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Infection and Immunity, August 2001, p. 4969-4979, Vol. 69, No. 8
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.
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

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