Safety Study of Inactivated Shigella Whole Cell Vaccine in Adults

Study Overview
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Brief Summary
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This is a research study about an experimental (investigational) oral inactivated whole cell Shigella flexneri 2a killed vaccine (Sf2aWC). Sf2aWC is a killed vaccine that is being made to prevent disease from Shigella., which causes bloody, watery diarrhea. Infants and children living in developing countries experience the greatest consequences of this disease. The purpose of this study is to find a dose of the vaccine that is safe, tolerable, and develops an immune response. About 82 healthy adults, ages 18-45, will participate in this study. This study will require volunteers to stay in the research facility for several nights for the first dose. Participants in Cohorts 2, 3, and 4 will not be required to stay overnight for the second and third doses. Participants will be assigned to receive 1 of 4 vaccine doses by mouth. Study procedures include: stool samples, blood samples and documenting side effects. Participants will be involved in study related procedures for about 8 months.

Detailed Description
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Despite the public health burden of Shigella spp. on travelers, deployed soldiers and, most significantly, young children in the developing world, there is no licensed vaccine against Shigella. The rationale for using Shigella flexneri 2a whole cell killed vaccine (Sf2aWC), is that it is expected to be especially well tolerated by subjects. If Sf2aWC is safe and immunogenic, it may be combined with S. sonnei and S. flexneri 3a as the basis of a multivalent vaccine, because these three components should cover up to 80% of shigella infections in developing countries and over 90% in developed countries. This is a single site, Phase 1, double-blind, randomized, placebo-controlled, dose-escalation study in healthy adult subjects. Approximately 82 subjects will be enrolled into four separate cohorts and will be randomized to receive Sf2aWC or placebo. The placebo preparation will be bicarbonate buffer. Cohort 1 subjects will receive a single oral dose of Sf2aWC (2.6±0.8 x 10^8 vp/mL) or placebo. Dosing and 72 hours of supervised post-vaccination safety follow-up will be conducted in the Center for Immunization Research, Johns Hopkins School of Public Health (CIR) Inpatient Unit. Before enrolling subjects in subsequent cohorts, safety data from the previous Cohort(s) through Study Day 7 will be evaluated and reviewed by the Safety Review Committee (SRC). Cohorts 2, 3, and 4 participants will receive three doses of Sf2aWC vaccine or placebo at 0, 1 and 2 months. The first immunization will be administered in the CIR inpatient unit, followed by 72 hours of direct post-immunization observation. If after review by the SRC the first dose appears safe and well tolerated, subsequent doses will be administered on an outpatient basis. Safety will be assessed by solicited symptoms/subject memory aid and laboratory evaluations. Adverse events (AE)s will be graded according to standardized criteria. The immunogenicity outcome measures of interest include serum immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies by ELISA against S. flexneri 2a Lipopolysaccharide (LPS) and S. flexneri 2a invasive protein antigens (Ipa), cytokine assays, B and T cell memory responses, and vaccine-specific IgA responses. The proposed sample size of twenty per group in Cohorts 2, 3, and 4 would be sufficient to select the appropriate dose to move into the next study phase, providing that a difference in the immunogenicity between the two arms is 20% or greater. Participants will include 82 healthy adult male and female subjects, ages 18 to 45 inclusive. The primary objective of this study is to assess the safety and tolerability of Sf2aWC vaccine when administered in three oral doses over a range of dose levels in healthy adult subjects. The secondary objective is to assess the immunogenicity of the Sf2aWC vaccine over a range of doses in healthy adult subjects.

Official Title
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A Phase 1 Study to Evaluate the Safety, Tolerability, and Immunogenicity of an Oral Inactivated Whole Cell Shigella Flexneri 2a Vaccine in Healthy Adult Subjects

Conditions
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Shigellosis

Intervention / Treatment
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* Biological: Vaccine: 2.6±0.8 x 10^8 vp/mL, 1 dose
* Biological: Vaccine: 2.6±0.8 x 10^9 vp/mL, 3 doses
* Biological: Vaccine: 2.6±0.8 x 10^10 vp/mL, 3 doses
* Biological: Vaccine: 2.6±0.8 x 10^11 vp/mL, 3 doses
* Biological: Placebo: 1-3 doses


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adults, male or female, age 18 to 45 years (inclusive) at the time of enrollment. Completion and review of comprehension test (achieved >70% accuracy). Signed informed consent form. Available for the required follow-up period and scheduled clinic visits. Negative urine pregnancy test before each vaccination for female subjects of childbearing potential. Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study. Abstinence is also acceptable. Exclusion Criteria: Presence of a significant medical or psychiatric condition that in the opinion of the investigator precludes participation in the study. Some medical conditions, that are adequately treated and stable, would not preclude entry into the study. These conditions might include stable asthma, hypertension or depression controlled with medication. Clinically significant abnormalities on physical examination. Clinically significant abnormalities in screening hematology, serum chemistry, or urinalysis as determined by PI or PI in consultation with Medical Monitor. History of febrile illness within 48 hours prior to vaccination. BMI <19 or >34. Positive blood test for HBsAG, hepatitis C virus (HCV), HIV-1, Human leukocyte antigen (HLA)-B27. Women currently nursing. History of reactive arthritis. Evidence of current excessive alcohol consumption Evidence of current drug use or drug dependence. Regular use of anti-diarrheal, anti-constipation, or antacid therapy (excluding use associated with spicy meals). Abnormal stool pattern (fewer than 3 stools per week or more than 3 stools per day) on a regular basis; loose or liquid stools on other than an occasional basis. Personal or family history of an inflammatory arthritis. History of allergy to soy products. History of microbiologically confirmed Shigella infection within 3 years. Prior receipt of experimental Shigella vaccine or live Shigella challenge within 3 years. Symptoms of travelers' diarrhea associated with travel to countries where Shigella or other enteric infections are endemic (most of the developing world) within 1 year prior to dosing. Occupation involving handling of Shigella bacteria currently, or in the past 3 years. History of diarrhea during the 7 days before vaccination. Use of antibiotics during the 7 days before vaccination. Use of proton pump inhibitors, H2 blockers, or antacids within 48 hours prior to dosing. Inability to comply with inpatient rules and regulations. Use of immunosuppressive and/or immunomodulative drugs such as corticosteroids or chemotherapeutics that may influence antibody development. Participation in research involving another investigational product (defined as receipt of investigational product or exposure to invasive investigational device) 30 days before planned date of first vaccination.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Received one oral dose of 2.6±0.8 x 10^8 vp/mL Shigella flexneri 2a whole cell killed vaccine (Sf2aWC) | Biological: Vaccine: 2.6±0.8 x 10^8 vp/mL, 1 dose<br>* Shigella flexneri 2a whole cell killed vaccine (Sf2aWC): 2.6±0.8 x 10^8 vp/mL administered on Day 0<br>|
| Experimental: Cohort 2<br>Received three oral doses of 2.6±0.8 x 10^9 vp/mL Shigella flexneri 2a whole cell killed vaccine (Sf2aWC) | Biological: Vaccine: 2.6±0.8 x 10^9 vp/mL, 3 doses<br>* Shigella flexneri 2a whole cell killed vaccine (Sf2aWC): 2.6±0.8 x 10^9 vp/mL administered on Days 0, 28, and 56<br>|
| Experimental: Cohort 3<br>Received three oral doses of 2.6±0.8 x 10^10 vp/mL Shigella flexneri 2a whole cell killed vaccine (Sf2aWC) | Biological: Vaccine: 2.6±0.8 x 10^10 vp/mL, 3 doses<br>* Shigella flexneri 2a whole cell killed vaccine (Sf2aWC): 2.6±0.8 x 10^10 vp/mL administered on Days 0, 28, and 56<br>|
| Experimental: Cohort 4<br>Received three oral doses of 2.6±0.8 x 10^11 vp/mL Shigella flexneri 2a whole cell killed vaccine (Sf2aWC) | Biological: Vaccine: 2.6±0.8 x 10^11 vp/mL, 3 doses<br>* Shigella flexneri 2a whole cell killed vaccine (Sf2aWC): 2.6±0.8 x 10^11 vp/mL administered on Days 0, 28, and 56<br>|
| Placebo Comparator: Placebo<br>Received oral dose of placebo concurrent with Cohort 1 (one dose), 2, 3, or 4 (3 doses). | Biological: Placebo: 1-3 doses<br>* Placebo administered on Day 0 (if 1 dose) or Day 0, 28, and 56 (3 doses)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Reactogenicity Per Subject and Treatment Group | Local and systemic reactogenicity was assessed post-vaccination using targeted physical examinations, vital signs and clinical laboratory tests, and diary cards (completed following discharge daily through Day 7). Reactogenicity included: nausea, vomiting, fever, abdominal pain, abdominal cramping, bloating, malaise, headache, decreased appetite, generalized myalgias, chills, light-headedness, constipation, excessive flatulence, reactive arthritis, dysentery, loose stool, diarrhea, hypovolemia, joint pain, defecation urgency, and oral temperature. | 7 days after each vaccination (Day 0, Day 35, Day 63) | 
| Frequency of Unsolicited Adverse Events With a Reasonable Possibility That the Study Product Caused the Event |  | 6 months after final vaccination (Day 168 or Day 224) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects in Cohort 3 With Positive Immunologic Response in Total Immunoglobulin A (IgA) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 16 weeks | 
| Geometric Mean Titer (GMT) of Total Immunoglobulin A (IgA) Response in Cohort 3 | Whole blood samples were collected for determination of ALS (antibody from lymphocytes supernatant). Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 16 weeks | 
| Number and Percentage of Subjects in Cohort 4 With Positive Immunologic Response in Total Immunoglobulin A (IgA) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 63 days | 
| Geometric Mean Titer (GMT) of Total Immunoglobulin A (IgA) Response in Cohort 4 | Whole blood samples were collected for determination of ALS (antibody from lymphocytes supernatant). Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 63 days | 
| Number and Percentage of Subjects in Cohort 4 With Positive Immunologic Response in Fecal Immunoglobulin A (IgA) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 63 days | 
| Geometric Mean Titer (GMT) of Fecal Immunoglobulin A (IgA) Response in Cohort 4 | Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 63 days | 
| Number and Percentage of Subjects in Cohort 3 With Positive Immunologic Response in Serum Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 35 days | 
| Number and Percentage of Subjects in Cohort 4 With Positive Immunologic Response in Serum Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 63 days | 
| Geometric Mean Titer (GMT) of Serum Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response in Cohort 3 | S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 35 days | 
| Geometric Mean Titer (GMT) of Serum Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response in Cohort 4 | S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 63 days | 
| Number and Percentage of Subjects in Cohort 3 With Positive Immunologic Response in Serum Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 16 weeks | 
| Number and Percentage of Subjects in Cohort 4 With Positive Immunologic Response in Serum Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 16 weeks | 
| Geometric Mean Titer (GMT) of Serum Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response in Cohort 3 | S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 35 days | 
| Geometric Mean Titer (GMT) of Serum Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response in Cohort 4 | S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 16 weeks | 
| Number and Percentage of Subjects With Positive Immunologic Response in Serum Antibody From Lymphocytes Supernatant (ALS) Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 63 days | 
| Geometric Mean Titer (GMT) of Serum Antibody From Lymphocytes Supernatant (ALS) Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response From Baseline | S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 63 days | 
| Number and Percentage of Subjects With Positive Immunologic Response in Serum Antibody From Lymphocytes Supernatant (ALS) Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 63 days | 
| Geometric Mean Titer (GMT) of Serum Antibody From Lymphocytes Supernatant (ALS) Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response | S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 63 days | 
| Number and Percentage of Subjects With Positive Immunologic Response in Invasion Plasmid Antigens B (IpaB) Lymphocytes Supernatant (ALS) Immunoglobulin A (IgA) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 63 days | 
| Geometric Mean Titer (GMT) of Invasion Plasmid Antigens B (IpaB) Lymphocytes Supernatant (ALS) Immunoglobulin A (IgA) Response | Whole blood samples were collected for determination of ALS (antibody from lymphocytes supernatant). Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 63 days | 
| Number and Percentage of Subjects With Positive Immunologic Response in Invasion Plasmid Antigen D (IpaD) Lymphocytes Supernatant (ALS) Immunoglobulin A (IgA) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 63 days | 
| Geometric Mean Titer (GMT) of Invasion Plasmid Antigen D (IpaD) Lymphocytes Supernatant (ALS) Immunoglobulin A (IgA) Response | Whole blood samples were collected for determination of ALS (antibody from lymphocytes supernatant). Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 63 days | 
| Number and Percentage of Subjects in Cohort 3 With Positive Immunologic Response in Fecal Immunoglobulin A (IgA) Response From Baseline | A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. | 16 weeks | 
| Geometric Mean Titer (GMT) of Fecal Immunoglobulin A (IgA) Response in Cohort 3 | Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values <0.15 were changed to 0.14. | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Shigella, vaccine, shigellosis, dysentery, whole cell