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Infection and Immunity, August 2006, p. 4884-4891, Vol. 74, No. 8
0019-9567/06/$08.00+0     doi:10.1128/IAI.00500-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Reduction of the Ganglioside Binding Activity of the Tetanus Toxin HC Fragment Destroys Immunogenicity: Implications for Development of Novel Tetanus Vaccines

Omar Qazi,1 Dorothea Sesardic,2 Robert Tierney,2 Zahra Söderbäck,2 Dennis Crane,2 Barbara Bolgiano,2 and Neil Fairweather1*

Centre for Molecular Microbiology and Infection, Imperial College London, London SW7 2AZ, United Kingdom,1 Division of Bacteriology, National Institute for Biological Standards and Control, South Mimms, Potters Bar, Hertfordshire EN6 3QG, United Kingdom2

Received 28 March 2006/ Returned for modification 5 May 2006/ Accepted 2 June 2006

In this study, the immunogenicities of the nontoxic HC fragment of tetanus toxin and derivatives lacking ganglioside binding activity were compared with that of tetanus toxoid after subcutaneous immunization of mice. Wild-type HC (HCWT) protein and tetanus toxoid both elicited strong antibody responses against toxoid and HC antigens and provided complete protection against toxin challenge. Mutants of HC containing deletions essential for ganglioside binding elicited lower responses than HCWT. HCM115, containing two amino acid substitutions within the ganglioside binding site, provided reduced protection against tetanus toxin challenge compared with HCWT, consistent with lower anti-HC and anti-toxoid antibody titers. Circular-dichroism spectroscopy and intrinsic fluorescence spectroscopy showed minimal structural perturbation in HCM115. We conclude that the presence of the ganglioside binding site within HC may be essential for induction of a fully protective anti-tetanus response comparable to that induced by tetanus toxoid by subcutaneous injection.

* Corresponding author. Mailing address: Centre for Microbiology and Infection, Imperial College London, Flowers Building, South Kensington Campus, London SW7 2AZ, United Kingdom. Phone: 44 (0) 20 7594 5247. Fax: 44 (0) 20 7594 3069. E-mail: n.fairweather{at}imperial.ac.uk.

Editor: D. L. Burns

Infection and Immunity, August 2006, p. 4884-4891, Vol. 74, No. 8
0019-9567/06/$08.00+0     doi:10.1128/IAI.00500-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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