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Infection and Immunity, September 1999, p. 4400-4406, Vol. 67, No. 9
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Genetically Detoxified Mutants of Heat-Labile Toxin from Escherichia coli Are Able To Act as Oral Adjuvants

Gill Douce,1,dagger Valentina Giannelli,2 Mariagrazia Pizza,2 David Lewis,3 Paul Everest,1,Dagger Rino Rappuoli,2 and Gordon Dougan1,*

Department of Biochemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY,1 and Department of Communicable Diseases, St. George's Hospital Medical School, London SW17 ORE,3 United Kingdom, and Chiron Vaccines Immunological Research Institute, Siena 53100, Italy2

Received 12 March 1999/Returned for modification 15 April 1999/Accepted 29 May 1999

Detoxified mutants of the Escherichia coli heat-labile toxin (LT) act as mucosal adjuvants to intranasally presented coadministered antigens. Here, we compare the adjuvant activity of a panel of detoxified derivatives of LT, using both intranasal (i.n.) and oral (p.o.) routes of administration. The mutants used as adjuvants varied in sensitivity to proteases and toxicity. With keyhole limpet hemocyanin (KLH) as the bystander antigen, the immune responses to i.n. immunizations were consistently higher than the equivalent p.o.-delivered proteins. LT-G192, a mutant which demonstrates a 10-fold reduction in toxicity in vitro, demonstrated wild-type adjuvant activity both i.n. and p.o., inducing similar titers of KLH specific antibody in the sera and immunoglobulin A in local mucosal secretions as wild-type LT. In line with previous data, the nontoxic holotoxoid LT-K63 induced intermediate immune responses in both the serum and mucosal secretions which were lower than those achieved with wild-type LT but at least 10-fold higher than those measured when the antigen was administered with LT-B. Although significant levels of local and systemic anti-KLH antibodies were induced following p.o. immunization with LT-K63, cellular proliferative responses to KLH was poor or undetectable. In contrast, LT and LT-G192 induced significant T-cell responses to KLH following p.o. immunization. These proliferating cells secreted both gamma interferon and interleukin-5, suggesting that the type of immune response induced following p.o. coimmunization with LT and purified protein is a mixed Th1/Th2 response.

* Corresponding author. Mailing address: Department of Biochemistry, Imperial College of Science, Technology and Medicine, Exhibition Rd., London SW7 2AY, United Kingdom. 44 (0)171-594-5256. Fax: 44 (0)171-594-5255. E-mail: g.dougan{at}ic.ac.uk.

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

Dagger Present address: Department of Infectious Diseases, Hammersmith Hospital, London, United Kingdom.

Infection and Immunity, September 1999, p. 4400-4406, Vol. 67, No. 9
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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