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Infection and Immunity, July 2002, p. 3457-3467, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3457-3467.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Characterization of Salmonella enterica Derivatives Harboring Defined aroC and Salmonella Pathogenicity Island 2 Type III Secretion System (ssaV) Mutations by Immunization of Healthy Volunteers

Zoë Hindle,1 Steven N. Chatfield,1 Jo Phillimore,2 Matthew Bentley,1 Julie Johnson,3 Catherine A. Cosgrove,2 Marjan Ghaem-Maghami,2 Amy Sexton,2 Mohammad Khan,3 Frank R. Brennan,1 Paul Everest,1 Tao Wu,1 Derek Pickard,4 David W. Holden,4 Gordon Dougan,4 George E. Griffin,2 Deborah House,4 Joseph D. Santangelo,1 Shahid A. Khan,1 Jaqueline E. Shea,1 Robert G. Feldman,1 and David J. M. Lewis2*

Microscience, Wokingham Berkshire RG41 5TU,1 Departments of Infectious Diseases,2 Microbiology, St. George's Hospital Medical School, London SW17 0RE,3 Centre for Molecular Microbiology and Infection, Imperial College of Science, Technology, and Medicine, London SW7 2AZ, United Kingdom4

Received 26 November 2001/ Returned for modification 8 January 2002/ Accepted 11 March 2002

The attenuation and immunogenicity of two novel Salmonella vaccine strains, Salmonella enterica serovar Typhi (Ty2 {Delta}aroC {Delta}ssaV, designated ZH9) and S. enterica serovar Typhimurium (TML {Delta}aroC {Delta}ssaV, designated WT05), were evaluated after their oral administration to volunteers as single escalating doses of 107, 108, or 109 CFU. ZH9 was well tolerated, not detected in blood, nor persistently excreted in stool. Six of nine volunteers elicited anti-serovar Typhi lipopolysaccharide (LPS) immunoglobulin A (IgA) antibody-secreting cell (ASC) responses, with three of three vaccinees receiving 108 and two of three receiving 109 CFU which elicited high-titer LPS-specific serum IgG. WT05 was also well tolerated with no diarrhea, although the administration of 108 and 109 CFU resulted in shedding in stools for up to 23 days. Only volunteers immunized with 109 CFU of WT05 mounted detectable serovar Typhimurium LPS-specific ASC responses and serum antibody responses were variable. These data indicate that mutations in type III secretion systems may provide a route to the development of live vaccines in humans and highlight significant differences in the potential use of serovars Typhimurium and Typhi.

* Corresponding author. Mailing address: Division of Infectious Diseases, St. George's Hospital Medical School, London SW17 0RE, United Kingdom. Phone: 44-020-8725-5826. Fax: 44-020-8725-3487. E-mail: d.lewis{at}sghms.ac.uk.

Editor: D. L. Burns

Infection and Immunity, July 2002, p. 3457-3467, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3457-3467.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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