Dose-Finding Study of Lyophilized Shigella Sonnei 53G Cha... | NCT02816346

Name	Class
United States Department of Defense	FED
Children's Hospital Medical Center, Cincinnati	OTHER

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 1: target dose of 500 CFU	Experimental	Shigella sonnei 53G: Investigational Product: One dose of Shigella sonnei rehydrated challenge strain 53G (Lot 1794) suspension in 2 mL of cold sterile water combined and diluted in cold, sterile normal saline 0.9% (i.e. challenge suspension). Mode of Administration: After a 90 minute fast subjects will drink the 120 mL of sodium bicarbonate (to neutralize gastric acidity) and then drink the challenge suspension within 5 minutes. Received target dose of 500 colony-forming units (CFU) of Shigella sonnei 53G (actual dose: 510, 717, 588, and 567 CFU).	Biological: Shigella sonnei 53G
Cohort 2: target dose of 1000 CFU	Experimental	Shigella sonnei 53G: Investigational Product: One dose of Shigella sonnei rehydrated challenge strain 53G (Lot 1794) suspension in 2 mL of cold sterile water combined and diluted in cold, sterile normal saline 0.9% (i.e. challenge suspension). Mode of Administration: After a 90 minute fast subjects will drink the 120 mL of sodium bicarbonate (to neutralize gastric acidity) and then drink the challenge suspension within 5 minutes. Received target dose of 1000 colony-forming units (CFU) of Shigella sonnei 53G (actual dose: 817 CFU), since the attack rate of shigellosis for Cohort 1 was below the protocol target of 60%.	Biological: Shigella sonnei 53G
Cohort 3: target dose of 1000 CFU	Experimental	Shigella sonnei 53G: Investigational Product: One dose of Shigella sonnei rehydrated challenge strain 53G (Lot 1794) suspension in 2 mL of cold sterile water combined and diluted in cold, sterile normal saline 0.9% (i.e. challenge suspension). Mode of Administration: After a 90 minute fast subjects will drink the 120 mL of sodium bicarbonate (to neutralize gastric acidity) and then drink the challenge suspension within 5 minutes. Received target dose of 1000 colony-forming units (CFU) of Shigella sonnei 53G (actual dose: 913 CFU. Although the target dose was the same as Cohort 2, the safety monitoring committee felt that the per-protocol a priori definition of shigellosis was too restrictive and that increasing the dose above 1000 CFU may lead to unnecessarily high toxicity.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Shigella sonnei 53G	Biological	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)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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	11 days after administration of S. sonnei

Secondary Outcomes

Measure	Description	Time Frame
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.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male or non-pregnant female between 18 and 49 years of age (inclusive).
General good health defined as (a) no significant medical illness, (b) no clinically significant physical examination findings and (c) no screening laboratory values significantly outside the normal limits of the testing laboratory within 45 days of challenge.
Demonstrate comprehension of the protocol procedures and knowledge of study by passing a written examination (pass grade ≥70%) on day -1.
Willing to sign an informed consent form (ICF).
Willingness to participate for an inpatient stay lasting up to 11 days and an outpatient follow-up lasting 6 months from challenge.
Willing to not smoke during the inpatient stay.
Available for all planned follow-up visits.
Negative serum pregnancy test at screening and negative urine pregnancy test on the day of admission to the inpatient phase for female subjects of childbearing potential. Females of childbearing potential must agree to use an effective method of birth control (birth control pills, injection hormonal contraceptive, implant hormonal contraceptive,

hormonal patch, intrauterine device (IUD), sterilization by hysterectomy or tubal ligation, spermicidal products and barrier methods such as cervical sponge, diaphragm, or condom) within two months of challenge and during the entire study. Abstinence is acceptable. A woman is eligible if she is monogamous with a vasectomized partner.
Willing to not donate blood for up to 6 months after completion of the inpatient phase of the study.
Willing to refrain from participation in another investigational vaccine or drug trial at least until after completion of the 6 month follow-up safety call.

Exclusion Criteria:

Presence of a significant medical condition (e.g. psychiatric conditions, alcohol or illicit drug abuse/dependency, or gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active gastritis or gastroesophageal reflux disease, inflammatory bowel disease), or other laboratory abnormalities which in the opinion of the investigator precludes participation in the study.
Immunosuppressive illness or immunoglobulin A (IgA) deficiency
Positive serology results for HIV, HBsAg, hepatitis C virus (HCV), or syphilis (RPR) antibodies.
Evidence of inflammatory arthritis on exam and/or human leukocyte antigen B27 (HLA-B27) positive.
Family history of inflammatory arthritis.
Significant abnormalities in screening lab hematology or serum chemistry, as determined by PI.
Allergy to fluoroquinolones or trimethoprim-sulfamethoxazole
Fewer than 3 stools per week or more than 3 stools per day as the usual frequency.
History of diarrhea in the 2 weeks prior to planned inpatient phase
Use of antibiotics during the 7 days before receiving the challenge inoculum dosing
Use of prescription and/or over the counter (OTC) medications that contain Imodium, acetaminophen, aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs, during the 48 hours prior to investigational product administration
Travel within two years prior to dosing to countries where Shigella infection is endemic.
Use of any medication known to affect the immune function [e.g., oral steroids, parenteral steroids, or high-dose inhaled steroids (>800 μg/day of beclomethasone dipropionate or equivalent and others): nasal and topical steroids are allowed] within 30 days preceding receipt of the challenge inoculum or planned use during the active study period.
Serologic evidence of Shigella sonnei (titer > 1:2500)
A positive urine test for opiates.
A chronic disease (such as hypertension, hyperlipidemia or anxiety/depression) for which doses of prescription medications are not stable for at least the past 3 months.
Scheduled and/or long-term use of oral steroids, parenteral steroids, or high-dose inhaled steroids (>800 μg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (Nasal, intra-articular, and topical steroids are allowed)
Have immunocompromised household contacts.
A clinically significant abnormality on physical examination, including a systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, or a resting pulse >100 beats/min or <55 beats/min (<50 beats/min for conditioned athletes).
Pregnant, nursing, or plan to become pregnant within 6 months of receipt of the study product.
In the 4 weeks following challenge, subject will be living with or having daily contact with elderly persons aged 70 years or more, diapered individuals, persons with disabilities, children <2 years old, or a woman known to be pregnant or nursing, or anyone with diminished immunity. This includes contact at home, school, day-care, nursing homes, or similar places.
Work in a health care setting, day care center, or as a food handler in the 4 weeks following the challenge with S. sonnei.
Use of any investigational drug or any investigational vaccine within 60 days preceding challenge, or planned use during the 6 months after receipt of the study agent.
Have received a licensed, live vaccine within 28 days or a licensed inactivated vaccine within 14 days of receiving the challenge inoculum.
Inability to comply with inpatient rules and regulations.
Has any other condition that, in the opinion of the Investigator, would jeopardize the safety or rights of a participant or would render the subject unable to comply with the protocol.
Received blood or blood products within the past six months.

Name	Affiliation	Role
Robert Frenck, MD	Children's Hospital Medical Center, Cincinnati	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Cincinnati Children's Hospital Medical Center		Cincinnati	Ohio	45229	United States

PubMed Identifier	Type	Citation	Retractions
40152601	Derived	Liechty Z, Baldwin A, Isidean S, Suvarnapunya A, Frenck R, Porter C, Goodson M. Dynamics of the gut microbiome in subjects challenged with Shigella sonnei 53G in a controlled human infection model. mSphere. 2025 Apr 29;10(4):e0090624. doi: 10.1128/msphere.00906-24. Epub 2025 Mar 28.

Arm/Group Information

ID	Title	Description
FG000	Cohort 1: S. Sonnei 53G Target Dose 500 CFU	Shigella sonnei 53G: Investigational Product: One dose of Shigella sonnei rehydrated challenge strain 53G (Lot 1794) suspension in 2 mL of cold sterile water combined and diluted in cold, sterile normal saline 0.9% (i.e. challenge suspension). Mode of Administration: After a 90 minute fast subjects will drink the 120 mL of sodium bicarbonate (to neutralize gastric acidity) and then drink the challenge suspension within 5 minutes. Target Dose: 500cfu (doses were to be increased or lowered based on results of preceding cohorts)
FG001	Cohort 2: S. Sonnei 53G Target Dose 1000 CFU	Received higher dose of Shigella sonnei 53G if ≥ 60% of subjects in Cohort 1 experienced shigellosis, or lower dose if not. Shigella sonnei 53G: Investigational Product: One dose of Shigella sonnei rehydrated challenge strain 53G (Lot 1794) suspension in 2 mL of cold sterile water combined and diluted in cold, sterile normal saline 0.9% (i.e. challenge suspension). Mode of Administration: After a 90 minute fast subjects will drink the 120 mL of sodium bicarbonate (to neutralize gastric acidity) and then drink the challenge suspension within 5 minutes. Dose: 1000 cfu (doses were to be increased or lowered based on results of preceding cohorts)
FG002	Cohort 3: S. Sonnei 53G Target Dose of 1000 CFU	Received higher dose of Shigella sonnei 53G if ≥ 60% of subjects in Cohort 2 experienced shigellosis, or lower dose if not. Shigella sonnei 53G: Investigational Product: One dose of Shigella sonnei rehydrated challenge strain 53G (Lot 1794) suspension in 2 mL of cold sterile water combined and diluted in cold, sterile normal saline 0.9% (i.e. challenge suspension). Mode of Administration: After a 90 minute fast subjects will drink the 120 mL of sodium bicarbonate (to neutralize gastric acidity) and then drink the challenge suspension within 5 minutes. Dose: 1000 cfu (doses were to be increased or lowered based on results of preceding cohorts)
FG003	Cohort 4: S. Sonnei 53G Target Dose 1500 CFU	Received higher dose of Shigella sonnei 53G if ≥ 60% of subjects in Cohort 3 experienced shigellosis, or lower dose if not. Shigella sonnei 53G: Investigational Product: One dose of Shigella sonnei rehydrated challenge strain 53G (Lot 1794) suspension in 2 mL of cold sterile water combined and diluted in cold, sterile normal saline 0.9% (i.e. challenge suspension). Mode of Administration: After a 90 minute fast subjects will drink the 120 mL of sodium bicarbonate (to neutralize gastric acidity) and then drink the challenge suspension within 5 minutes. Dose: 1500 cfu (doses were to be increased or lowered based on results of preceding cohorts)
FG004	Cohort 5: S. Sonnei 53G Target Dose 1150 CFU	Received higher dose of Shigella sonnei 53G if ≥ 60% of subjects in Cohort 4 experienced shigellosis, or lower dose if not. Shigella sonnei 53G: Investigational Product: One dose of Shigella sonnei rehydrated challenge strain 53G (Lot 1794) suspension in 2 mL of cold sterile water combined and diluted in cold, sterile normal saline 0.9% (i.e. challenge suspension). Mode of Administration: After a 90 minute fast subjects will drink the 120 mL of sodium bicarbonate (to neutralize gastric acidity) and then drink the challenge suspension within 5 minutes. Dose: 1150 cfu (doses were to be increased or lowered based on results of preceding cohorts)

ID	Title	Description
BG000	Cohort 1	Received 500 colony-forming units (CFU) of Shigella sonnei 53G. Shigella sonnei 53G: 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)

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Geometric Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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

Posted

Count of Participants

Participants

11 days after administration of S. sonnei

ID	Title	Description
OG000	Cohort 1

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_ICF	Yes	No	Yes	Study Protocol and Informed Consent Form	Apr 14, 2017	Aug 6, 2018	Prot_ICF_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Oct 16, 2017	Aug 6, 2018	SAP_001.pdf

ID	Term
D004756	Enterobacteriaceae Infections
D016905	Gram-Negative Bacterial Infections
D001424	Bacterial Infections
D001423	Bacterial Infections and Mycoses