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Infection and Immunity, June 2002, p. 2950-2958, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.2950-2958.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Construction, Characterization, and Animal Testing of WRSd1, a Shigella dysenteriae 1 Vaccine

Malabi M. Venkatesan,1* Antoinette B. Hartman,1 John W. Newland,1 Vessela S. Ivanova,1 Thomas L. Hale,1 Marie McDonough,2 and Joan Butterton2

Department of Enteric Infections, Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910,1 Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts 021142

Received 19 December 2001/ Returned for modification 5 February 2002/ Accepted 2 March 2002

WRSd1 is a Shigella dysenteriae 1 vaccine containing deletions of the virG(icsA) gene required for intercellular spreading and a 20-kb chromosomal region encompassing the Shiga toxin genes (stxAB). WRSd1 was constructed from S. dysenteriae 1 strain 1617 that was originally isolated during the 1968 to 1969 epidemic of Shiga dysentery in Guatemala. The virG(icsA) deletion was constructed from a streptomycin-resistant (Strr) mutant of 1617 by a filter mating procedures using a virG(icsA) deletion derivative, p{Delta}virG2. A colony that was invasive for HeLa cells and negative for the virG(icsA) gene by Southern blotting was grown anaerobically on plates containing chlorate for selection of resistant colonies that had lost the entire Shiga toxin gene. A virG(icsA) stxAB Strr mutant selected from the chlorate plates was designated WRSd1. This candidate vaccine was evaluated for safety, immunogenicity, and protective efficacy using the guinea pig keratoconjunctivitis model. WRSd1 was Sereny negative, and two applications of this strain to the cornea elicited a significant protective immune response against the S. dysenteriae 1 O antigen. Vaccination with WRSd1 conferred protection against challenge with each of three virulent S. dysenteriae 1 strains. Since a vaccine protecting against multiple Shigella species is required for most areas where Shigella is endemic, protection studies using a combination vaccine of Shigella sonnei vaccine strain WRSS1, Shigella flexneri 2a vaccine strain SC602, and WRSd1 were also performed. Guinea pigs vaccinated with a mixture of equal amounts of the three vaccine strains were protected against challenge with each of the homologous virulent strains. Unlike WRSS1 and SC602, however, the level of protection afforded by WRSd1 in a combination vaccine was lower than the protection elicited by a pure culture. A current Good Manufacturing Practice product of WRSd1 given intragastrically to rhesus monkeys proved safe and immunogenic.

* Corresponding author. Mailing address: Dept. of Enteric Infections, Walter Reed Army Institute of Research (WRAIR), 503, Forney Drive, Room 3S12, Silver Spring, MD 20910. Phone: 301-319-9764. Fax: 301-319-9801. E-mail: malabi.venkatesan{at}na.amedd.army.mil.

Editor: W. A. Petri, Jr.

Infection and Immunity, June 2002, p. 2950-2958, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.2950-2958.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • 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]  


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