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Completed

NCT Number: NCT04992520

Controlled Human Infection Model Challenge/Rechallenge

The goal of this study is to better understand Shigella immunity. The study will compare the shigellosis rate in participants previously challenged with a different Shigella serotype to the attack rate in participants not previously exposed to Shigella (naive participants).

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Key information

Conditions

Shigellosis Bacterial Infections Bacterial Infections and Mycoses Digestive System Diseases Dysentery Dysentery, Bacillary Enterobacteriaceae Infections Gastroenteritis Gastrointestinal Diseases Gram-Negative Bacterial Infections Infections Intestinal Diseases

Age range

18 year–50 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Center for Immunization Research (CIR) at Johns Hopkins School of Public Health (JHSPH)

Baltimore, Maryland, 21224, United States

About this study

This is a single-center controlled human infection model (CHIM) study designed to assess the cross-protective efficacy and markers of protection after challenge and heterologous rechallenge with Shigella strains of different serotypes in naïve healthy adult volunteers.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Healthy adults, male or female, aged 18 to 50 years (all inclusive) at the time of enrollment.
  • General good health, without clinically significant medical history, physical examination findings, or clinical laboratory abnormalities per judgment of Principal Investigator (PI).
  • Willingness to participate in the study after all aspects of the protocol have been explained and written informed consent obtained.
  • Completion of a training session and demonstrated comprehension of the protocol procedures and knowledge of Shigella-associated illness by passing a written examination (70% passing score).
  • Availability for the study duration, including all planned follow-up visits.
  • Female participants must have a negative pregnancy test at screening and prior to each challenge.
  • Female participants must agree to avoid pregnancy for 29 days following the last challenge dose by use of an efficacious hormonal or barrier method of birth control during the study. Abstinence is acceptable. Female participants unable to bear children must have this documented (e.g., tubal ligation or hysterectomy).
  • Willingness to refrain from participation in a study of another investigational agent for 90 days following the last challenge dose.

Exclusion criteria

  • Presence of a significant medical or psychiatric condition that in the opinion of the investigator precludes participation in the study. Some medical conditions that are adequately treated and stable would not preclude entry into the study.
  • Clinically significant abnormalities in screening on physical exam or screening laboratory results as determined by PI or PI in consultation with the research monitor and Sponsor.
  • Recent receipt of another investigational product (within 30 days before enrollment).
  • Positive enzyme-linked immunosorbent assay (ELISA) and confirmatory tests for human immunodeficiency virus (HIV).
  • Positive hepatitis C (HCV) ELISA and confirmatory test (e.g., HCV ribonucleic acid (RNA)).
  • Positive hepatitis B virus surface antigen (HBsAg) by ELISA.
  • Use of any medication that affects immune function (e.g., corticosteroids and others) within 30 days preceding the first challenge or planned use during the active study period (topical and ophthalmologic steroids are allowable).
  • Evidence of impaired immune function or immune compromise (known immunodeficiency syndrome; either congenital, acquired, or iatrogenic; active autoimmune disease; repeated serious infections without known cause).
  • Immunoglobulin A (IgA) deficiency (serum IgA < 7 mg/dL or below the limit of detection of the assay).
  • Positive blood test for human leukocyte antigen (HLA)-B27.
  • Personal or family history of an inflammatory arthritis.
  • Currently pregnant or nursing.
  • Have household contacts who are < 2 years old or > 80 years old or infirm or immunocompromised.
  • Employment as a health care worker with direct patient care, in a daycare center (for children or the elderly), or direct food handler; includes individuals who work directly with food in commercial establishments.
  • Evidence of current alcohol or drug dependence, or history of dependence in the last 6 months.
  • Recent vaccination (including licensed vaccines) or receipt of an investigational product (within 30 days before challenge through 90 days following the last challenge dose). Annual influenza vaccine, an emergency authorized or licensed COVID-19 vaccine, or a TdaP or Travelers' diarrhea (TD) booster may be administered beyond 30 days after each challenge.
  • Treatment with immunoglobulins or blood products within 3 months of challenge.
  • Current or prior history of inflammatory bowel disease or irritable bowel syndrome or abnormal stool pattern (> 3/day or < 3/ week, or loose or liquid stools).
  • Chronic use of anti-diarrheal, anti-constipation, or antacid therapy; or use of these medications in the 7 days prior to challenge.
  • Use of proton pump inhibitors or H2 blockers (H2-receptor antagonists) within 48 hours prior to challenge.
  • Use of antibiotics within 7 days prior to challenge.
  • Known allergy to any 2 of the following antibiotics: ciprofloxacin, trimethoprim-sulfamethoxazole, or penicillin.
  • Symptoms of travelers' diarrhea associated with travel to countries where Shigella or other enteric infections are endemic (most of the developing world) within 3 years prior to challenge OR planned travel to endemic countries during the active study period.
  • History of shigellosis, Shigella vaccination or challenge, or a laboratory worker with known exposure to Shigella within the last 5 years.
  • Serum immunoglobulin G (IgG) titer > 2500 to either Shigella flexneri 2a or Shigella sonnei lipopolysaccharide.
  • Any other criteria which, in the investigator's opinion, would compromise the ability of the volunteer to participate in the study, the safety of the study, or the results of the study.

Treatment and study plan

Shigella sonnei 53G

Biological

Shigella sonnei (S. sonnei) strain 53G (Lot 1794); Mode of Administration: Delivered with sodium bicarbonate orally after a 90 minute fast.

Shigella flexneri 2a 2457T

Biological

Shigella flexneri (S. flexneri) strain 2457T (Lot 1617); Mode of Administration: Delivered with sodium bicarbonate orally after a 90 minute fast.

Primary outcomes

  1. Percentage of Participants With Shigellosis Following Shigella Challenge

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    Shigellosis was defined as:

    • Severe diarrhea: ≥ 6 loose (grade 3-5) stools within 24 hours or >800 - 999 g loose stools within any 24-hour window, or
    • Moderate diarrhea (4 - 5 loose stools within 24 hours or 401-800 g loose stools within any 24-hour window) with fever (oral temperature of ≥ 101.2°F / 38°C) OR with ≥ 1 moderate constitutional or enteric symptom OR ≥ 2 episodes of vomiting in a 24-hour period, or
    • Dysentery: ≥ 2 loose stools with gross blood (hemoccult positive) in 24 hours AND fever OR ≥ 1 moderate constitutional/enteric symptom OR ≥ 2 episodes of vomiting in 24 hours.

    Constitutional/Enteric symptoms include nausea, abdominal cramps/pain, myalgia, arthralgia, or malaise.

    Stools were graded on the following scale:

    • Grade 1, firm formed;
    • Grade 2, soft formed;
    • Grade 3, viscous opaque liquid or semi-liquid;
    • Grade 4, watery opaque liquid;
    • Grade 5, clear watery or mucoid liquid. Outcome data were evaluated by an independent, blinded adjudication board.

Secondary outcomes

  1. Maximum Volume of Loose Stools in Any 24-hour Period

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    During the 8-day inpatient period after each challenge all stools were weighed and graded according to the following scale:

    • Grade 1, firm formed;
    • Grade 2, soft formed;
    • Grade 3, viscous opaque liquid or semi-liquid;
    • Grade 4, watery opaque liquid;
    • Grade 5, clear watery or mucoid liquid.

  2. Percentage of Participants With Severe Diarrhea

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    During the 8-day inpatient period after each challenge all stools were weighed and graded according to the following scale:

    • Grade 1, firm formed;
    • Grade 2, soft formed;
    • Grade 3, viscous opaque liquid or semi-liquid;
    • Grade 4, watery opaque liquid;
    • Grade 5, clear watery or mucoid liquid.

    Severe diarrhea was defined as ≥ 6 loose (Grade 3-5) stools within 24 hours or > 800 grams of loose (Grade 3-5) stools within any 24-hour window.

  3. Percentage of Participants With Diarrhea of Any Severity

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    During the 8-day inpatient period after each challenge all stools were weighed and graded according to the following scale:

    • Grade 1, firm formed;
    • Grade 2, soft formed;
    • Grade 3, viscous opaque liquid or semi-liquid;
    • Grade 4, watery opaque liquid;
    • Grade 5, clear watery or mucoid liquid.

    Participants met the criteria for diarrhea if they had ≥ 2 loose (Grade 3-5) stools weighing ≥ 200 grams within any 48-hour window or any loose stools weighing ≥ 300 grams.

  4. Total Weight of Grade 3-5 Stools Per Participant After Challenge

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    During the 8-day inpatient period after each challenge all stools were weighed and graded according to the following scale:

    • Grade 1, firm formed;
    • Grade 2, soft formed;
    • Grade 3, viscous opaque liquid or semi-liquid;
    • Grade 4, watery opaque liquid;
    • Grade 5, clear watery or mucoid liquid.

  5. Percentage of Participants With Nausea, Vomiting, Anorexia, Abdominal Pain/Cramps Rated as Moderate to Severe

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    During the 8-day inpatient period after each challenge, nausea, vomiting, anorexia, and abdominal pain/cramps were monitored and graded (except for vomiting) according to the following:

    Mild: Discomfort noted, but no disruption of normal daily activities; slightly bothersome; relieved with or without symptomatic treatment.

    Moderate: Discomfort sufficient to reduce or affect normal daily activity to some degree; bothersome; interferes with activities, only partially relieved with symptomatic treatment.

    Severe: Discomfort sufficient to reduce or affect normal daily activity considerably; prevents regular activities; not relieved with symptomatic treatment.

    Vomiting was graded according the the following:

    Mild: One episode within a 24-hour period Moderate: Two episodes within a 24-hour period Severe: Three or more episodes within a 24-hour period.

  6. Percentage of Participants With Dysentery

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    During the 8-day inpatient period after each challenge all stools were weighed and graded according to the following scale:

    • Grade 1, firm formed;
    • Grade 2, soft formed;
    • Grade 3, viscous opaque liquid or semi-liquid;
    • Grade 4, watery opaque liquid;
    • Grade 5, clear watery or mucoid liquid.

    Dysentery was defined as ≥ 2 loose stools (Grade 3-5) with gross blood (hemoccult positive) in 24 hours AND fever OR ≥ 1 moderate constitutional/enteric symptom OR ≥2 episodes of vomiting in 24 hours.

    Constitutional/enteric symptoms included nausea, abdominal cramps/pain, myalgia, arthralgia, and malaise.

  7. Time to Onset of Diarrhea

    Time frame: From challenge administration to the end of the 8-day inpatient period (Days 1-8 and Days 90-97 for challenge 2)

  8. Number of Participants With More Severe Diarrhea

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    During the 8-day inpatient period after each challenge all stools were weighed and graded according to the following scale:

    • Grade 1, firm formed;
    • Grade 2, soft formed;
    • Grade 3, viscous opaque liquid or semi-liquid;
    • Grade 4, watery opaque liquid;
    • Grade 5, clear watery or mucoid liquid.

    More severe diarrhea was defined as ≥ 10 loose (Grade 3-5) stools within 24 hours or ≥ 1000 grams loose stools within any 24-hour window.

  9. Number of Participants With Fever After Challenge

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    Fever: measured oral temperature ≥ 38°C confirmed within about 20 minutes.

  10. Shigella Clinical Severity Score

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    The Shigella clinical severity score is a composite, ordinal disease score that consists of three parameters: self-reported symptoms (arthralgia, nausea, myalgia, headache, anorexia, and abdominal cramps and pain), clinical signs (blood in stool, fever, and vomiting) and stool output (maximum loose stool output / 24 hours). Each parameter is scored based off maximum severity clinical signs, self-reported symptoms and stool output experienced over over the 8-day period.

    The Shigella clinical severity score ranges from 0 to 9, where 0 = no or mild symptoms only and 9 = severe symptoms.

  11. Number of Colony Forming Units (CFUs) of the Challenge Strain Per Gram of Stool

    Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)

    Analysis of stool samples to quantify challenge strains in the stool are not yet complete. Data will be reported once the assays have been completed.

Sponsors and collaborators

Lead sponsor

PATH

Other

Collaborators

  • Johns Hopkins University Center for Immunization Research (CIR)
  • United States Department of Defense

Registry information

Official study title

Controlled Human Infection Model Challenge/Rechallenge: Shigella Flexneri 2a and S. Sonnei Cross-protective Antigens Discovery in Healthy Adults in the United States

Important dates

Study start
2022
Primary completion
2023
Study completion
2023
First posted
Aug 5, 2021
Registry last updated
Jan 31, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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