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Infection and Immunity, July 1999, p. 3437-3443, Vol. 67, No. 7
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Vaccination against Shigellosis with Attenuated Shigella flexneri 2a Strain SC602

Trinka S. Coster,1 Charles W. Hoge,2 Lillian L. VanDeVerg,2,dagger Antoinette B. Hartman,2 Edwin V. Oaks,2 Malabi M. Venkatesan,2 Dani Cohen,3 Guy Robin,3 Annick Fontaine-Thompson,4,Dagger Philippe J. Sansonetti,4 and Thomas L. Hale2,*

Medical Division, United States Army Medical Research Institute for Infectious Diseases, Fort Detrick, Maryland 217021; Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Washington, D.C. 203072; Post 02149, Israel Defense Force Medical Corps, Israel3; and Unité de Pathogénie Microbienne Moléculaire, Unité U389 de l'Institut National de la Santé et de la Recherche Médicale, Institut Pasteur, 75015, Paris, France4

Received 23 December 1998/Returned for modification 15 February 1999/Accepted 12 April 1999

The Shigella flexneri 2a SC602 vaccine candidate carries deletions of the plasmid-borne virulence gene icsA (mediating intra- and intercellular spread) and the chromosomal locus iuc (encoding aerobactin) (S. Barzu, A. Fontaine, P. J. Sansonetti, and A. Phalipon, Infect. Immun. 64:1190-1196, 1996). Dose selection studies showed that SC602 causes shigellosis in a majority of volunteers when 3 × 108 or 2 × 106 CFU are ingested. In contrast, a dose of 104 CFU was associated with transient fever or mild diarrhea in 2 of 15 volunteers. All volunteers receiving single doses of >= 104 CFU excreted S. flexneri 2a, and this colonization induced significant antibody-secreting cell and enzyme-linked immunosorbent assay responses against S. flexneri 2a lipopolysaccharide in two-thirds of the vaccinees. Seven volunteers who had been vaccinated 8 weeks earlier with a single dose of 104 CFU and 7 control subjects were challenged with 2 × 103 CFU of virulent S. flexneri 2a organisms. Six of the control volunteers developed shigellosis with fever and severe diarrhea or dysentery, while none of the vaccinees had fever, dysentery, or severe symptoms (P = 0.005). Three vaccinees experienced mild diarrhea, and these subjects had lower antibody titers than did the fully protected volunteers. Although the apparent window of safety is narrow, SC602 is the first example of an attenuated S. flexneri 2a candidate vaccine that provides protection against shigellosis in a stringent, human challenge model.

* Corresponding author. Mailing address: Department of Enteric Infections, Walter Reed Army Institute of Research, Washington, DC 20307. Phone: (202) 782-3344. Fax: (202) 782-3299. E-mail: Dr._Thomas_Hale{at}wrsmtp-ccmail.army.mil.

dagger Present address: Joint Vaccine Acquisition Program, Fort Detrick, Md.

Dagger Present address: Pharma Division, F. Hoffman-Laroche, Ltd., CH-4002 Basel, Switzerland.

Infection and Immunity, July 1999, p. 3437-3443, Vol. 67, No. 7
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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Copyright © 1999 by the American Society for Microbiology. All rights reserved.