1754, November 15, 2004.
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Background. We created a live, attenuated, oral Shigella vaccine by constructing a lineage of guanine auxotrophs and conducted a double-blind, placebo-controlled trial to ascertain (1) the attenuation profile of [DELTA]guaBA Shigella flexneri 2a, which harbors deletions in the guanine nucleotide synthesis pathway (CVD 1204); (2) additional attenuation conferred by deletions in set and sen genes encoding Shigella enterotoxins (ShETs) 1 and 2, respectively (CVD 1208); and (3) the relative immunogenicity of these constructs.
Methods. Inpatient volunteers received a single oral dose of CVD 1204, CVD 1208 (107, 108, or 109 cfu), or placebo. Clinical, immunologic, and microbiologic responses were evaluated.
Results. Reactogenicity occurred in 8 of 23 recipients of CVD 1204, characterized by diarrhea (30%), fever (22%), and/or dysentery (17%), but in only 1 (5%) of 21 recipients of CVD 1208 (brief fever) (P = .02, Fisher's exact test). Antilipopolysaccharide responses, as measured by antibody-secreting cell, serum, or fecal antibody levels, occurred in 67%, 71%, and 100% of recipients of CVD 1204 and in 86%, 43%, and 100% of recipients of CVD 1208 at doses of 107, 108, and 109 cfu, respectively.
Conclusions. We conclude that 1 or both ShETs are virulence determinants in humans; their inactivation, in combination with [DELTA]guaBA, leads to a well-tolerated and immunogenic Shigella vaccine candidate.
(C) Copyright Oxford University Press 2004.
