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Infection and Immunity, August 2001, p. 4734-4741, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.4734-4741.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Construction, Genotypic and Phenotypic Characterization, and Immunogenicity of Attenuated Delta guaBA Salmonella enterica Serovar Typhi Strain CVD 915

Jin Yuang Wang,1,2 Marcela F. Pasetti,1,3 Fernando R. Noriega,1,3,dagger Richard J. Anderson,1,2,Dagger Steven S. Wasserman,1,2 James E. Galen,1,2 Marcelo B. Sztein,1,3 and Myron M. Levine1,2,3,*

Center for Vaccine Development,1 Division of Infectious Diseases and Tropical Pediatrics, Department of Pediatrics,3 and Division of Geographic Medicine, Department of Medicine,2 University of Maryland School of Medicine, Baltimore, Maryland 21201

Received 9 January 2001/Returned for modification 1 March 2001/Accepted 27 April 2001

A promising live attenuated typhoid vaccine candidate strain for mucosal immunization was developed by introducing a deletion in the guaBA locus of pathogenic Salmonella enterica serovar Typhi strain Ty2. The resultant Delta guaBA mutant, serovar Typhi CVD 915, has a gene encoding resistance to arsenite replacing the deleted sequence within guaBA, thereby providing a marker to readily identify the vaccine strain. CVD 915 was compared in in vitro and in vivo assays with wild-type strain Ty2, licensed live oral typhoid vaccine strain Ty21a, or attenuated serovar Typhi vaccine strain CVD 908-htrA (harboring mutations in aroC, aroD, and htrA). CVD 915 was less invasive than CVD 908-htrA in tissue culture and was more crippled in its ability to proliferate after invasion. In mice inoculated intraperitoneally with serovar Typhi and hog gastric mucin (to estimate the relative degree of attenuation), the 50% lethal dose of CVD 915 (7.7 × 107 CFU) was significantly higher than that of wild-type Ty2 (1.4 × 102 CFU) and was only slightly lower than that of Ty21a (1.9 × 108 CFU). Strong serum O and H antibody responses were recorded in mice inoculated intranasally with CVD 915, which were higher than those elicited by Ty21a and similar to those stimulated by CVD 908-htrA. CVD 915 also elicited potent proliferative responses in splenocytes from immunized mice stimulated with serovar Typhi antigens. Used as a live vector, CVD 915(pTETlpp) elicited high titers of serum immunoglobulin G anti-fragment C. These encouraging preclinical data pave the way for phase 1 clinical trials with CVD 915.

* Corresponding author. Mailing address: Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore St., Baltimore MD 21201. Phone: (410) 706-7588. Fax: (410) 706-6205. E-mail: mlevine{at}medicine.umaryland.edu.

dagger Present address: Clinical Development, Aventis Pasteur, Swiftwater, PA 18370.

Dagger Present address: Wellcome Centre for Human Genetics, Headington, Oxford OX3 7EQ, United Kingdom.

Infection and Immunity, August 2001, p. 4734-4741, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.4734-4741.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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