Phase 2 Shigella Vaccine and Challenge

Study Overview
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Brief Summary
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This is a trial to evaluate the safety, reactogenicity, immunogenicity and efficacy of a 10^6 cfu dose of an oral live-attenuated S. sonnei vaccine candidate, WRSs2, in up to 120 healthy males and non-pregnant females aged 18-49, inclusive. This is a two-phase study, an outpatient WRSs2 vaccination phase and an inpatient S. sonnei 53G challenge phase. After the initiation of the study, two participants had Grade 3 diarrhea and/or vomiting in the days following vaccination. The vaccination dose was reduced to 5X10^5, enrollment was changed to 2 arms and randomized 2:1 (vaccine: placebo). Participants with morbid obesity were excluded and weight loss medications prohibited. The Primary Objective of this study is to estimate combined vaccine efficacy of 2 doses of WRSs2 (10^6 cfu or 5X10^5 cfu) in preventing shigellosis, following challenge with S. sonnei strain 53G.

Detailed Description
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This is a double-blind, placebo controlled, randomized study to test the safety, reactogenicity, immunogenicity and efficacy of up to a 10^6 cfu dose of an oral live-attenuated S. sonnei vaccine (WRSs2) to protect against shigellosis after a targeted oral challenge with S. sonnei 53G, a virulent strain of S. sonnei. Up to 120 subjects, healthy males and non-pregnant females aged 18-49, will be enrolled and randomized in this study. Using the 10^6 CFU dose, subjects were randomized 1:1:1 into one of three vaccination arms to receive 2 doses of study agent 28 days apart. Arm 1 received 2 doses of WRSs2, Arm 2 received placebo followed by WRSs2 and Arm 3 received 2 doses of placebo. Twenty-eight (+2) days after the second dose of study agent, subjects were admitted to the inpatient unit and given an oral challenge of approximately 1500 cfu of 53G. The goal was to have 90 subjects (30 per arm) receive a challenge dose of 53G. The study duration is approximately 24 months with subject participation duration approximately 8 months. After the initiation of the study, two participants had Grade 3 diarrhea and/or vomiting in the days following vaccination. The vaccination dose was reduced to 5X10^5, enrollment was changed to 2 arms and randomized 2:1 (vaccine: placebo). Participants with morbid obesity were excluded and weight loss medications prohibited. The Primary Objective of this study is to estimate combined vaccine efficacy of 2 doses of WRSs2 (10^6 cfu or 5X10^5 cfu) in preventing shigellosis, following challenge with S. sonnei strain 53G. The Secondary Objectives are to:1) Estimate vaccine efficacy of 1 dose of 10^6 cfu, 2 doses of 10^6 cfu, and 2 doses of 5x10^5 cfu of WRSs2 in preventing shigellosis following challenge with S. sonnei strain 53G. 2) Evaluate the safety of WRSs2; 3) Evaluate immune responses following vaccination (immunogenicity) with WRSs2 and after challenge with S. sonnei strain 53G by serum anti-LPS and anti-Invaplex IgG and IgA by ELISA; 4) Determine fecal shedding of S. sonnei after WRSs2 vaccination and 53G challenge by qualitative stool culture.

Official Title
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A Double-Blind Placebo Controlled Randomized Phase 2 Trial to Evaluate the Safety, Reactogenicity and Immunogenicity of a Live-Attenuated Shigella Sonnei Vaccine, WRSs2 and Determine Its Efficacy in a Challenge Model of S. Sonnei 53G in Healthy Adults

Conditions
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Immunisation, Shigella Infection

Intervention / Treatment
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* Other: Placebo
* Biological: Shigella sonnei strain 53G
* Biological: WRSs2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide informed consent prior to initiation of any study procedures. Are able to understand and comply with planned study procedures and be available for all study visits. Is 18-49 years of age inclusive and in sufficiently good health* to be safely enrolled in this study as determined by medical history, medication use, and abbreviated physical exam. *Good health is defined by the absence of any exclusionary medical conditions. If the subject has another current, ongoing medical condition, the condition cannot meet any of the following criteria: 1) first diagnosed within 3 months of enrollment; 2) is worsening in terms of clinical outcome in last 6 months; or 3) involves need for medication that may pose a risk to subject's safety or impede assessment of adverse events or immunogenicity if they participate in the study. Topical, nasal, and inhaled medications (with the exception of inhaled corticosteroids as outlined in the Subject Exclusion Criteria, herbals, vitamins, and supplements are permitted. Oral temperature is less than 100.4 degrees Fahrenheit. Pulse is 50 to 100 beats per minute (bpm), inclusive. Systolic blood pressure is 90 to 140 mmHg, inclusive. Diastolic blood pressure is 55 to 90 mmHg, inclusive. Females of childbearing potential** may enroll if subject has practiced adequate contraception*** = / > 30 days prior to enrollment and agrees to continue adequate contraception for the entire study. **Child-bearing potential is defined as not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or <1 year of the last menses if menopausal. ***Adequate contraception includes; non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the subject enrollment, barrier methods such as condoms or diaphragms with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives (the pill). Females of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to enrollment. Drug screen for opiates is negative. BMI (Body Mass Index) between 18 and 40kg/m^2. Exclusion Criteria: Have any disease or medical condition that, in the opinion of the site principal investigator or appropriate sub-investigator, is a contraindication to study participation****. **** Including acute or chronic disease or medical condition that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of this trial. These include: History of inflammatory bowel disease (IBD) (including ulcerative colitis, Crohn's disease, indeterminate colitis, or celiac disease). Irritable bowel syndrome (IBS) within the past 12 months or any active uncontrolled gastrointestinal disorders or diseases as assessed by the investigator. Including: symptoms or evidence of active gastritis or gastroesophageal reflux disease, gastric surgery or gastric acid hyper-secretory disorders (e.g., Zollinger-Ellison syndrome), gastrointestinal obstruction, ileus, gastric retention, bowel perforation, toxic colitis, persistent infectious gastroenteritis, persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection. Known active neoplastic disease (Non-melanoma, treated, skin cancers are permitted), a history of any hematologic malignancy, or have used anticancer chemotherapy/radiation therapy (cytotoxic) within 3 years prior to study enrollment. Personal or family history of reactive arthritis. Reported history of HIV, Hepatitis B, or Hepatitis C History of immunodeficiency due to congenital or hereditary causes, underlying illness or treatment. Positive serology results for HLA-B27, HIV, HBsAg, or HCV antibodies. Have clinically significant abnormalities as determined by study investigator in other screening laboratory tests, as outlined in the protocol. Have participated in a previous Shigella challenge study or reports having received vaccination for Shigella previously. Have a previously laboratory confirmed case of disease caused by S. sonnei or serology positive (>1:2500) for anti S. sonnei LPS IgG ELISA titer at screening. Has a history of diarrhea in the 14 days prior to enrollment. Have fewer than 3 stools per week or more than 3 stools per day as the usual frequency. Recent history/current use of immunosuppressive/immunomodulating disease therapy. Known hypersensitivity to ciprofloxacin or trimethoprim-sulfamethoxazole; sodium bicarbonate; or any components of vaccine, placebo, or challenge material. Received or plan to receive a licensed live vaccine within 30 days prior to enrollment. Received or plan to receive a licensed, inactivated, Coronavirus disease 2019 (COVID-19) vaccine or an influenza vaccine within +-7 days from receipt of study product. Have a history of severe reactions following previous immunization with any licensed or unlicensed vaccine. Received Ig or other blood products (with exception of Rho D Ig) within 90 days prior to enrollment. Have taken oral or parenteral (including intra-articular) corticosteroids of any dose, or high-dose inhaled corticosteroids**within 30 days prior to enrollment. ** High-dose defined per age as using inhaled high dose per reference chart Estimated Comparative Daily Dosages https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf Have taken systemic antibiotics within 7 days prior to enrollment. Have taken prescription and/or OTC medication containing loperamide, acetaminophen, aspirin, ibuprofen, or other non-steroidal anti-inflammatory < / = 48 hours prior to enrollment. Have a history of alcohol or drug abuse within 1 year prior to enrollment. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within 5 years prior to enrollment. Work or plan to work in either a health care setting, day care center, or as a food handler or have known daily contact with individuals with possible increased susceptibility****** to Shigella within 14 days after discharge from inpatient challenge. ****** Immunocompromised, elderly persons aged 70 years or more, diapered individuals, persons with disabilities, children < 2 years old, a woman known to be pregnant or nursing, or anyone with diminished immunity. Known daily contact includes contact at home, school, day-care, nursing home, or similar places. Are pregnant, breastfeeding or plan to become pregnant or breastfeed at any given time during the study. Have fever or an acute illness******* as determined by the site principal investigator or appropriate sub-investigator, within 72 hours prior to enrollment. ******* An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site principal investigator or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol Received an experimental agent (including vaccine, drug, biologic, device, blood product, or medication, other than from participation in this trial) within 30 days prior to the first study vaccination or expect to receive an investigational product during the study period which might affect safety or assessment of study endpoints. Taking prescription or over-the-counter medication for weight reduction.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Vaccine: 1 ml of saline containing10^6 or 5X10^5 cfu of the WRSs2 vaccine in 30 ml of sterile normal saline administered orally on Day 1 and Day 29. Challenge: 1 ml of S. sonnei 53G challenge in 30 ml of sterile saline administered orally on Day 57. N=40 | Biological: Shigella sonnei strain 53G<br>* 1.5 x 10^3 Colony Forming Units (cfu) Shigella sonnei 53G, a virulent strain of wildtype Shigella sonnei<br>Biological: WRSs2<br>* 10^6 Colony Forming Units (cfu) dose of an oral live-attenuated Shigella sonnei vaccine candidate derived from a virulent S. sonnei strain Moseley (WRSs2)-a live, attenuated vaccine that has been manufactured under cGMP conditions at the WRAIR PBF<br>|
| Experimental: Arm 2<br>Placebo + Vaccine: 30 ml of sterile normal saline placebo administered orally on Day 1 and 1 ml of saline containing 10^6 cfu of the WRSs2 vaccine in 30 ml of sterile normal saline administered orally on Day 29. Challenge: 1 ml of S. sonnei 53G challenge in 30ml of sterile saline administered orally on Day 57. N=40 | Other: Placebo<br>* 0.9% Sterile Normal Saline, USP<br>Biological: Shigella sonnei strain 53G<br>* 1.5 x 10^3 Colony Forming Units (cfu) Shigella sonnei 53G, a virulent strain of wildtype Shigella sonnei<br>Biological: WRSs2<br>* 10^6 Colony Forming Units (cfu) dose of an oral live-attenuated Shigella sonnei vaccine candidate derived from a virulent S. sonnei strain Moseley (WRSs2)-a live, attenuated vaccine that has been manufactured under cGMP conditions at the WRAIR PBF<br>|
| Placebo Comparator: Arm 3<br>Placebo: 31 ml of sterile normal saline placebo administered orally on Day 1 and Day 29. Challenge: 1 ml of S. sonnei 53G challenge in 30 ml of sterile saline administered orally on Day 57. N=40 | Other: Placebo<br>* 0.9% Sterile Normal Saline, USP<br>Biological: Shigella sonnei strain 53G<br>* 1.5 x 10^3 Colony Forming Units (cfu) Shigella sonnei 53G, a virulent strain of wildtype Shigella sonnei<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of shigellosis following challenge with S. sonnei strain 53G | In the pooled group of subjects receiving 2 doses of 10^6 cfu or 5x10^5 cfu of WRSs2, compared to subjects receiving 2 doses of placebo | Day 57 through Day 63 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of shedding 53G post-challenge |  | Day 57 through Day 65 | 
| Duration of shedding S. sonnei by culture post-vaccination |  | Day 1 through Day 56 | 
| Maximum S. sonnei LPS-specific and Invaplex-specific serum IgG and IgA titer by ELISA |  | Post-challenge through Day 113 | 
| Maximum S. sonnei LPS-specific and Invaplex-specific serum IgG and IgA titer by ELISA |  | Post-vaccination through Day 56 | 
| Number of subjects shedding 53G in their stool by culture |  | Day 57 through Day 65 | 
| Number of subjects shedding vaccine strain in their stool by culture |  | Day 1 through Day 43 | 
| Number of subjects with >/= 4-fold rise from pre-challenge (Day 56) in S. sonnei LPS-specific and Invaplex-specific serum IgG and IgA by ELISA |  | Days 64, 71, 85, and 113 | 
| Number of subjects with >/= 4-fold rise from pre-vaccination in S. sonnei LPS-specific and Invaplex-specific serum IgG and IgA by ELISA |  | Days 15, 29, 43, and 56 | 
| Occurrence of Serious Adverse Events (SAEs) |  | Day 1 through Day 180 or resolution/stabilization | 
| Occurrence of shigellosis following challenge with S. sonnei strain 53G | In subjects receiving 1 dose of 10^6 cfu, 2 doses of 10^6 cfu, or 2 doses of 5X10^5 cfu of WRSs2, compared to subjects receiving 2 doses of placebo. | Day 57 through Day 63 | 
| Occurrence of solicited systemic Adverse Events (AEs) |  | Day 1 through Day 36 | 
| Occurrence of vaccine-related unsolicited Adverse Events (AEs) |  | Day 1 through Day 57 | 
| Peak fold-rise in S. sonnei LPS-specific and Invaplex-specific serum IgG and IgA titer by ELISA |  | Pre-challenge through Day 113 | 
| Peak fold-rise in S. sonnei LPS-specific and Invaplex-specific serum IgG and IgA titer by ELISA |  | Pre-vaccination through Day 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Challenge, Double-blind, Efficacy, Healthy Adults, Immunogenicity, Live-attenuated Shigella sonnei Vaccine, Phase 2 Trial, Placebo-controlled, Protective efficacy, Randomized, Reactogenicity, Safety, Shigella sonnei 53G Challenge, WRSs2