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Infection and Immunity, August 2001, p. 4969-4979, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.4969-4979.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Construction and Characterization of Genetically Defined aro omp Mutants of Enterotoxigenic Escherichia coli and Preliminary Studies of Safety and Immunogenicity in Humans

Arthur K. Turner,1 Tamsin D. Terry,1,dagger David A. Sack,2 Patricia Londoño-Arcila,1 and Michael J. Darsley1,*

Acambis Ltd., Cambridge CB1 9PT, United Kingdom,1 and Vaccine Testing Unit, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland2

Received 18 December 2000/Returned for modification 30 March 2001/Accepted 4 May 2001

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea in travelers to countries where the disease is endemic and causes a major disease burden in the indigenous population, particularly children. We describe here the generation and preclinical characterization of candidate strains of ETEC which are intended to provide the basis of a live attenuated oral vaccine to prevent this disease. It has been shown previously that a spontaneously arising toxin-negative variant ETEC strain, E1392/75-2A, could confer 75% protection against challenge when administered to volunteers. Unfortunately this strain induced mild diarrhea in 15% of recipients. To eliminate the unacceptable reactogenicity of strain E1392/75-2A, it was further attenuated by introducing three different combinations of defined deletion mutations into the chromosome. A mouse intranasal model of immunization was developed and used to show that all of the strains were immunogenic. Immune responses against colonization factor antigens (CFAs) were particularly strong when the bacterial inocula were grown on "CFA agar," which induces strong expression of these antigens. Two of the strains were selected for a phase I dose escalation safety study with healthy adult volunteers. Freshly grown organisms were harvested from CFA agar plates and administered to volunteers as a suspension containing from 5 × 107 to 5 × 109 CFU. The vaccine was well tolerated at all doses and induced significant immune responses in all recipients at the highest dose of either strain. The results provide the basis for further clinical evaluation of these vaccine candidates.

* Corresponding author. Mailing address: Acambis Ltd., Peterhouse Technology Park, 100 Fulbourn Road, Cambridge CB1 9PT, United Kingdom. Phone: (44) 1223 275300. Fax: 44-0-1223-416-300. E-mail: michael.darsley{at}acambis.co.uk.

dagger Present address: Department of Microbiology and Parasitology, University of Queensland, St Lucia QLD 4067, Australia.

Infection and Immunity, August 2001, p. 4969-4979, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.4969-4979.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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