Shigella Flexneri 2a Invaplex 50 Vaccine Dose Finding and Assessment of Protection

Study Overview
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Brief Summary
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The purpose of this study is to select a safe and immunogenic dose of Invaplex 50 intranasal vaccine, and to assess protection of Invaplex 50 intranasal vaccine against diarrhea, dysentery, and fever following challenge with the Shigella flexneri 2a 2457T strain.

Official Title
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Shigella Flexneri 2a Invaplex 50 Vaccine Dose Finding and Assessment of Protection

Conditions
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Shigellosis

Intervention / Treatment
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* Biological: 240 µg Shigella flexneri 2a Invaplex 50 vaccine
* Biological: 480 µg Shigella flexneri 2a Invaplex 50 vaccine
* Biological: 690 Shigella flexneri 2a Invaplex 50 vaccine
* Other: Shigella challenge strain


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, adult, 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. Women: negative pregnancy test with understanding (through informed consent process) to not become pregnant during the study or within two (2) months following study completion. Exclusion Criteria: General Health Health problems affecting study participation from medical history specifically to include chronic medical conditions such as psychiatric conditions, diabetes mellitus and hypertension or any other condition requiring chronic daily therapy that would place the volunteer at increased risk - as determined by a study physician, current use of antihypertensive medications, or other medications that may interact with pseudoephedrine in the event it is required to treat rhinorrhea). Clinically significant abnormalities on physical examination. Use of immunosuppressive drugs such as corticosteroids or chemotherapeutics that may influence antibody development. Women currently nursing 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 or anytime throughout the duration of the study. Positive blood test for HBsAG, HCV, HIV-1. Clinically significant abnormalities on basic laboratory screening. Immunosuppressive illness or IgA deficiency (below the normal limits). Research specific Presence of nasal polyps, ulcers, or deviated nasal septum (further defined in section 4.2). History of chronic sinusitis or chronic/seasonal rhinitis (further defined in section 4.2) History of rhinoplasty. History of reactive airway disease (asthma), chronic obstructive pulmonary disease, or chronic bronchitis. History of Bell's palsy. Current smoker or smoker in past 3 months ('smoker' defined as daily cigarette cigar, or pipe use for a period of at least 1 month). Regular use (weekly or more often of antidiarrheal, anti-constipation, or antacid therapy 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. Positive blood test for HLA-B27. Prior exposure to Shigella History of microbiologically confirmed Shigella infection. Received previous experimental Shigella vaccine or live Shigella challenge. Travel to countries where Shigella or other enteric infections are endemic (most of the developing world) within two years prior to dosing. Occupation involving handling of Shigella bacteria currently, or in the past 3 years. Serum IgG titer ≥ 2500 to Shigella LPS Additionally, subjects participating in stage 2 with any of the following will be excluded: Are employed as a food handler, daycare provider or work in a nursing home, or are in direct care of an immunocompromised person, a child <2 years of age or frail elderly. Significant abnormalities in pre-admission screening lab hematology, serum chemistry, urinalysis or EKG (EKG only in volunteers ≥40 years), as determined by PI or the PI in consultation with the medical monitor and sponsor. Allergy to ciprofloxacin on ampicillin (excluded if allergic to either). History of diarrhea in the 2 weeks prior to planned inpatient phase. Use of antibiotics during the 7 days before Shigella inoculation or proton pump inhibitors, H2 blockers, or antacids within 48 hours of inoculation. Inability to comply with inpatient rules and regulations.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: Group A, Dolphin 240 µg<br>240 µg Shigella flexneri 2a Invaplex 50 vaccine. The investigational vaccine was supplied as 1 mL of a sterile, clear liquid in a 3 mL glass vial. Each vial contained 3.5 mg of protein and 567 μg of lipopolysaccharides (LPS). 230 μL of the formulated vaccine (or placebo, sterile saline) was added to a nasal spray applicator (DolphinTM). | Biological: 240 µg Shigella flexneri 2a Invaplex 50 vaccine<br>* Vaccines were administered intranasally on Days 0, 14, and 28. The investigational vaccine was supplied as 1 mL of a sterile, clear liquid in a 3 ml glass vial. Each vial contained 3.5 mg of protein and 567 μg of LPS. The pH was 8.9 and the buffer was 250 mM NaCl in 20 mM Tris.<br>|
| Experimental: Stage 1: Group B, Dolphin 480 µg<br>480 µg Shigella flexneri 2a Invaplex 50 vaccine. The investigational vaccine was supplied as 1 mL of a sterile, clear liquid in a 3 mL glass vial. Each vial contained 3.5 mg of protein and 567 μg of LPS. 230 μL of the formulated vaccine (or placebo, sterile saline) was added to a nasal spray applicator (DolphinTM). | Biological: 480 µg Shigella flexneri 2a Invaplex 50 vaccine<br>* Vaccines were administered intranasally on Days 0, 14, and 28. The investigational vaccine was supplied as 1 mL of a sterile, clear liquid in a 3 ml glass vial. Each vial contained 3.5 mg of protein and 567 μg of LPS. The pH was 8.9 and the buffer was 250 mM NaCl in 20 mM Tris.<br>|
| Experimental: Stage 1: Group C, Dolphin 690 µg<br>690 Shigella flexneri 2a Invaplex 50 vaccine. The investigational vaccine was supplied as 1 mL of a sterile, clear liquid in a 3 mL glass vial. Each vial contained 3.5 mg of protein and 567 μg of LPS. 230 μL of the formulated vaccine (or placebo, sterile saline) was added to a nasal spray applicator (DolphinTM). | Biological: 690 Shigella flexneri 2a Invaplex 50 vaccine<br>* Vaccines were administered intranasally on Days 0, 14, and 28. The investigational vaccine was supplied as 1 mL of a sterile, clear liquid in a 3 ml glass vial. Each vial contained 3.5 mg of protein and 567 μg of LPS. The pH was 8.9 and the buffer was 250 mM NaCl in 20 mM Tris.<br>|
| Other: Stage 1: Group D, Pipette 240 µg<br>240 µg Shigella flexneri 2a Invaplex 50 vaccine. The investigational vaccine was supplied as 1 mL of a sterile, clear liquid in a 3 mL glass vial. Each vial contained 3.5 mg of protein and 567 μg of LPS. These subjects received 200 μL the vaccine via electronic pipette. This group is for lot bridging only, not included in dose-finding study. | Biological: 240 µg Shigella flexneri 2a Invaplex 50 vaccine<br>* Vaccines were administered intranasally on Days 0, 14, and 28. The investigational vaccine was supplied as 1 mL of a sterile, clear liquid in a 3 ml glass vial. Each vial contained 3.5 mg of protein and 567 μg of LPS. The pH was 8.9 and the buffer was 250 mM NaCl in 20 mM Tris.<br>|
| Other: Stage 2: Immunized / Challenge<br>The selected dose was to be administered with the Dolphin™ using the vaccination schedule from stage 1. Immunized and challenged with Shigella challenge strain approximately 42 days after receiving the last vaccination following a 90-minute fast. | Other: Shigella challenge strain<br>* 300 colony forming units (CFU) of Shigella challenge strain, Shigella flexneri 2a strain 2457T<br>* Other names: Shigella challenge material;|
| Placebo Comparator: Stage 2: Controls<br>A control was to be administered with the DolphinTM using the vaccination schedule from Stage 1. Non-immunized and challenged with Shigella challenge strain approximately 42 days after receiving the last vaccination following a 90-minute fast. | Other: Shigella challenge strain<br>* 300 colony forming units (CFU) of Shigella challenge strain, Shigella flexneri 2a strain 2457T<br>* Other names: Shigella challenge material;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Fecal samples were collected through day 77 or until discharge (all stools collected for weighing/grading; maximum of 3 stools/day for culture; rectal swab obtained if no stool provided). | 7 days after challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-challenge Loose Stool Samples Occurrences by Study Group |  | 7 days after challenge | 
| Post-challenge Loose Stool Sample Volumes by Study Group |  | 7 days after challenge | 
| Post-challenge Loose Stool Sample Durations by Study Group |  | 7 days after challenge | 
| S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group |  | 56 days post-challenge | 
| Number of Subjects Exhibiting an Immune Response to Invaplex 50 and/or LPS | Immune responder is defined as someone with both a serologic and an ASC response to either Invaplex 50 or LPS. Immune response defined as Serology: ≥ 4-fold increase in baseline serum titer antibody cecreting cells (ASC): ≥ 10 ASC per 106 peripheral blood mononuclear cells(PBMC). | 56 days post-vaccination in stage 1 |