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Infection and Immunity, April 2008, p. 1766-1773, Vol. 76, No. 4
0019-9567/08/$08.00+0     doi:10.1128/IAI.00797-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Transcutaneous Immunization with Cross-Reacting Material CRM197 of Diphtheria Toxin Boosts Functional Antibody Levels in Mice Primed Parenterally with Adsorbed Diphtheria Toxoid Vaccine{triangledown}

Paul Stickings,1 Marisa Peyre,1 Laura Coombes,1 Sylviane Muller,2 Rino Rappuoli,3 Giuseppe Del Giudice,3 Charalambos D. Partidos,2,{dagger} and Dorothea Sesardic1*

Division of Bacteriology, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Hertfordshire EN6 3QG, United Kingdom,1 UPR 9021, Institut de Biologie Moléculaire et Cellulaire, CNRS, 15 rue René Descartes, 67084 Strasbourg, France,2 Novartis Vaccines, Via Fiorentina 1, 53100 Siena, Italy3

Received 11 June 2007/ Returned for modification 5 September 2007/ Accepted 22 January 2008

Transcutaneous immunization (TCI) capitalizes on the accessibility and immunocompetence of the skin, elicits protective immunity, simplifies vaccine delivery, and may be particularly advantageous when frequent boosting is required. In this study we examined the potential of TCI to boost preexisting immune responses to diphtheria in mice. The cross-reacting material (CRM197) of diphtheria toxin was used as the boosting antigen and was administered alone or together with either one of two commonly used mucosal adjuvants, cholera toxin (CT) and a partially detoxified mutant of heat-labile enterotoxin of Escherichia coli (LTR72). We report that TCI with CRM197 significantly boosted preexisting immune responses elicited after parenteral priming with aluminum hydroxide-adsorbed diphtheria toxoid (DTxd) vaccine. In the presence of LTR72 as an adjuvant, toxin-neutralizing antibody titers were significantly higher than those elicited by CRM197 alone and were comparable to the functional antibody levels induced after parenteral booster immunization with the adsorbed DTxd vaccine. Time course study showed that high levels of toxin-neutralizing antibodies persisted for at least 14 weeks after the transcutaneous boost. In addition, TCI resulted in a vigorous antigen-specific proliferative response in all groups of mice boosted with the CRM197 protein. These findings highlight the promising prospect of using booster administrations of CRM197 via the transcutaneous route to establish good herd immunity against diphtheria.

* Corresponding author. Mailing address: Division of Bacteriology, NIBSC, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, United Kingdom. Phone: 44 (0) 1707 641447. Fax: 44 (0) 1707 641054. E-mail: dsesardic{at}nibsc.ac.uk

{triangledown} Published ahead of print on 28 January 2008.

Editor: J. L. Flynn

{dagger} Present address: Axion Analytical Laboratories, 14 North Peoria St., Chicago, IL.

Infection and Immunity, April 2008, p. 1766-1773, Vol. 76, No. 4
0019-9567/08/$08.00+0     doi:10.1128/IAI.00797-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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