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Infection and Immunity, October 1999, p. 5124-5132, Vol. 67, No. 10
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Local and Systemic Neutralizing Antibody Responses Induced by Intranasal Immunization with the Nontoxic Binding Domain of Toxin A from Clostridium difficile

Stephen J. Ward,1,dagger Gill Douce,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, West Smithfield, London ECIA 7BE,1 and Department of Biochemistry, Imperial College of Science, Technology and Medicine, London SW7 2AZ,2 United Kingdom

Received 9 April 1999/Returned for modification 26 May 1999/Accepted 27 July 1999

Fourteen of the 38 C-terminal repeats from Clostridium difficile toxin A (14CDTA) were cloned and expressed either with an N-terminal polyhistidine tag (14CDTA-HIS) or fused to the nontoxic binding domain from tetanus toxin (14CDTA-TETC). The recombinant proteins were successfully purified by bovine thyroglobulin affinity chromatography. Both C. difficile toxin A fusion proteins bound to known toxin A ligands present on the surface of rabbit erythrocytes. Intranasal immunization of BALB/c mice with three separate 10-µg doses of 14CDTA-HIS or -TETC generated significant levels of anti-toxin A serum antibodies compared to control animals. The coadministration of the mucosal adjuvant heat labile toxin (LT) from Escherichia coli (1 µg) significantly increased the anti-toxin A response in the serum and at the mucosal surface. Importantly, the local and systemic antibodies generated neutralized toxin A cytotoxicity. Impressive systemic and mucosal anti-toxin A responses were also seen following coadministration of 14CDTA-TETC with LTR72, an LT derivative with reduced toxicity which shows potential as a mucosal adjuvant for humans.

* Corresponding author. Mailing address: Department of Infectious and Tropical Diseases, The London School of Hygiene and Tropical Medicine, Keppel St., London WC1E 7H7, United Kingdom. Phone: 44 (0) 171 927 2288. E-mail: BrendanWren{at}Lshtm.ac.uk.

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

Infection and Immunity, October 1999, p. 5124-5132, Vol. 67, No. 10
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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