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).
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
46
Shigella sonnei (S. sonnei) strain 53G (Lot 1794); Mode of Administration: Delivered with sodium bicarbonate orally after a 90 minute fast.
Shigella flexneri (S. flexneri) strain 2457T (Lot 1617); Mode of Administration: Delivered with sodium bicarbonate orally after a 90 minute fast.
Center for Immunization Research (CIR) at Johns Hopkins School of Public Health (JHSPH)
Baltimore, Maryland, United States
Percentage of Participants With Shigellosis Following Shigella Challenge
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Maximum Volume of Loose Stools in Any 24-hour Period
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Percentage of Participants With Severe Diarrhea
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
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Percentage of Participants With Diarrhea of Any Severity
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Total Weight of Grade 3-5 Stools Per Participant After Challenge
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Percentage of Participants With Nausea, Vomiting, Anorexia, Abdominal Pain/Cramps Rated as Moderate to Severe
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Percentage of Participants With Dysentery
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
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)
Number of Participants With More Severe Diarrhea
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Number of Participants With Fever After Challenge
Fever: measured oral temperature ≥ 38°C confirmed within about 20 minutes.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Shigella Clinical Severity Score
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Number of Colony Forming Units (CFUs) of the Challenge Strain Per Gram of Stool
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.
Time frame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)