A Phase 1, Dose Escalation Study, to Evaluate a New Shigella Sonnei Vaccine in Healthy Adults.

Study Overview
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Brief Summary
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This Phase 1 clinical trial is aimed to evaluate the safety and immunogenicity of 3 doses of 5 sequentially escalating dosages of a candidate vaccine against Shigella sonnei (1790GAHB vaccine) administered by intramuscular route in healthy adults (18 to 45 years of age at enrollment). The safety profile of the 1790GAHB vaccine is evaluated in comparison to that of placebo (GAHB-Placebo), constituted by an aluminum hydroxide suspension having the same concentration as study vaccine formulations. A total of 50 eligible subjects will be assigned to one of five sequential cohorts of 10 subjects each. Within each cohort, in an observer-blind fashion, subjects will be randomized to receive three vaccinations, four weeks apart, of either 1790GAHB vaccine (at five antigen concentrations) or GAHB placebo. A Data Safety Monitoring Board will be in place to receive a summary of all safety data obtained during one week follow-up post-first vaccination with the lower dose. Based on evaluation of the safety data, the Data Safety Monitoring Board will make a recommendation, as to whether the next cohort should be vaccinated with higher antigen concentration or not. Expected duration of the study for an individual subject is 9 months. Each subject will be followed-up for 6 months after the 3rd vaccination.

Official Title
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A Phase 1, Randomized, Observer Blinded, Placebo Controlled, Single Center, Dose Escalation Study to Evaluate the Safety and Immunogenicity of 3 Vaccinations With Shigella Sonnei Vaccine (1790GAHB) Administered Intramuscularly in Healthy Adults.

Conditions
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Shigellosis

Intervention / Treatment
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* Biological: S. sonnei 1790GAHB
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females of age ≥18 years to ≤45 years. Individuals who, after the nature of the study has been explained to them, and prior to any protocol specific procedures being performed, have given written consent according to local regulatory requirements. Individuals in good health as determined by the outcome of medical history, physical examination, hematological / hematochemical blood tests (including presence of high antibody titers against S. sonnei by agglutination test), urinalysis and clinical judgment of the investigator. If women of child-bearing potential, have a negative pregnancy test prior study vaccination and willingness to use acceptable birth control measures for the entire study duration. Individuals affiliated to a social security regimen. Exclusion Criteria: Individuals with behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the subject's ability to participate in the study. Individuals with any progressive or severe neurological disorder, seizure disorder or Guillain-Barré syndrome. Individuals who are not able to understand and to follow all required study procedures for the whole period of the study. Individuals with history of any illness that, in the opinion of the investigator, might interfere with the results of the study or pose additional risk to the subjects due to participation in the study. Individuals human leukocyte antigen (HLA) -B27 positive and/or with history of reactive arthritis. Individuals with known or suspected HIV infection or HIV related disease, with history of an autoimmune disorder or any other known or suspected impairment /alteration of the immune system, or under immunosuppressive therapy including use of systemic corticosteroids or chronic use of inhaled high-potency corticosteroids (i.e. prednisone, or equivalent ≥10 mg/day) within the previous 28 days, or in chemotherapy treatment within the past 168 days. Individuals with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time. Individuals with any serious chronic or progressive disease according to judgment of the investigator (e.g., neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease). Individuals who have any malignancy or lymphoproliferative disorder. Individuals with history of allergy to vaccine components. Individuals participating in any clinical trial with another investigational product 28 days prior to first study visit or intent to participate in another clinical study at any time during the conduct of this study. Individuals who received any other vaccines within 4 weeks prior to enrollment in this study or who are planning to receive any vaccine within the entire study duration except influenza vaccination, which is not allowed within the period included between 28 days before 1st vaccination and 28 days after 3rd vaccination. Individuals who have received blood, blood products, and/or plasma derivatives including parenteral immunoglobulin preparations in the past 12 weeks. Individuals who are part of study personnel or close family members to the personnel conducting this study or employees of the clinical trial site institution. Individuals with body temperature > 38.0 degrees Celsius within 3 days of intended study vaccination. Individuals with Body Mass Index (BMI)> 30 kg/m2 Individuals with history of substance or alcohol abuse within the past 2 years. Women who are pregnant or are breast-feeding, or are of childbearing age who have not used or do not plan to use acceptable birth control measures, for the duration of the study. Females with history of stillbirth, neonatal loss, or previous infant with anomaly. Individuals who have a previously laboratory confirmed or suspected disease caused by S. sonnei. Individuals who have had household contact with/and or intimate exposure to an individual with laboratory confirmed S. sonnei. Any condition, which, in the opinion of the investigator may pose an increased and unreasonable safety risk to the subject if participating to the present 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S. sonnei 1790GAHB - 1 mcg<br>Subjects enrolled in COHORT A receiving 3 injections of S. sonnei 1790GAHB - 1 mcg | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 5 mcg<br>Subjects enrolled in COHORT B receiving 3 injections of S. sonnei 1790GAHB - 5 mcg | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 25 mcg<br>Subjects enrolled in COHORT C receiving 3 injections of S. sonnei 1790GAHB - 25 mcg | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 50 mcg<br>Subjects enrolled in COHORT D receiving 3 injections of S. sonnei 1790GAHB - 50 mcg | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 100 mcg<br>Subjects enrolled in COHORT E receiving 3 injections of S. sonnei 1790GAHB - 100 mcg | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Placebo Comparator: Placebo<br>2 subjects enrolled in each COHORT A, B, C, D, E receiving 3 injections of Placebo. These were pooled in one Placebo group in the analyses | Biological: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Solicited Local Reaction After Any Vaccination | Any erythema/induration refers to: ≥25 mm in diameter. Grade 3 (severe) refers to erythema/induration >100 mm in diameter. Grade 3 (severe) for injection site pain refers to: prevents daily activity | During a 7-day (Days 1-7) post vaccination period following any injection | 
| Number of Subjects With Solicited Systemic Reaction After Any Vaccination | Any= Incidence of any symptom regardless of intensity grade. Grade 3 = symptom that prevented daily activities | During a 7-day (Days 1 to 7) post vaccination period following any injection | 
| Number of Subjects With Neutrophils Results Below and Above the Normal Ranges | Day 8: VISIT 2 (D7 post 1st vac) | At Day 8 | 
| Number of Subjects With Neutrophils Results Below and Above the Normal | Day 36: VISIT 3.1 (D7 post 2nd vac.) | At Day 36 | 
| Number of Subjects With Neutrophils Results Below and Above the Normal | Day 57: VISIT 4 (3rd vac.) | At Day 57 | 
| Number of Subjects With Neutrophils Results Below and Above the Normal | Day 64: VISIT 4.1 (D7 post 3rd vac.) | At Day 64 | 
| Number of Subjects With Neutrophils Results Below and Above the Normal | Day 85: VISIT 5 (1 month post 3rd vac.) | At Day 85 | 
| Number of Subjects With Neutrophils Results Below and Above the Normal | Day 225: VISIT 6 (6 months post 3rd vac.) | At Day 225 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-LPS S. Sonnei Serum IgG Geometric Mean Concentration (GMCs) |  | At baseline, at 28 days after each vaccination and at 168 days after last vaccination | 
| Number of Subjects With Seroresponse for Anti-LPS S. Sonnei | Seroresponse is defined as: If half of the baseline value is greater than 25 ELISA Unit (EU) then an increase of at least 50% in the post-vaccination sample as compared to baseline [i.e. ((Post-vac minus baseline)/baseline)100% ≥ 50%]. If half of the baseline value is less or equal to 25 EU then an increase of at least 25 EU in the post-vaccination sample as compared to baseline (i.e. [post-vac minus baseline] ≥25 EU) | At 28 days after each vaccination and 168 days after last vaccination | 
| Number of Subjects With High Seroresponse for Anti-LPS S. Sonnei (IgG ELISA ≥121 EU) | High seroresponse is defined as a post vaccination titer ≥X anti-LPS serum IgG units in the GSK (former Novartis) ELISA that correspond to a titer of 1:800 in the ELISA method used by Cohen et al. To determine the value for 'X' the GSK (former Novartis) anti-LPS ELISA was calibrated against the Cohen ELISA and it was found that a concentration of 121 EU EU/mL corresponds to a titer of 1:800 in the Cohen assay | At baseline, at 28 days after each vaccination and at 168 days after last vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prevention, Shigella sonnei