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Infection and Immunity, May 1999, p. 2145-2152, Vol. 67, No. 5
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Immunogenicity of a Salmonella typhimurium aroA aroD Vaccine Expressing a Nontoxic Domain of Clostridium difficile Toxin A

Stephen J. Ward,1,dagger Gill Douce,2,dagger Dayse Figueiredo,2,Dagger Gordon Dougan,2 and Brendan W. Wren1,*

Microbial Pathogenicity Research Group, Department of Microbiology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London EC1A 7BE,1 and Department of Biochemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY,2 United Kingdom

Received 6 August 1998/Returned for modification 1 October 1998/Accepted 3 February 1999

The C-terminal repeat domain of Clostridium difficile toxin A harbors toxin-neutralizing epitopes and is considered to be a candidate component of a vaccine against C. difficile-associated disease (CDAD). Fourteen of the 38 C-terminal toxin A repeats (14CDTA) were cloned into pTECH-1 in frame with the immunogenic fragment C of tetanus toxin (TETC) to generate plasmid p56TETC. Expression of the TETC-14CDTA fusion protein was driven from the anaerobically inducible nirB promoter within attenuated Salmonella typhimurium BRD509 (aroA aroD). The TETC-14CDTA fusion protein was purified and shown to bind to known toxin A receptors found on the surface of rabbit erythrocytes. Intranasal (i.n.) and intragastric (i.g.) immunization with 107 and 1010 CFU, respectively, of BRD509(p56TETC) generated significant (P < 0.05) anti-toxin A serum responses after a single dose. Antibody titers were elevated following a boosting dose with either live vaccine or a subcutaneous injection of 0.5 µg of purified 14CDTA protein. Importantly, serum from mice immunized with BRD509(p56TETC) neutralized toxin A cytotoxicity. Both i.n. and i.g. immunizations also generated toxin A-specific immunoglobulin A on the pulmonary and intestinal mucosa, respectively. Intranasal vaccination induced consistently higher serum and mucosal anti-toxin A antibody responses. Significant anti-tetanus toxoid serum and mucosal antibodies were also generated by both immunization routes. The availability of live attenuated Salmonella typhi for human use may allow the development of a multivalent mucosal vaccine against CDAD, tetanus, and typhoid.

* Corresponding author. Mailing address: Microbial Pathogenicity Research Group, Department of Microbiology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, West Smithfield, London EC1A 7BE, United Kingdom. Phone: 0171 6018411. Fax: 0171 6018409. E-mail: b.w.wren{at}mds.qmw.ac.uk.

dagger Present address: Medeva Development, Vaccine Research Unit, Department of Biochemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, United Kingdom.

Dagger Present address: Laboratorio Especial de Microbiologia, Instituto Butantan, São Paulo, SP 05503-900, Brazil.

Infection and Immunity, May 1999, p. 2145-2152, Vol. 67, No. 5
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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