Shigella CVD 31000: Study of Responses With Shigella-ETEC Vaccine Strain CVD 1208S-122

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a live, oral, combined Shigella-ETEC vaccine candidate, known as strain CVD 1208S-122, is safe and immunogenic.

Detailed Description
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The purpose of this study is to determine whether a live, oral, combined Shigella-ETEC vaccine candidate, known as strain CVD 1208S-122, is safe and immunogenic. This will be a phase 1, double-blind, placebo-controlled, dose-escalating, single-center study, involving three vaccine dosage escalation cohorts (10^8, 10^9, and 10^10 cfu vaccine organisms). Each of the three dose-escalation cohorts will consist of 8 study participants who will be randomly allocated to receive either vaccine (n=6) or placebo (n=2), as a single, oral dose. An independent Safety Monitoring Committee (SMC) will review the available safety data for Cohorts 1 - 3 through 7 days post-vaccination before proceeding to the enrollment of the next cohort. The fourth cohort will be an adaptive design cohort consisting of 30 study participants to be randomly allocated to receive either two doses of vaccine (n=12), one dose of vaccine (n=12), or two doses of placebo (n=6), with the dosage selection based on the highest well-tolerated dose in the dose-escalation cohorts (1 - 3), as determined by the SMC. Each of the dose-escalation cohorts (1 - 3) will receive the oral dose of blinded study product while in the inpatient setting. During the following subsequent 96 hours (4 days), participants will remain on the inpatient research isolation ward to be closely monitored, and each stool will be collected by study staff. The evaluation and monitoring of participants enrolled in the fourth cohort will be conducted entirely in the outpatient setting.

Official Title
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Phase 1 Study of the Safety, Tolerability, and Immunogenicity of Oral Doses of CVD 1208S-122, a Prototype Attenuated Shigella Flexneri 2a Live Vector Expressing Enterotoxigenic Escherichia Coli Antigens

Conditions
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Shigella Infection, Enterotoxigenic Escherichia Coli Infection

Intervention / Treatment
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* Biological: strain CVD 1208S-122
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18 - 49 years of age Written informed consent provided Determined to be in good health* based on medical history and review of concomitant medications *Good health as defined by an absence of an active chronic medical condition which requires daily prescription medication(s). Participants may be eligible if the medical condition only requires infrequent as needed (PRN) medication and if the investigator determines that the condition does not pose a risk to participant safety or the assessment of reactogenicity and immunogenicity. Any chronic medical condition which does not require a daily prescription medication but might pose a risk to a participant with rapid dehydration (i.e., rapid intravascular volume changes) would be ineligible to participate. Documented acceptable results from screening laboratory work (defined in Appendix B), including: Complete blood count (CBC) with differential for total white blood cell count (WBC), absolute neutrophil count (ANC), hemoglobin (Hg), platelet count Creatinine, alanine aminotransferase (ALT), total bilirubin Serum Immunoglobulin A (IgA) level Human immunodeficiency virus (HIV) antibody, Hepatitis B surface antigen (HBsAg), Hepatitis C virus antibody (HCV) HLA-B27 histocompatibility testing Serum Beta human chorionic gonadotropin (β-HCG) test, if the participant is a woman of child-bearing potential A passing score (≥70%) on a Comprehension Assessment Tool Agrees not to participate in another clinical trial during the study period Females of child-bearing potential† agree to use an acceptable form of birth control‡ from enrollment and through at least 4 weeks after vaccination †Females of child-bearing potential, defined as having not been sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure® 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 has passed since the last menses, if menopausal. ‡Acceptable birth control includes barrier methods such as condoms or diaphragms/cervical cap with spermicide; effective intrauterine devices; NuvaRing®; and licensed hormonal methods such as implants, injectables or oral contraceptives (the pill) or alternatively, monogamous relationship with a vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving the study vaccination, abstinence from sexual intercourse with a male partner, or sexual relationships with non-male partners. Available for up to a 6-day inpatient stay For Participants of Cohorts 1-3 during the time when a U.S. Public Health Emergency for COVID-19 exists, SARS-CoV-2 testing must be performed upon admission to the inpatient ward and must document a negative test result prior to vaccination. Exclusion Criteria: A positive pregnancy test at screening or within 24 h prior to study product dosing A female who is breastfeeding Poor venous access, as defined by inability to obtain venous blood, for screening labs, after 3 venipuncture attempts Abnormal vital signs, defined as: Systolic BP >150 mmHg or Diastolic BP >90 mmHg Resting heart rate >100 bpm Oral temperature ≥38.0°C Having received prior vaccines for or have had prior infection with ETEC, LT, cholera, or Shigella, within the past 3 years History of diarrhea during travel to a developing country within the past 3 years History of chronic gastrointestinal illness, including severe dyspepsia, lactose intolerance, or another significant gastrointestinal tract disease (e.g., irritable bowel syndrome, inflammatory bowel syndrome, gastric ulcer disease) Regular use (≥once weekly) of laxatives, anti-diarrheal agents, anti-constipation agents, or antacid therapies History of major gastrointestinal surgery (uncomplicated laparoscopic appendectomy or cholecystectomy >1-year prior is permitted) Abnormal bowel habits, as defined by <3 stools per week or >2 stools per day in the past 6 months Use of systemic antimicrobials§ within the past 2 weeks use of topical (skin), otic, or ophthalmic antibiotics is acceptable, if those doses are not expected to result in significant systemic absorption levels Use of oral, parenteral or high-dose inhaled steroids within 30 days Use of any medication which might affect immune function# within 30 days #examples include anti-cancer drugs, immunomodulating monoclonal antibody therapeutics, and rheumatologic therapies Diagnosis of schizophrenia or other major psychiatric disease Alcohol or drug abuse within last 5 years Presence of immunosuppression, which could be due to active neoplastic disease or a history of any hematologic malignancy (excluding resolved non-melanoma skin cancers), radiation therapy, or primary or secondary immunodeficiencies History of allergy to quinolone (e.g., ciprofloxacin) or sulpha drugs (e.g., trimethoprim-sulfamethoxazole) Known history of seizure disorder (remote history of a childhood seizure disorder which has completely resolved is acceptable) Occupation involving the handling of ETEC, cholera, or Shigella bacteria Occupation in food handling industry or care of very young children (<2 years old), elderly (≥70 years), or immunocompromised During the time when a U.S. Public Health Emergency for COVID-19 exists, within 14 days prior to the time of vaccination, the presence of 2 or more of any of the following symptoms: fever (≥38°C, chills, myalgia, headache, sore throat, or new olfactory and taste disorder During the time when a U.S. Public Health Emergency for COVID-19 exists, within 14 days prior to the time of vaccination, the presence of 1 or more of any of the following respiratory symptoms: cough which cannot otherwise be explained, shortness of breath, or difficulty breathing 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: 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Shigella Vaccine at 10^8 cfu or Placebo<br>3:1 randomization to one dose of vaccine or placebo (Cohort n=8) | Biological: strain CVD 1208S-122<br>* Live, attenuated, vaccine strain of S. flexneri 2a expressing CFA/I and LT of enterotoxigenic E. coli<br>Other: Placebo<br>* Sodium bicarbonate buffer<br>|
| Experimental: Cohort 2: Shigella Vaccine at 10^9 cfu or Placebo<br>3:1 randomization to one dose of vaccine or placebo (Cohort n=8) | Biological: strain CVD 1208S-122<br>* Live, attenuated, vaccine strain of S. flexneri 2a expressing CFA/I and LT of enterotoxigenic E. coli<br>Other: Placebo<br>* Sodium bicarbonate buffer<br>|
| Experimental: Cohort 3: Shigella Vaccine at 10^10 cfu or Placebo<br>3:1 randomization to one dose of vaccine or placebo (Cohort n=8) | Biological: strain CVD 1208S-122<br>* Live, attenuated, vaccine strain of S. flexneri 2a expressing CFA/I and LT of enterotoxigenic E. coli<br>Other: Placebo<br>* Sodium bicarbonate buffer<br>|
| Experimental: Cohort 4: Shigella Vaccine or Placebo<br>2:2:1 randomization to receive either two doses of vaccine, 1 dose of vaccine and one dose of placebo, or two doses of placebo at Days 1 and 29 (Cohort n=30) | Biological: strain CVD 1208S-122<br>* Live, attenuated, vaccine strain of S. flexneri 2a expressing CFA/I and LT of enterotoxigenic E. coli<br>Other: Placebo<br>* Sodium bicarbonate buffer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number, Proportion, and Severity of Fever, Diarrhea, or Dysentery | The number, proportion, and severity of fever, diarrhea, or dysentery (hemoccult testing will only be performed during the inpatient days) within 7 days of vaccination, for all those receiving vaccine and for each of the vaccine dosages evaluated | 7 days following vaccination | 
| Number, Proportion, and Severity of Solicited Local and Systemic Adverse Reactions | The number, proportion, and severity of solicited local and systemic adverse reactions (diarrhea, dysentery, fever, nausea, vomiting, abdominal discomfort, tenesmus, myalgia, arthralgia, and anorexia) within 7 days of vaccination for all those receiving vaccine and for each of the vaccine dosages evaluated | 7 days following vaccination | 
| Number, Proportion, Severity, and Relatedness of Non-Serious Unsolicited Adverse Reactions | The number, proportion, severity, and relatedness of non-serious unsolicited adverse reactions within 28 days of vaccination for all those receiving vaccine and for each of the vaccine dosages evaluated | 28 days following vaccination | 
| Number, Proportion, and Severity of Clinical Safety Laboratory Adverse Events | The number, proportion, and severity of clinical safety laboratory adverse events from the time of each study vaccination through approximately 7 days after each study vaccination. | 7 days following vaccination | 
| Occurrence of SUSARs | The occurrence of SUSARs in the study | The entire study period (6-7 months) | 
| Occurrence of all SAEs | The occurrence of all SAEs, regardless of the assessment of relatedness, from the time of the first vaccination through approximately 6 months after the last study vaccination | The entire study period (6-7 months) | 
| Geometric Mean Number of Vaccine Organisms | The geometric mean number (and interquartile range) of vaccine organisms, per day and at the peak of shedding, expressed as cfu/mL for each dosage group | for each day of the 7 days following vaccination | 
| Number and Proportion of Sequential Days of Fecal Shedding of Shigella Organisms | The number and proportion of sequential days of fecal shedding of Shigella organisms which are documented to contain the genes expressing ETEC antigens for each dosage group. Genetically stable organisms will be defined as being PCR positive for Shigella (ipaH or virG), CFA/I (cfaB), and LTB (eltB) | for each day of the 7 days following vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vaccine, strain CVD 1208S-122