Dose-Finding Study of Lyophilized Shigella Sonnei 53G Challenge Strain

NCT02816346 | Completed Phase 1 Results DMC

• 1 other identifier: VAC-048
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Healthy

Keywords

shigella

Outcome Measures

Primary Outcomes (1)

• 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 (6)

• Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Stool: Lipopolysaccharide (LPS) Antigen

  Baseline (days -5,-1), Day 3, Day 7, and Day 14

• Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Stool: Invaplex Antigen

  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

  57 days

• Geometric Mean Titer (GMT) of Immunoglobulin A (IgA) Antibodies in Serum: Lipopolysaccharide (LPS) Antigen

  57 days

• Geometric Mean Titer (GMT) of Immunoglobulin G (IgG) Antibodies in Serum: Invaplex Antigen

  57 days

Study Arms (5)

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.

Biological: Shigella sonnei 53G

Cohort 4: target dose of 1500 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 1500 colony-forming units (CFU) of Shigella sonnei 53G (actual dose: 1760 CFU) since the attack rate of shigellosis for Cohort 2 and 3 was below the protocol target of 60%.

Biological: Shigella sonnei 53G

Cohort 5: target dose of 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 1150 colony-forming units (CFU) of Shigella sonnei 53G (actual dose: 1760 CFU) as the final confirmatory cohort since it was felt that the disease rate and profile of Cohort 4 was appropriate.

Biological: Shigella sonnei 53G

Interventions

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)

Cohort 1: target dose of 500 CFU; Cohort 2: target dose of 1000 CFU; Cohort 3: target dose of 1000 CFU; Cohort 4: target dose of 1500 CFU; Cohort 5: target dose of CFU

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• PATH: lead
• United States Department of Defense: collaborator
• Children's Hospital Medical Center, Cincinnati: collaborator

Study Sites (1)

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Publications (1)

• 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.

  PMID: 40152601 DERIVED

MeSH Terms

Conditions

Dysentery, Bacillary

Condition Hierarchy (Ancestors)

Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Dysentery; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Results Point of Contact

• Title: Jorge Flores
• Organization: PATH

jeflores@path.org

(202) 822-0033

Study Officials

• Robert Frenck, MD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 24, 2016
• First Posted: June 28, 2016
• Study Start: September 12, 2016
• Primary Completion: December 31, 2017
• Study Completion: December 31, 2017
• Last Updated: June 3, 2019
• Results First Posted: June 3, 2019

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)