A Study to Evaluate the Efficacy, Safety and Immunogenicity of a Vaccine Designed to Protect Against Infection With Shigella Sonnei in Healthy Adults

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety and immunogenicity of the GSK3536852A vaccine, which was designed to protect against shigellosis caused by Shigella sonnei (S. sonnei) and is using the new Generalized Modules for Membrane Antigens (GMMA) platform technology developed by GlaxoSmithKline (GSK) Vaccines Institute for Global Health (GVGH). The study vaccine could be the stepping stone for the development of a multivalent broadly protective Shigella vaccine for vaccination of impoverished communities where shigellosis is endemic. However, a standalone monovalent vaccine against S. sonnei could be used to protect travelers against diarrheal shigellosis, as the vast majority of travelers' shigellosis is caused by S. sonnei, and even to protect infants in endemic regions where shigellosis is primarily caused by S. sonnei. The GSK3536852A vaccine has been tested in two Phase I dose escalation studies in Europe to assess its safety and immunogenicity via three routes of administration: intramuscular (IM), intranasal (IN) and intradermal (ID). The results from the first study (dose escalation with IM vaccination) have shown that the vaccine has an acceptable safety profile and is well-tolerated up to a dose of 100 micrograms (µg). The results from the second study (dose escalation with ID, IN and IM vaccination) showed that GSK3536852A vaccine is well-tolerated also when administered by the ID and IN routes of vaccination. However, immunogenicity data have shown that GSK3536852A vaccine administered by the ID and IN routes is not as immunogenic as GSK3536852A vaccine administered by the IM route. Therefore, it has been decided to proceed with the clinical development program of this vaccine only using the IM vaccination route. In terms of dosage, the regimen tested in Phase I studies (three doses given one month apart) did not show any significant benefit from the third dose in terms of immunogenicity, therefore a two dose schedule was selected for next studies. A Phase IIa study, conducted in endemic regions of Africa (i.e., Kenya), has been completed and confirmed the acceptable safety profile and immunogenicity of GSK3536852A vaccine. Performing this vaccine-human challenge study may give the opportunity to establish evidence of clinical protection induced by the candidate S. sonnei vaccine (GSK3536852A vaccine) at an early development stage.

Detailed Description
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The original study protocol has been amended due to requests from the Food and Drug Administration (FDA), requests from the funder of the study, Bill & Melinda Gates Foundation (BMGF), to add an additional interim analysis for immunogenicity data that will accelerate the release of key results to help the planning of other studies, and to further align the protocol to other GSK studies and to the challenge model established at the Cincinnati Children's Hospital Medical Centre.

Official Title
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Efficacy, Safety and Immunogenicity of GVGH Shigella Sonnei Vaccine (1790GAHB) in a Human Challenge Study of Healthy Non-immune Adults

Conditions
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Dysentery, Bacillary

Intervention / Treatment
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* Biological: S.sonnei vaccine
* Drug: Placebo
* Biological: S. sonnei 53G challenge strain


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol. Written informed consent obtained from the subject prior to performing any study specific procedure. Individuals who, after the nature of the study has been explained to them, have shown adequate comprehension of the study procedures and knowledge of study. A male or female between, and including, 18 and 50 years of age at the time of the first vaccination. Healthy subjects as established by medical history and clinical examination before entering into the study. Seronegative for human immunodeficiency virus (HIV), hepatitis B and C. Female subjects of non-childbearing potential may be enrolled in the study. Female subjects of childbearing potential may be enrolled in the study, if the subject: Has practiced adequate contraception for 30 days prior to vaccination, and Has a negative pregnancy test on the day of vaccination, and Has agreed to continue adequate contraception during the entire study period. Exclusion Criteria: Received an investigational or non-registered medicinal product within 30 days prior to informed consent, or planned use during the study period. Any 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. History of any neurological disorders or seizures. Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the subject due to participation in the study. Human Leukocyte Antigen (HLA)-B27 positive test at screening and/or with history of reactive arthritis. Clinical conditions representing a contraindication to intramuscular vaccination and blood draws. Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine/placebo dose. For corticosteroids, this will mean prednisone ≥ 20 milligrams (mg)/day, or equivalent. Inhaled except for doses > 800 µg/day and topical steroids are allowed. Administration of long-acting immune-modifying drugs at any time during the study period. Subjects may be on chronic or as needed medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition. Known bleeding diathesis or any condition that may be associated with a prolonged bleeding time. Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product. History of having participated in a previous Shigella challenge study. Individuals who have a previously laboratory confirmed case of disease caused by S. sonnei or serology positive for local anti S. sonnei LPS IgG Screening-ELISA at screening. History of any serious chronic or progressive disease according to judgment of the investigator. History of any malignancy or lymphoproliferative disorder. Known to be part of study personnel or being a close family member to the personnel conducting this study. History of anaphylactic reaction or allergy to vaccine/placebo or challenge agent components or any other allergies deemed by the investigator to increase the risk of an AE if they were to participate in the study. Known allergy to ciprofloxacin or the other antibiotics used for treatment as deemed by the investigator. Individuals receiving a course of antibiotics within a week of the challenge will be ineligible to receive the challenge strain. History of gastric acid hyper-secretory disorders as assessed and judged by the investigator or any other significant intestinal disorder. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. Family history of congenital or hereditary immunodeficiency. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine/placebo or challenge agent. Acute disease and/or fever at the time of enrolment. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests. Chronic medical diagnoses or conditions should be stable for the last 60 days. This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis or condition in the 60 days prior to enrolment. A clinically significant sign or symptoms of acute illness, significant anomalies in vital signs. Known to handle food as part of work related activities. Hepatomegaly, right upper quadrant abdominal pain or tenderness. Received immunoglobulins or any blood products within 180 days prior to informed consent or planned administration during the study period. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions. Females with history of stillbirth, neonatal loss, or previous infant with anomaly, except those who have had a planned termination of pregnancy, hysterectomy or bilateral tubal ligation. History of chronic alcohol consumption and/or drug abuse. Chronic alcohol consumption is defined as: a prolonged period of frequent, heavy alcohol use; the inability to control drinking once it has begun; physical dependence manifested by withdrawal symptoms when the individual stops using alcohol; tolerance, or the need to use more and more alcohol to achieve the same effects; a variety of social and/or legal problems arising from alcohol use. Known to have close household or professional contacts with people with immunosuppressive condition. Documented HIV, hepatitis B and C positive subject. 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. Subjects with a baseline neutrophil count below 1800 cells per microliter (cells/µL) lower limit of normal range (LLN) OR with clinically significant abnormalities in other laboratory values, according to local reference ranges and investigator judgment. Previous history of Benign Ethnic Neutropenia, or drug related Neutropenia. Concomitant treatment with neutropenic agents.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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 Group<br>Male or female subjects between, and including, 18 and 50 years of age at the time of the first vaccination, received 2 doses of the S. sonnei study vaccine at Day 1 and Day 29 respectively, by intramuscular injection into the upper deltoid region of the non-dominant arm. At 28 days after the second dose (Day 57), subjects received the challenge dose of S. sonnei 53G strain, orally. | Biological: S.sonnei vaccine<br>* Subjects receiving 2 doses of the study vaccine by intramuscular route, 28 days apart (at Day 1 and Day 29).<br>* Other names: GSK3536852A vaccine;Biological: S. sonnei 53G challenge strain<br>* Subjects receiving the challenge dose of S. sonnei 53G strain, orally, at Day 57.<br>|
| Placebo Comparator: Placebo Group<br>Male or female subjects between, and including, 18 and 50 years of age at the time of the first vaccination, received 2 doses of the placebo at Day 1 and Day 29 respectively, by intramuscular injection into the upper deltoid region of the non-dominant arm. At 28 days after the second dose (Day 57), subjects received the challenge dose of S. sonnei 53G strain, orally. | Drug: Placebo<br>* Subjects receiving 2 doses of placebo by intramuscular route, 28 days apart (at Day 1 and Day 29).<br>* Other names: GAHB-Placebo;Biological: S. sonnei 53G challenge strain<br>* Subjects receiving the challenge dose of S. sonnei 53G strain, orally, at Day 57.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With at Least One Episode of Shigellosis According to the Protocol Primary Case Definition | Attack rate of shigellosis expressed as percentage of subjects with at least one episode of shigellosis after challenge, and 90% confidence interval (CI) (Clopper-Pearson method). Episodes of shigellosis fulfilling primary case definition: Shedding of S. sonnei 53G accompanied by moderate or severe diarrhea OR shedding with oral temperature greater than or equal to (≥) 38.5°C. Moderate diarrhea consists of 4 to 5 loose or watery (Grade [G]3 to 5) stools or 400 to 800 grams of G3 to 5 stools within 24 hours. Severe diarrhea consists of 6 or more loose or watery (G3 to 5) stools or > 800 grams of G3 to 5 stools within 24 hours or required medical intervention. In case of severe diarrhea, medical intervention is defined as intravenous fluids administration or anticipation of antibiotic treatment before the 5th day after challenge. G3 = viscous opaque liquid or semi-liquid which assumes the shape of the bowl; G4 = watery opaque liquid; G5 = clear watery or mucoid liquid. | Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With at Least One Episode of Shigellosis According to Controlled Human Infection Model (CHIM) Working Group Case Definition for Shigellosis | Percentage of subjects with shigellosis fulfilling the CHIM expert working group case definition for shigellosis, and 90% confidence interval (CI) (Clopper-Pearson method). According to the working group, the participant must fulfil any of the three following possible endpoints to qualify as having reached the CHIM case definition for this objective: 1. Severe diarrhea defined as [[≥ 6 loose stools in 24 hours] OR [˃800 grams loose stools in 24 hours]; 2. Moderate diarrhea defined as [4-5 loose stools in 24 hours OR 400-800 grams loose stools in 24 hours] AND [oral temperature [≥ 38.0°C OR [≥ 1 moderate constitutional/enteric symptom OR [≥ 2 episodes of vomiting in 24 hours]; 3. Dysentery defined as [[≥ 2 loose stools with gross blood (hemoccult positive) in 24 hours] AND [oral temperature [≥ 38.0°C OR [≥ 1 moderate constitutional/enteric symptom OR [≥ 2 episodes of vomiting in 24 hours]. | Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64) | 
| Percentage of Subjects With at Least One Episode of Shigellosis | Percentage of subjects with shigellosis fulfilling the following definition of shigellosis (with 90% confidence interval (CI) - Clopper-Pearson method): 1) severe diarrhea OR 2) moderate diarrhea AND oral temperature ≥ 38.0 °C OR ≥ 1 moderate constitutional/enteric symptom OR 3) dysentery [[≥ 2 loose stools with gross blood (hemoccult positive) in 24 hours] AND [≥ 1 reportable constitutional/enteric symptom]]. | Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64) | 
| Percentage of Subjects With at Least One Episode of More Severe Shigellosis | Percentage of subjects with more severe shigellosis fulfilling the following definition of more severe shigellosis (with 90% confidence interval (CI) - Clopper-Pearson method): 1) moderate OR severe diarrhea AND oral temperature ≥ 38.0 °C OR ≥ 1 severe constitutional/enteric symptom OR 2) dysentery [[≥ 2 loose stools with gross blood (hemoccult positive) in 24 hours] AND [oral temperature ≥ 38.0°C OR ≥ 1 severe constitutional/enteric symptom]]. | Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64) | 
| Percentage of Subjects With Specific Disease Symptoms | Percentage of subjects with 90% CI-Clopper-Pearson method was also measured for: shedding of S.sonnei strain 53G (defined as positivity of ≥1 stool sample by culture/quantitative Polymerase Chain Reaction/both); severe diarrhea; more severe diarrhea; dysentery; confirmed S.sonnei 53G shedding AND moderate or severe diarrhea OR dysentery OR presence of oral temperature ≥ 38.5°C OR presence of 1 or more severe intestinal symptoms (abdominal pain, cramping, nausea, vomiting, gas, and anorexia) abbreviated as shedding of S.sonnei 53G and […; disease not fulfilling the protocol primary case definition for shigellosis associated or not with mild to moderate symptoms including: ≥1 stool and no moderate or severe diarrhea evidence, abdominal pain, abdominal cramps, gas, anorexia, nausea, headache, myalgia, malaise, arthralgia, fever, vomiting and intravenous fluid administration. Any=any symptom regardless of intensity grade or relation to study vaccination and/or challenge administration. | Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64) | 
| Mean Number of Grade 3-5 Stools Per Subject | The mean number of grade 3-5 stools (and standard deviation) were calculated per subject from challenge to discharge. | Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64) | 
| Weight of Grade 3-5 Stools | Mean and standard deviation (SD) of weights were expressed in grams. The following measures were calculated: mean and SD of the weight of grade 3-5 stools calculated on all subjects (Weight/all subjects), mean and SD of the weight of grade 3-5 stools calculated on subjects with at least one grade 3-5 stool (Weight/subj.with at least 1 grade 3-5 stool), Cumulative mean and SD weight of grade 3-5 stools per subjects, accumulated from challenge to discharge (Cumulative weight/all subjects). | Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64) | 
| Time (Days) From Challenge Administration to Onset of Shigellosis, According to the Primary Case Definition | Median time to onset of shigellosis was to be estimated with Kaplan-Meier method among subjects who received the challenge agent. The day associated to the first shigellosis was the time of onset of shigellosis. Subjects who did not have shigellosis were censored at the time on the day of discharge. Median time (in days) to onset of shigellosis and 90% confidence interval (CI) could not be calculated in any of the groups because less than 50% of subjects experienced the event (shigellosis) during the observation period. | Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64) | 
| Number of Subjects With Any Solicited Local Adverse Events (AEs) | Solicited local AEs include: pain, erythema and induration at injection site. Any = occurrence of local adverse event regardless of intensity grade. Any erythema or induration at injection site is any symptom with a surface diameter greater than 25 millimeters. | During the 7-day period after each vaccination (vaccine/placebo administered at Day 1 and Day 29) | 
| Number of Subjects With Any Solicited Systemic AEs | Solicited systemic AEs include: arthralgia, chills, fatigue, headache, malaise, myalgia, fever (oral temperature ≥ 38.0°C). Any = occurrence of systemic adverse event regardless of intensity and relation to study vaccination. | During the 7-day period after each vaccination (vaccine/placebo administered at Day 1 and Day 29) | 
| Number of Subjects With Any Unsolicited AEs During the 28-day Post-vaccination Period | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to study vaccination. | During the 28-day period across doses (vaccine/placebo administered at Day 1 and Day 29) | 
| Number of Subjects With Any Unsolicited AEs During the 28-day Follow-up Period After Challenge | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to study vaccination and/or challenge agent administration. | During the 28-day follow-up period after challenge (challenge administered at Day 57) | 
| Number of Subjects With Any Serious Adverse Events (SAEs) and Related SAEs | Serious adverse events (SAEs) assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. Related SAEs = SAEs assessed by the investigator as related to the study vaccination and/or challenge agent administration. | From Day 1 up to study end at Day 237 | 
| Number of Subjects With Any Adverse Events of Special Interest (AESI) (i.e., Symptomatic Neutropenia) | AESI are predefined (serious or non-serious) AEs of scientific and medical concern specific to the product or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor can be appropriate, because such an event might warrant further investigation in order to characterize and understand it. | From Day 1 up to study end at Day 237 | 
| Number of Subjects With Change From Baseline in Hematological Laboratory Parameters With Respect to Normal Laboratory Ranges | Among hematological parameters assessed are: Basophils, Eosinophils, Erythrocytes, Hematocrit, Hemoglobin, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets. Below = below the normal laboratory range defined for the specified laboratory parameter; Above = above the normal laboratory range defined for the specified laboratory parameter; Within = within the normal laboratory range defined for the specified laboratory parameter. Category naming has been defined as follows: Parameter, time point, range indicator at Baseline, range indicator at the specified time point: e.g.: Basophils, Day 8, Within, Within . Note: All subjects whose neutrophil value was below the threshold defined in the Protocol, at any time during the study, were re-tested until neutropenia resolution. | At Day 8, at Day 36 and at Day 237 | 
| Anti-S. Sonnei Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Antibody Concentrations at Pre-vaccination and After the First and Second Vaccination | Anti-S. sonnei LPS IgG antibody concentrations are presented as geometric mean concentrations (GMCs), determined by Enzyme-linked immunosorbent assay (ELISA) and expressed in ELISA units per milliliter (EU/mL). Note: regarding the 28 days after second vaccination protocol timing, sample collection could have been performed either at Day 56 or at Day 57. For all the subjects, samples were collected at Day 56, and therefore, results are presented for Day 56 (27 days after the second vaccination) timing. | At Day 1 (pre-vaccination), at Day 8 (7 days after the first vaccination), at Day 29 (28 days after the first vaccination), at Day 36 (7 days after the second vaccination) and at Day 56 (27 days after the second vaccination) | 
| Anti-S. Sonnei LPS IgG Antibody Concentrations at Pre-challenge and After Challenge | Anti-S. sonnei LPS IgG antibody concentrations are presented as GMCs, as determined by ELISA and expressed in EU/mL. Note: regarding the 28 days after second vaccination protocol timing, sample collection could have been performed either at Day 56 or at Day 57. For all the subjects, samples were collected at Day 56, and therefore, results are presented for Day 56 (27 days after the second vaccination) timing. | At Day 56 (pre-challenge), at Day 64 (7 days after challenge) and at Day 85 (28 days after challenge) | 
| Number of Subjects Achieving a Post-vaccination Anti-S. Sonnei LPS Concentration ≥ 268 EU/mL | This antibody response cut-off was based on the results of the previous Phase I studies and estimated results of the median antibody titer after natural infection by S. sonnei. The threshold 121 EU/mL planned per protocol has been recalibrated to 268 EU/mL following an investigation of reliability of the ELISA assay. Note: regarding the 28 days after second vaccination protocol timing, sample collection could have been performed either at Day 56 or at Day 57. For all the subjects, samples were collected at Day 56, and therefore, results are presented for Day 56 (27 days after the second vaccination) timing. | At Day 29 (28 days after the first vaccination) and at Day 56 (27 days after the second vaccination) | 
| Number of Seroresponders for Anti-S. Sonnei LPS | Seroresponse definition as reported in the protocol was assay specific and specifically related to assay, as run in Marburg Lab for the previous GVGH Shigella studies. This assay was further characterized and optimized before being used in GVGH for the current Phase 2b study. Since the assay used in current study is not comparable with the assay used in previous GVGH studies, the seroresponse definition is no longer appropriate (as it is valid only for Marburg assay). With the acknowledgment that seroresponse results are no longer meaningful, the study team choose to report the results for transparency. Note: regarding the 28 days after second vaccination protocol timing, sample collection could have been performed either at Day 56 or at Day 57. For all the subjects, samples were collected at Day 56, and therefore, results are presented for Day 56 (27 days after the second vaccination timing. | At Day 29 (28 days after the first vaccination) and at Day 56 (27 days after the second vaccination) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Challenge, Efficacy, Shigellosis, Vaccination