Experimental infection of healthy volunteers with enterotoxigenic Escherichia coliwild-type strain TW10598 in a hospital ward

Abstract

BackgroundEnterotoxigenic Escherichia coli (ETEC) is an important cause of childhood diarrhea in resource-limited regions. It is also an important cause of diarrhea in travellers to these areas.To evaluate the protective efficacy of new ETEC vaccines that are under development, there is a need to increase the capacity to undertake Phase IIB (human challenge) clinical trials and to develop suitable challenge models.MethodsAn in-hospital study was performed where fasting adult volunteers were experimentally infected with 1 × 106 to 1 × 109 colony forming units (CFUs) of the wild-type ETEC strain TW10598, which had been isolated from a child with diarrhea in West Africa in 1997. We recorded symptoms and physical signs and measured serum immune response to the TW10598 bacterium.ResultsWe included 30 volunteers with mean age 22.8 (range 19.8, 27.4) years. The most common symptoms were diarrhea (77%), abdominal pain (67%), nausea (63%), and abdominal cramping (53%). Seven subjects (23%) experienced fever, none were hypotensive. Most of the volunteers responded with a substantial rise in the level of serum IgA antibodies against the challenge strain.ConclusionsWe established the capacity and methods for safely undertaking challenge studies to measure the efficacy of ETEC vaccine candidates in a hospital ward. Strain TW10598 elicited both clinical symptoms and an immune response across the doses given.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-482) contains supplementary material, which is available to authorized users.

Salivary IgA from the sublingual compartment as a novel noninvasive proxy for intestinal immune induction

“…That a few of the volunteers had a high anti-ETEC titer before the experimental challenge is to be expected as they might still be colonized with E. coli strains that share epitopes with our challenge strain. Furthermore, some of the volunteers could have travelled to ETEC endemic countries up to 9 months before they were challenged 27 and might thus have been infected with ETEC similar to our challenge strain.…”

“…The serum IgA response was reported in our initial publication describing the clinical setting of the volunteers participating in the study. 27 In the pre-infection sera (day 0), the IgG geometric mean (GM) level of antibodies directed against TW10598 was 37.9 AU per ml. The highest GM serum IgG level was observed at day 10, with a titer of 425.1 AU per ml.…”

“…A total of 30 healthy young adult volunteers were infected with the wild-type ETEC strain TW10598. 27 Peripheral venous blood, salivary secretions, intestinal lavage, and lymphocytes for ALS were collected before infection (day 0) and at different time points thereafter.…”

“…The fold increase in GM IgG antibody levels were 5.0 (confidence interval, CI: 3.1, 8.1), 11.2 (CI: 6.7, 18.9), and 10.1 (CI: 6.4, 15.9). Similarly to the IgA response, 27 there was no detectable serum IgG response against the heterologous ETEC strain (H10407) (GM titers of 9.0, 9.1, 8.9, and 9.6 AU per ml at days 0, 7, 10, and 28, respectively).…”

Development of an enterotoxigenic Escherichia coli vaccine based on the heat-stable toxin

“…So far, mouse models are restricted to studying the protective efficacy of antigens in ETEC colonization 103,104 and protection against lethal ETEC doses. 58 Furthermore, human challenge models for evaluating the protective efficacy of ETEC vaccines have so far focused on strains that also produce LT. 105,106 There is a need to develop a human challenge model for ETEC that only express STh, and important progress towards establishing such a model has recently been made. 107 Finally, since ETEC is an enteric pathogen, the ETEC vaccine needs to primarily induce mucosal IgA responses.…”