Evaluate a New Shigella Sonnei Vaccine Administered Either by Intradermal, Intranasal or Intramuscular Route 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 a candidate vaccine against Shigella sonnei (1790GAHB vaccine) when administered at different dosages by different routes (intradermally, intranasally or intramuscularly) 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 52 eligible subjects will be assigned to one of three sequential cohorts as follows: Cohort A) 0.1 μg ID and 5 μg IN Cohort B) 1 μg ID and 20 μg IN Cohort C) 10 μg ID, 80 μg IN and 5 μg IM 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. Specifically for IN and ID administration routes, 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, Placebo Controlled, Single Center, Dose Escalation Study to Evaluate the Safety and Immunogenicity of 3 Vaccinations With Shigella Sonnei Vaccine (1790GAHB) Administered Either by Intradermal, Intranasal or Intramuscular Route 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 have been explained to them, have given written consent according to local regulatory requirements. Individuals in good health as determined by the outcome of medical history, physical examination, hematology, renal, bone and liver panels (including negative for agglutination testing of S. sonnei), urinalysis and clinical judgment of the investigator. If women of childbearing potential, have a negative pregnancy test prior to study vaccination and willingness to use acceptable contraceptive measures for the entire study duration. Individuals available for follow-up for the duration of the study. Individuals registered with a general practitioner. Exclusion Criteria: Individuals with a history of recurrent wheezing, asthma, respiratory allergies, allergic rhinitis, nasal surgery or significant nasal abnormalities (e.g. polyps), and Bell's palsy. Presence of nasal piercings. Symptoms of upper respiratory tract infection within 3 days of intended study vaccination is a temporary exclusion criterion. Individuals unwilling to abstain from medications or other agents that are applied via the nasal route from 24 hours prior to each nasal dosing through to the safety assessment 1 week later. 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 with human leukocyte antigen (HLA) -B27 positive and/or with history of reactive arthritis Individuals with known HIV, HBV and HCV 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 within the previous 30 days, or were in chemotherapy treatment within the past 6 months. 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 90 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 4 weeks before 1st vaccination and 4 weeks 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. BMI > 30 kg/m2. Individuals with history of substance or alcohol abuse within the past 2 years. Women who are pregnant or breast-feeding or 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 ascertained or suspected disease caused by S. sonnei or positive S. sonnei serology at screening 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 - 0.1 mcg - ID<br>Subjects enrolled in COHORT A receiving 3 injections of S. sonnei 1790GAHB - 0.1 mcg intradermally (ID) | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 1 mcg - ID<br>Subjects enrolled in COHORT B receiving 3 injections of S. sonnei 1790GAHB - 1 mcg intradermally (ID) | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 10 mcg - ID<br>Subjects enrolled in COHORT C receiving 3 injections of S. sonnei 1790GAHB - 10 mcg intradermally (ID) | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 5 mcg - IN<br>Subjects enrolled in COHORT A receiving 3 injections of S. sonnei 1790GAHB - 5 mcg intranasally (IN) | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 20 mcg - IN<br>Subjects enrolled in COHORT B receiving 3 injections of S. sonnei 1790GAHB - 20 mcg intranasally (IN) | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 80 mcg - IN<br>Subjects enrolled in COHORT C receiving 3 injections of S. sonnei 1790GAHB - 80 mcg intranasally (IN) | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Experimental: S. sonnei 1790GAHB - 5 mcg - IM<br>Subjects enrolled in COHORT C receiving 3 injections of S. sonnei 1790GAHB - 5 mcg intramuscularly (IM) | Biological: S. sonnei 1790GAHB<br> <br> * Other names: Shigella sonnei vaccine;|
| Placebo Comparator: Placebo - ID<br>2 subjects enrolled in each COHORT A, B and C receiving 3 injections of Placebo intradermally (ID). These were pooled in one Placebo group in the analyses | Biological: Placebo<br> <br> |
| Placebo Comparator: Placebo - IN<br>2 subjects enrolled in each COHORT A, B and C receiving 3 injections of Placebo intranasally (IN). These were pooled in one Placebo group in the analyses | Biological: Placebo<br> <br> |
| Placebo Comparator: Placebo - IM<br>2 subjects enrolled in COHORT C receiving 3 injections of Placebo intramuscularly (IM) | 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/swelling refers to: ≥25 mm in diameter. Grade 3 (severe) refers to erythema/induration/swelling >100 mm in diameter. Grade 3 (severe) for injection site pain/nasal pain/facial edema/rhinorrhea 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. (1989 J. Clin. Microbiol. 27:162). 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