Impact of lower challenge doses of enterotoxigenic Escherichia coli on clinical outcome, intestinal colonization and immune responses in adult volunteers.
2018 04
Journal Article
Authors:
Chakraborty, S.;
Harro, C.;
DeNearing, B.;
Brubaker, J.;
Connor, S.;
Maier, N.;
Dally, L.;
Flores, J.;
Bourgeois, L.;
Walker, R.;
Sack, D.A.
Secondary:
PLoS Negl Trop Dis
Volume:
12
Pagination:
e0006442
Issue:
4
PMID:
29702652
DOI:
10.1371/journal.pntd.0006442
Keywords:
Administration, Oral; Adult; Antibodies, Bacterial; Antigens, Bacterial; Diarrhea; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Feces; Female; Humans; Immunity, Mucosal; Intestines; Male; Middle Aged; Volunteers; Young Adult
Abstract:
A reliable and effective human challenge model is needed to help down-select the most promising ETEC vaccines currently under development. Such a model would need to reliably induce diarrhea in a high proportion of volunteers using the lowest possible inoculum to maximize safety and sensitivity. Previously we validated a challenge model that utilized a dose of 2x107 CFU of ETEC strain H10407 (LT+, ST+, CFA/I+ and O78+) to induce attack rates for moderate to severe diarrhea (MSD) of ~60-70%. Here we detail efforts to further refine the model in an attempt to determine if a lower challenge dose of H10407 can be used. Thirty subjects were randomized 1:1 to receive an oral administration of H10407 at doses of 106 or 105 CFU in bicarbonate buffer. After challenge, subjects were monitored for signs and symptoms of enteric illness and stool samples were collected to detect shedding of the challenge strain. Systemic and mucosal immune responses were measured using serum, antibody in lymphocyte supernatant and fecal samples. The attack rate was 13.3% (2/15) and 26.7% (4/15) for MSD in the 105 and 106 groups, respectively. Four MSD cases met criteria for early antibiotic treatment. All subjects but one shed the challenge strain in fecal samples. The frequency and magnitude of anti-LT toxin, CFA/I and LPS O78 immune responses were antigen, dose, severity of diarrhea and shedding levels dependent. Notably, although of lower magnitude, there were considerable immune responses in the subjects with no diarrhea. This may indicate that immune responses to asymptomatic infections of ETEC in children in the endemic countries may contribute to protection. Based on this and our prior studies, we conclude that a dose of 2x107 H10407 remains the lowest practical dose for use in future volunteer studies evaluating candidate vaccines and other preventive or therapeutic ETEC interventions.TRIAL REGISTRATION: ClinicalTrials.gov NCT00844493.
