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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Biological: Shigella sonnei 53G

Detailed Description

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
• Enrollment (Actual): 56
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or non-pregnant female between 18 and 49 years of age (inclusive).
2. 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.
3. Demonstrate comprehension of the protocol procedures and knowledge of study by passing a written examination (pass grade ≥70%) on day -1.
4. Willing to sign an informed consent form (ICF).
5. Willingness to participate for an inpatient stay lasting up to 11 days and an outpatient follow-up lasting 6 months from challenge.
6. Willing to not smoke during the inpatient stay.
7. Available for all planned follow-up visits.

8. 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.

9. Willing to not donate blood for up to 6 months after completion of the inpatient phase of the study.
10. 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:

1. 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.
2. Immunosuppressive illness or immunoglobulin A (IgA) deficiency
3. Positive serology results for HIV, HBsAg, hepatitis C virus (HCV), or syphilis (RPR) antibodies.
4. Evidence of inflammatory arthritis on exam and/or human leukocyte antigen B27 (HLA-B27) positive.
5. Family history of inflammatory arthritis.
6. Significant abnormalities in screening lab hematology or serum chemistry, as determined by PI.
7. Allergy to fluoroquinolones or trimethoprim-sulfamethoxazole
8. Fewer than 3 stools per week or more than 3 stools per day as the usual frequency.
9. History of diarrhea in the 2 weeks prior to planned inpatient phase
10. Use of antibiotics during the 7 days before receiving the challenge inoculum dosing
11. 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
12. Travel within two years prior to dosing to countries where Shigella infection is endemic.
13. 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.
14. Serologic evidence of Shigella sonnei (titer > 1:2500)
15. A positive urine test for opiates.
16. 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.
17. 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)
18. Have immunocompromised household contacts.
19. 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).
20. Pregnant, nursing, or plan to become pregnant within 6 months of receipt of the study product.
21. 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.
22. Work in a health care setting, day care center, or as a food handler in the 4 weeks following the challenge with S. sonnei.
23. 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.
24. Have received a licensed, live vaccine within 28 days or a licensed inactivated vaccine within 14 days of receiving the challenge inoculum.
25. Inability to comply with inpatient rules and regulations.
26. 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.
27. Received blood or blood products within the past six months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: target dose of 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. 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; 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)
Experimental: Cohort 2: target dose of 1000 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. 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; 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)
Experimental: Cohort 3: target dose of 1000 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. 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; 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)
Experimental: Cohort 4: target dose of 1500 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. 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; 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)
Experimental: Cohort 5: target dose of 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. 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; 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 Outcome Measures

Outcome Measure	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.	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.	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	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).	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).	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).	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).	57 days

Collaborators and Investigators

• Sponsor: PATH
• Collaborators: United States Department of Defense; Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Robert Frenck, MD, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start: September 12, 2016
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: June 24, 2016
• First Submitted That Met QC Criteria: June 24, 2016
• First Posted (Estimate): June 28, 2016

Study Record Updates

• Last Update Posted (Actual): June 3, 2019
• Last Update Submitted That Met QC Criteria: February 21, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: shigella
• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Enterobacteriaceae Infections; Dysentery; Dysentery, Bacillary
• Other Study ID Numbers: VAC-048

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO