Development of an S. sonnei human challenge model using a newly manufactured lyophilized lot of S. sonnei strain 53G (Lot 1794) that can be used in the future as a challenge strain for all S. sonnei vaccine candidates. An adaptable dosing plan was used to determine the dose of Shigella sonnei 53G that induces the primary outcome in approximately 60% of subjects.
Primary objectives: 1. Establish a human challenge model of S. sonnei 53G infection using a lyophilized formulation of the challenge strain. 2. Identify a dose of lyophilized S. sonnei 53G that induces the primary outcome in approximately 60% of subjects with no adverse safety concerns. Secondary objectives: 1. Estimate quantitative shedding and basic immunogenicity of the challenge strain. 2. Collect and archive blood and fecal samples for systems biology, microbiome, and other omics-based work to be conducted under a separate research protocol in future studies.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
56
Investigational Product: Shigella sonnei strain 53G (Lot 1794) Mode of Administration: Delivered with sodium bicarbonate orally after a 90 minute fast. Dose: 500-1500 cfu (doses were to be increased or lowered based on results of preceding cohorts)
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Number of Participants With Shigellosis
Per protocol definition: shedding of S. sonnei in the stool accompanied by moderate-severe diarrhea (4 or more loose/watery Grade 3-5 stools or 400+ gram stools per 24 hours, or requires medical intervention) and/or dysentery (a Grade 3, 4, or 5 stool with gross blood on at least 2 occasions and reportable constitutional symptoms) along with moderate fever (Oral temperature of ≥101.2°F) or one or more severe intestinal symptoms. Alternative endpoint 1 definition: severe diarrhea, or moderate diarrhea plus fever, or moderate diarrhea plus 1 moderate constitutional/enteric symptom, or dysentery. Alternative endpoint 2 definition: severe diarrhea, or moderate diarrhea plus fever, or moderate diarrhea plus 1 severe constitutional/enteric symptom, or dysentery plus 1 severe constitutional/enteric symptom
Time frame: 11 days after administration of S. sonnei
Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Stool: Lipopolysaccharide (LPS) Antigen
IgA (total and S. sonnei specific) will be determined in fecal extracts using standard ELISA. IgA was recovered from stool samples using a soybean trypsin inhibitor ethylenediaminetetraacetic acid (EDTA) procedure. The shigella-antigen specific activity was calculated by dividing the endpoint titer by the IgA concentration in matched samples.
Time frame: Baseline (days -5,-1), Day 3, Day 7, and Day 14
Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Stool: Invaplex Antigen
IgA (total and S. sonnei specific) will be determined in fecal extracts using standard ELISA. IgA was recovered from stool samples using a soybean trypsin inhibitor-EDTA procedure. The shigella-antigen specific activity was calculated by dividing the endpoint titer by the IgA concentration in matched samples.
Time frame: Baseline (days -5,-1), Day 3, Day 7, and Day 14
Geometric Mean Titer (GMT) of Immunoglobulin G (IgG) Antibodies in Serum: Lipopolysaccharide (LPS) Antigen
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Blood (10 mL) was collected on days -1, 7, 14, 28 and 56 for Immunoglobulin A (IgA), Immunoglobulin M (IgM), and Immunoglobulin G (IgG) assay by Enzyme linked immunosorbent assay (ELISA).
Time frame: 57 days
Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Serum: Lipopolysaccharide (LPS) Antigen
Blood (10 mL) was collected on days -1, 7, 14, 28 and 56 for Immunoglobulin A (IgA), Immunoglobulin M (IgM), and Immunoglobulin G (IgG) assay by Enzyme linked immunosorbent assay (ELISA).
Time frame: 57 days
Geometric Mean Titer (GMT) of Immunoglobulin G (IgG) Antibodies in Serum: Invaplex Antigen
Blood (10 mL) was collected on days -1, 7, 14, 28 and 56 for Immunoglobulin A (IgA), Immunoglobulin M (IgM), and Immunoglobulin G (IgG) assay by Enzyme linked immunosorbent assay (ELISA).
Time frame: 57 days
Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Serum: Invaplex Antigen
Blood (10 mL) was collected on days -1, 7, 14, 28 and 56 for Immunoglobulin A (IgA), Immunoglobulin M (IgM), and Immunoglobulin G (IgG) assay by Enzyme linked immunosorbent assay (ELISA).
Time frame: 57 days