A Study of the Safety and Immune Response of 2 Doses of a New Shigella Vaccine in Kenyan Adults

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and the immunogenicity of two different doses of the GVGH S. sonnei vaccine in healthy adults and represents the first step towards testing of the GMMA vaccine in the vaccine target population of children from developing countries where shigellosis is endemic.

Official Title
-----------------
A Phase 2a, Observer Blind, Randomized, Controlled, Single Center Study To Evaluate The Safety, Reactogenicity And Immunogenicity Of 2 Doses Of The GVGH 1790GAHB Vaccine Against Shigella Sonnei, Administered Intramuscularly In Adult Subjects From A Country Endemic For Shigellosis

Conditions
-----------------
Shigella Sonnei Infection

Intervention / Treatment
-----------------
* Biological: GVGH S. sonnei (1790GAHB) vaccine 25 μg
* Biological: GVGH S. sonnei (1790GAHB) vaccine 100 μg
* Biological: Menveo
* Biological: Boostrix


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Individuals ≥18 years to ≤45 years of age on the day of informed consent who are resident in the study area and are not planning to leave during the study period. Individuals who, after the nature of the study has been explained, have voluntarily given written consent according to local regulatory requirements, prior to study entry. Individuals who can comply with study procedures including follow-up. Individuals in good health as determined by the outcome of medical history, physical examination, hematology, renal function, and liver function tests, urine dipstick/urinalysis and the clinical judgment of the investigator. Males Or Females of childbearing potential who are using an effective birth control method which they intend to use for the duration of the study Or Females without childbearing potential (i.e. irrespective of birth control method) Prior to receipt of second study vaccination, subjects must be evaluated to confirm that they are eligible for subsequent vaccination. If subjects do not meet any of the original inclusion criteria listed above, they should not receive additional vaccinations. 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 previous Guillain-Barré syndrome. Individuals who, in the judgment of the investigator, may not be able to comply with all the required study procedures. 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 history of reactive arthritis. Individuals with known HIV or hepatitis B virus infection or HIV related disease, history of an autoimmune disorder or any other known or suspected impairment /alteration of the immune system. Individuals under systemic administration of corticosteroids (PO/IV/IM) for more than 14 consecutive days within 90 days prior to screening. Individuals with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time. Individuals with a neutrophil count lower than 1.8 x 10^9/L (applicable to the initial 18 subjects) or lower than 1.0 x 10^9/L (applicable to the additional subjects if approved by DSMB) at screening Individuals with any serious chronic or progressive disease according to judgment of the investigator (e.g., neoplasm, insulin dependent diabetes, Type 2 diabetes mellitus, hypertension, cardiac, renal or hepatic disease and tuberculosis). Individuals who have any malignancy or lymphoproliferative disorder. Individuals with history of allergy to vaccines components or any other allergies deemed by the investigator to increase the risk of an adverse event if they were to participate in the trial. Individuals participating in any clinical trial with another investigational product within 28 days prior to the screening study visit or intent to participate in another clinical study at any time during the conduct of this study. Individuals who received vaccines containing meningococcal A, C, W, Y or tetanus, diphtheria or pertussis antigens within 12 months before screening, or any other vaccines within 4 weeks prior to screening in this study or who are planning to receive any vaccine within the entire study duration. Individuals who have received blood, blood products, and/or plasma derivatives including parenteral immunoglobulin preparations in the 12 weeks prior to the first dose of the study vaccine. Individuals who are study personnel or immediate family members (parents, children, spouse and brothers/sisters) to the personnel conducting this study. Individuals with body temperature > 38.0°C within 3 days of intended study vaccination is a reason for delay of vaccination Individuals with Body Mass Index (BMI)> 30 kg/m^2 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 (for the two months preceding the 1st vaccination) and are not willing to use acceptable contraceptive measures, for the duration of the study. If subjects are women of childbearing potential, they must have a negative pregnancy test at screening visit and prior to enrollment (visit 1). For the purposes of this study acceptable methods of contraception are oral, injected or implantable contraceptives. Individuals who have a previously laboratory confirmed case of disease caused by S. sonnei. Any condition which, in the opinion of the investigator, may pose an increased and unreasonable safety risk to the subject if they participated in the study. Individuals with a previous history of Benign Ethnic Neutropenia or drug related neutropenia. Individuals who have or are likely to require concomitant treatment with neutropenic agents.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1790GAHB 25 μg Group<br>Subjects who received 2 injections of 1790GAHB vaccine containing 25 μg of S. sonnei. | Biological: GVGH S. sonnei (1790GAHB) vaccine 25 μg<br>* Two injections of the study vaccine were administered 28 days apart.<br>|
| Experimental: 1790GAHB 100 μg Group<br>Subjects who received 2 injections of 1790GAHB vaccine containing 100 μg of S. sonnei. | Biological: GVGH S. sonnei (1790GAHB) vaccine 100 μg<br>* Two injections of the study vaccine were administered 28 days apart.<br>|
| Active Comparator: Control Group<br>Subjects who received one dose of Menveo vaccine and a second dose of Boostrix vaccine. | Biological: Menveo<br>* One injection of Menveo was administered in subjects in the Control Group.<br>Biological: Boostrix<br>* One injection of Boostrix was administered in subjects in the Control Group.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Solicited Local and Systemic Adverse Reactions After Each Vaccination | Assessed solicited local adverse reactions were injection site erythema, induration, pain. Assessed systemic adverse reactions were headache, arthralgia, chills, fatigue, malaise, myalgia and temperature (body temperature measured axillary). Any = occurrence of the symptom regardless of intensity grade. Any temperature = body temperature ≥ 38.0°C. Severe symptom = pain, headache, arthralgia, chills, fatigue, malaise and myalgia that prevented normal activity. Severe redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. Severe temperature = body temperature > 40.0 °C. | From 30 minutes up to 7 days following each vaccination | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | An unsolicited AE is an AE that was not solicited using the Diary Card and that was spontaneously communicated by a subject who has signed the informed consent. Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses requiring hospitalization, or emergency room visit, or visit to/by a health care provider), or were of concern to the subject. Note: *disruptions= dose reduction, interruption or delay in study vaccination. | During 28 days following each vaccination | 
| Number of Subjects With Serious Adverse Events (SAEs) | An SAE is defined as any untoward medical occurrence that at any dose results in one or more of the following: death; is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate risk of death from the event as it occurred); it does not refer to an event which hypothetically might have caused death if it were more severe; required or prolonged hospitalization; persistent or significant disability/incapacity (i.e., the event causes a substantial disruption of a person's ability to conduct normal life functions); congenital anomaly/or birth defect; an important and significant medical event that may not be immediately life-threatening or resulting in death or hospitalization but, based upon appropriate medical judgment, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above. | Throughout the whole study period (from Day 1 up to Day 57) | 
| Number of Subjects With Deviations From Normal Ranges of Safety Laboratory Data at Day 8 by Baseline Ranges | The safety laboratory data included haematological parameters (basophils, eosinophils, erytrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, monocytes, platelets and neutrophils), and chemical parameters (Alkaline Phosphatase [ALP], Alanine Aminotransferase [ALA], Aspartate Aminotransferase [AST], Bilirubin [BILI], Blood Urea Nitrogen [BUN], Creatinine [CREAT], Gamma Glutamyl Transferase [GGT], Glucose [GLUC], Potassium [K], Lactate Dehydrogenase [LDH] and Sodium [Na]). Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter. | At Day 8 (7 days after first vaccination) | 
| Number of Subjects With Deviations From Normal Ranges of Safety Laboratory Data at Day 29 by Baseline Ranges | The safety laboratory data included haematological parameters (basophils, eosinophils, erytrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, monocytes, platelets and neutrophils), and chemical parameters (Alkaline Phosphatase [ALP], Alanine Aminotransferase [ALA], Aspartate Aminotransferase [AST], Bilirubin [BILI], Blood Urea Nitrogen [BUN], Creatinine [CREAT], Gamma Glutamyl Transferase [GGT], Glucose [GLUC], Potassium [K], Lactate Dehydrogenase [LDH] and Sodium [Na]). Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter. | At Day 29 (28 days after the first vaccination) | 
| Number of Subjects With Deviations From Normal Ranges of Safety Laboratory Data at Day 36 by Baseline Ranges | The safety laboratory data included haematological parameters (basophils, eosinophils, erytrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, monocytes, platelets and neutrophils), and chemical parameters (Alkaline Phosphatase [ALP], Alanine Aminotransferase [ALA], Aspartate Aminotransferase [AST], Bilirubin [BILI], Blood Urea Nitrogen [BUN], Creatinine [CREAT], Gamma Glutamyl Transferase [GGT], Glucose [GLUC], Potassium [K], Lactate Dehydrogenase [LDH] and Sodium [Na]). Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter. | At Day 36 (7 days after the second vaccination) | 
| Number of Subjects With Deviations From Normal Ranges of Safety Laboratory Data at Day 57 by Baseline Ranges | The safety laboratory data included haematological parameters (basophils, eosinophils, erytrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, monocytes, platelets and neutrophils), and chemical parameters (Alkaline Phosphatase [ALP], Alanine Aminotransferase [ALA], Aspartate Aminotransferase [AST], Bilirubin [BILI], Blood Urea Nitrogen [BUN], Creatinine [CREAT], Gamma Glutamyl Transferase [GGT], Glucose [GLUC], Potassium [K], Lactate Dehydrogenase [LDH] and Sodium [Na]). Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter. | At Day 57 (28 days after the second vaccination) | 
| Number of Subjects With Reported Reactive Arthritis or Neutropenia (AESIs) | Reactive arthritis is defined as non-purulent joint inflammation that develops in response to an infection in another part of the body. Since the inflammation is triggered by a previous condition, it is termed reactive. Intestinal pathogens that have been associated with reactive arthritis include Campylobacter, Salmonella, Yersinia, Clostridium difficile, and Shigella. If reactive arthritis is caused by an auto immune response, there is at least a possibility that it could be initiated by vaccination of susceptible people with the 1790GAHB vaccine. | Throughout the whole study period (from Day 1 up to Day 57) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-LPS S.Sonnei IgG ELISA Geometric Mean Concentrations (GMCs), by Baseline Titer | Anti-LPS S.Sonnei IgG ELISA concentrations were tabulated as unadjusted geometric mean concentrations (GMCs) and expressed as ELISA units (EU) per milliliter (mL), presented with their 95% confidence intervals (CIs). Since all subjects in the study were from an endemic country, they had pre-vaccination titers equal to or above (≥) LLOQ (limit of detection). | At Day 1, Day 29 (28 days after the first vaccination) and Day 57 (28 days after the second vaccination) | 
| Anti-LPS S. Sonnei Geometric Mean Ratios (GMRs) Between Post- and Pre-vaccination Samples | The ratio was expressed as unadjusted geometric mean ratio (GMR) and presented with its 95% confidence interval (CI). | At Day 1, Day 29 (28 days after the first vaccination) and Day 57 (28 days after the second vaccination) | 
| Number of Subjects With Seroresponse to Anti-LPS S. Sonnei IgG ELISA, by Baseline Titer | Seroresponse was defined as: if the baseline value was greater than 50 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 the baseline value was less or equal to 50 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). Since all subjects in the study were from an endemic country, they had pre-vaccination titers equal to or above (≥) LLOQ (limit of detection). | At Day 29 (28 days after the first vaccination) and Day 57 (28 days after the second vaccination) | 
| Number of Subjects With Titers Post Vaccination Concentration for Anti-LPS S. Sonnei ≥ 121 U/mL | The analysis cut-off value (121 U/mL) was expressed in units per milliliter (U/mL), as assessed by the Enzyme-Linked Immunosorbent Assay (ELISA). | At Day 1, Day 29 (28 days after the first vaccination) and Day 57 (28 days after the second vaccination) |