Refinement of the CS6-expressing enterotoxigenic Escherichia coli strain B7A human challenge model: A randomized trial.
Adolescent
Adult
Antibodies, Bacterial
/ blood
Antigens, Bacterial
/ analysis
Bacterial Load
Bacterial Toxins
/ immunology
Ciprofloxacin
/ therapeutic use
Diarrhea
/ etiology
Dose-Response Relationship, Immunologic
Enterotoxigenic Escherichia coli
/ immunology
Enterotoxins
/ immunology
Escherichia coli Infections
/ microbiology
Escherichia coli Proteins
/ analysis
Escherichia coli Vaccines
Fasting
Feces
/ microbiology
Female
Fluid Therapy
Humans
Immunoglobulin G
/ blood
Immunoglobulin M
/ blood
Lipopolysaccharides
/ immunology
Male
Middle Aged
Random Allocation
Time Factors
Young Adult
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
27
11
2019
accepted:
01
09
2020
entrez:
2
12
2020
pubmed:
3
12
2020
medline:
15
1
2021
Statut:
epublish
Résumé
Human challenge models for enterotoxigenic Escherichia coli (ETEC) facilitate vaccine down-selection. The B7A (O148:H28 CS6+LT+ST+) strain is important for vaccine development. We sought to refine the B7A model by identifying a dose and fasting regimen consistently inducing moderate-severe diarrhea. An initial cohort of 28 subjects was randomized (1:1:1:1) to receive B7A following an overnight fast at doses of 108 or 109 colony forming units (cfu) or a 90-minute fast at doses of 109 or 1010 cfu. A second cohort included naïve and rechallenged subjects who had moderate-severe diarrhea and were given the target regimen. Immune responses to important ETEC antigens were assessed. Among subjects receiving 108 cfu of B7A, overnight fast, or 109 cfu, 90-minute fast, 42.9% (3/7) had moderate-severe diarrhea. Higher attack rates (71.4%; 5/7) occurred in subjects receiving 109 cfu, overnight fast, or 1010 cfu, 90-minute fast. Upon rechallenge with 109 cfu of B7A, overnight fast, 5/11 (45.5%) had moderate-severe diarrhea; the attack rate among concurrently challenge naïve subjects was 57.9% (11/19). Anti-CS6, O148 LPS and LT responses were modest across all groups. An overnight fast enabled a reduction in the B7A inoculum dose; however, the attack rate was inconsistent and protection upon rechallenge was minimal.
Sections du résumé
BACKGROUND
Human challenge models for enterotoxigenic Escherichia coli (ETEC) facilitate vaccine down-selection. The B7A (O148:H28 CS6+LT+ST+) strain is important for vaccine development. We sought to refine the B7A model by identifying a dose and fasting regimen consistently inducing moderate-severe diarrhea.
METHODS
An initial cohort of 28 subjects was randomized (1:1:1:1) to receive B7A following an overnight fast at doses of 108 or 109 colony forming units (cfu) or a 90-minute fast at doses of 109 or 1010 cfu. A second cohort included naïve and rechallenged subjects who had moderate-severe diarrhea and were given the target regimen. Immune responses to important ETEC antigens were assessed.
RESULTS
Among subjects receiving 108 cfu of B7A, overnight fast, or 109 cfu, 90-minute fast, 42.9% (3/7) had moderate-severe diarrhea. Higher attack rates (71.4%; 5/7) occurred in subjects receiving 109 cfu, overnight fast, or 1010 cfu, 90-minute fast. Upon rechallenge with 109 cfu of B7A, overnight fast, 5/11 (45.5%) had moderate-severe diarrhea; the attack rate among concurrently challenge naïve subjects was 57.9% (11/19). Anti-CS6, O148 LPS and LT responses were modest across all groups.
CONCLUSIONS
An overnight fast enabled a reduction in the B7A inoculum dose; however, the attack rate was inconsistent and protection upon rechallenge was minimal.
Identifiants
pubmed: 33264302
doi: 10.1371/journal.pone.0239888
pii: PONE-D-19-31631
pmc: PMC7710093
doi:
Substances chimiques
Antibodies, Bacterial
0
Antigens, Bacterial
0
Bacterial Toxins
0
CS6 antigen, E coli
0
Enterotoxins
0
Escherichia coli Proteins
0
Escherichia coli Vaccines
0
Immunoglobulin G
0
Immunoglobulin M
0
Lipopolysaccharides
0
Ciprofloxacin
5E8K9I0O4U
heat-labile enterotoxin, E coli
D9K3SN2LNY
Types de publication
Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0239888Déclaration de conflit d'intérêts
None of the authors report a conflict of interest with the work presented in this paper.
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