Shigella CVD 30000: Study of Responses to Vaccination With Shigella Vaccine

Study Overview
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Brief Summary
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The purpose of this study is to determine whether SF2a-TT15 (a monovalent synthetic carbohydrate-based conjugate Shigella vaccine) is safe and effective in the prevention of Shigella infection.

Detailed Description
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The purpose of this study is to determine whether SF2a-TT15 (a monovalent synthetic carbohydrate-based conjugate Shigella vaccine) is safe and effective in the prevention of Shigella infection. This will be a phase 2b, double-blind, placebo-controlled, single-center study, involving a vaccination phase and a challenge phase. The vaccination phase will consist of study participants that will be 1:1 randomized to receive either the vaccine or placebo. Two doses of blinded study product will be given by intramuscular route of administration, separated by approximately 4 weeks. The challenge phase will consist of an inpatient stay of approximately 12 days during which eligible study participants will ingest an oral inoculum of wild-type S flexneri 2a strain 2457T and then be monitored for illness and treated with antibiotics when the primary endpoint is reached or upon 5 days post-challenge, whichever comes first, or when deemed necessary. Upon satisfying discharge criteria, study participants will complete outpatient clinic follow-up visits through  7 months after last dose of blinded study product (Day 237). The efficacy study will be enrolled through three cohorts of participants, each cohort consisting of approximately 30 subjects that will be involved in the vaccination phase and 22 subjects that will proceed with the challenge phase. There will be a fourth cohort of participants, consisting of 12 subjects, that will receive the vaccine in an open-label design-this cohort will provide serum samples which are intended to be used for generating serum standards for laboratory assays, as a part of ongoing and future clinical development of Shigella vaccines.

Official Title
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Phase 2b Study of the Safety, Immunogenicity, and Efficacy of a Monovalent Synthetic Carbohydrate-based Conjugate Vaccine (SF2a-TT15) for Protection Against Shigella Flexneri 2a Experimental Infection

Conditions
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Shigella

Intervention / Treatment
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* Biological: SF2a-TT15 Shigella Vaccine
* Other: Placebo
* Biological: S. flexneri 2a strain 2457T Challenge Agent


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female of age 18-45 years Provides written informed consent Healthy, based on history, exam, and medications Documented acceptable screening laboratory work, including: WBC, ANC, Hg, Platelets Creatinine, ALT, Bili Serum IgA HIV, HBsAg, HCV Negative for HLA-B27 (this criterion does not apply to cohort 4) Stool culture urinalysis Passing score on Comprehension Assessment Tool (greater than or equal to 70 percent correct answers) Agrees not to participate in another interventional clinical trial during the study period For females of child-bearing potential, must agree to acceptable birth control, 4 weeks before enrollment and through 4 weeks after last vaccination or challenge Available for a 12-day inpatient stay (this criterion does not apply to cohort 4) Exclusion Criteria: Positive pregnancy test at screening or within 24 hours of study product dosing Poor venous access, as defined by inability to obtain venous blood after 3 venipuncture attempts (this criterion does not apply to cohort 4) Abnormal vital signs, defined as: Systolic BP greater than 150 mmHg or Diastolic BP greater than 90 mmHg Resting heart rate greater than 100 Oral temperature greater than or equal to 100.4 degrees F Persons with IgA deficiency (serum IgA less than 70 mg per dL Serum S. flexneri 2a LPS igG titer greater than or equal to 2500 Received prior vaccines or had prior infection (natural or challenge) with ETEC or Shigella, within 5 years prior to enrollment Symptoms of Traveler's diarrhea associated with travel to countries where Shigella or other enteric infections are endemic (most of the developing world) within 3 years prior to enrollment History of chronic gastrointestinal illness, including sever dyspepsia, lactose intolerance, or other significant gastrointestinal tract disease Use of antimicrobials within 2 weeks of each dose of vaccine or the challenge Regular use (greater than or equal to weekly) of laxatives, anti-diarrheal agents, anti-constipation agents, or antacid therapies History of major gastrointestinal surgery (uncomplicated laparoscopic appendectomy or cholecystectomy greater than 1 year prior is permitted) Abnormal bowel pattern, defined by less than 3 stools per week or greater than 2 stools per day in the past 6 months Use of oral, parenteral or high-dose inhaled steroids within 30 days of each dose of vaccine or the challenge Use of any medication which might affect immune function within 30 days of each dose of vaccine or the challenge Current medical condition which requires daily or weekly prescribed medications for control (as medication use is limited during the inpatient stay), may be an exclusion criterion if in the judgement of the investigator the potential for missed doses could represent a significant risk to the subject's health History of reactive arthritis Diagnosis of schizophrenia or other major psychiatric disease History of seizure disorder within the last 5 years History of alcohol or drug abuse within the last 5 years Presence of immunosuppression Known significant allergy (i.e., anaphylaxis) to ciprofloxacin, trimethoprim-sulfamethoxazole (Bactrim), or a tetanus-containing vaccine 12-lead electrocardiogram with pathologic abnormalities (this criterion does not apply to cohort 4) Occupation in food handling industry, living with, or care of very young children (less than 5 years old), elderly (greater than 65 years), or immunocompromised (this criterion does not apply to cohort 4) Having any known legal obligations, court appearances, professional meetings, vacations, planned events, or other reasons which might interfere with a person's availability for a 12-day inpatient stay. (this criterion does no apply to cohort 4) Any other criteria which, in the investigator's opinion, would compromise the safety of the study, the ability of a subject to participate, or the results of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Shigella Vaccine or Placebo, Followed by Challenge<br>1:1 randomization to investigational Shigella vaccine or placebo (n=30). The majority of participants will then receive the Shigella challenge (n=22). | Biological: SF2a-TT15 Shigella Vaccine<br>* 0.5 mL of the vaccine is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29.<br>Other: Placebo<br>* 0.5 mL of normal saline is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29.<br>Biological: S. flexneri 2a strain 2457T Challenge Agent<br>* Each participant will drink 120 mL of sodium bicarbonate buffer solution. Approximately 1 to 2 minutes later, the participant will ingest approximately 1500 cfu of S. flexneri 2a strain 2457T suspended in 30 mL of the bicarbonate buffer solution.<br>|
| Experimental: Cohort 2: Shigella Vaccine or Placebo, Followed by Challenge<br>1:1 randomization to investigational Shigella vaccine or placebo (n=30). The majority of participants will then receive the Shigella challenge (n=22). | Biological: SF2a-TT15 Shigella Vaccine<br>* 0.5 mL of the vaccine is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29.<br>Other: Placebo<br>* 0.5 mL of normal saline is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29.<br>Biological: S. flexneri 2a strain 2457T Challenge Agent<br>* Each participant will drink 120 mL of sodium bicarbonate buffer solution. Approximately 1 to 2 minutes later, the participant will ingest approximately 1500 cfu of S. flexneri 2a strain 2457T suspended in 30 mL of the bicarbonate buffer solution.<br>|
| Experimental: Cohort 3: Shigella Vaccine or Placebo, Followed by Challenge<br>1:1 randomization to investigational Shigella vaccine or placebo (n=30). The majority of participants will then receive the Shigella challenge (n=22). | Biological: SF2a-TT15 Shigella Vaccine<br>* 0.5 mL of the vaccine is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29.<br>Other: Placebo<br>* 0.5 mL of normal saline is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29.<br>Biological: S. flexneri 2a strain 2457T Challenge Agent<br>* Each participant will drink 120 mL of sodium bicarbonate buffer solution. Approximately 1 to 2 minutes later, the participant will ingest approximately 1500 cfu of S. flexneri 2a strain 2457T suspended in 30 mL of the bicarbonate buffer solution.<br>|
| Experimental: Cohort 4: Shigella Vaccine Only, No Challenge<br>All volunteers receive the investigational Shigella vaccine (n=12). No Shigella challenge. | Biological: SF2a-TT15 Shigella Vaccine<br>* 0.5 mL of the vaccine is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protective Efficacy calculated as the change in attack rates | The point estimate of protective efficacy is to be calculated as the change in attack rates among placebo recipients and vaccinees divided by the attack rate among placebo recipients. The vaccine efficacy and the 90% and 95% confidence intervals will be calculated. | approximately eight months |