Shigellosis
Conditions
Brief summary
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.
Interventions
BIOLOGICAL240 µg Shigella flexneri 2a Invaplex 50 vaccine
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.
BIOLOGICAL480 µg Shigella flexneri 2a Invaplex 50 vaccine
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.
BIOLOGICAL690 Shigella flexneri 2a Invaplex 50 vaccine
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.
OTHERShigella challenge strain
300 colony forming units (CFU) of Shigella challenge strain, Shigella flexneri 2a strain 2457T
Sponsors
U.S. Army Office of the Surgeon General
U.S. Army Medical Research and Development Command
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | 7 days after challenge | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 56 days post-vaccination in stage 1 | 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stage 1: Group A, Dolphin 240 µg 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. 230 μL of the formulated vaccine (or placebo, sterile saline) was added to a nasal spray applicator (Dolphin™).
240 µg Shigella flexneri 2a Invaplex 50 vaccine: 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. | 12 |
| Stage 1: Group B, Dolphin 480 µg 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 (Dolphin™).
480 µg Shigella flexneri 2a Invaplex 50 vaccine: 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. | 12 |
| Stage 1: Group C, Dolphin 690 µg 690 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 (Dolphin™).
690 µg Shigella flexneri 2a Invaplex 50 vaccine: 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. | 12 |
| Stage 1: Group D, Pipette 240 µg 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.
240 µg Shigella flexneri 2a Invaplex 50 vaccine: 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. | 8 |
| Stage 2: Dolphin 690 ug (CTC WRAIR Site) 690 ug shigella flexneri 2a Invaplex 50 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.
Some individuals were randomly selected for the challenge phase. Shigella challenge strain: 800 colony forming units (CFU) of Shigella challenge strain, Shigella flexneri 2a strain 2457T | 10 |
| Stage 2: Placebo Group (CTC WRAIR Site) A control was to be administered with the Dolphin™ 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.
Some individuals were randomly selected for the challenge phase. Shigella challenge strain: 800 colony forming units (CFU) of Shigella challenge strain, Shigella flexneri 2a strain 2457T | 7 |
| Stage 2: Dolphin 690 ug (JHU CIR Site) 690 ug shigella flexneri 2a Invaplex 50 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.
Some individuals were randomly selected for the challenge phase. Shigella challenge strain: 800 colony forming units (CFU) of Shigella challenge strain, Shigella flexneri 2a strain 2457T | 31 |
| Stage 2: Placebo Group (JHU CIR Site) A control was to be administered with the Dolphin™ 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.
Some individuals were randomly selected for the challenge phase. Shigella challenge strain: 800 colony forming units (CFU) of Shigella challenge strain, Shigella flexneri 2a strain 2457T | 21 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Change in health status | 0 | 1 | 2 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Non-compliance | 0 | 0 | 0 | 0 | 1 | 2 | 2 | 0 |
| Overall Study | Positive drug test | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Unable to comply with study schedule | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrew for adverse event | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Stage 1: Group A, Dolphin 240 µg | Stage 1: Group B, Dolphin 480 µg | Stage 1: Group C, Dolphin 690 µg | Stage 1: Group D, Pipette 240 µg | Stage 2: Dolphin 690 ug (CTC WRAIR Site) | Stage 2: Placebo Group (CTC WRAIR Site) | Stage 2: Dolphin 690 ug (JHU CIR Site) | Stage 2: Placebo Group (JHU CIR Site) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 38.1 years STANDARD_DEVIATION 7.1 | 39.6 years STANDARD_DEVIATION 4.4 | 30.7 years STANDARD_DEVIATION 7.3 | 29.3 years STANDARD_DEVIATION 7.1 | 35.1 years STANDARD_DEVIATION 10.2 | 34.4 years STANDARD_DEVIATION 10.4 | 32.2 years STANDARD_DEVIATION 8.3 | 31.3 years STANDARD_DEVIATION 8.2 | 33.5 years STANDARD_DEVIATION 7.7 |
| Race/Ethnicity, Customized African-American | 7 Participants | 8 Participants | 9 Participants | 2 Participants | 6 Participants | 6 Participants | 27 Participants | 17 Participants | 82 Participants |
| Race/Ethnicity, Customized Caucasian | 5 Participants | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 21 Participants |
| Race/Ethnicity, Customized Data Missing | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 2 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 7 Participants | 3 Participants | 4 Participants | 2 Participants | 13 Participants | 15 Participants | 54 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 5 Participants | 5 Participants | 6 Participants | 5 Participants | 18 Participants | 6 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 41 | 0 / 28 |
| other Total, other adverse events | 10 / 12 | 11 / 12 | 11 / 12 | 41 / 41 | 28 / 28 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 41 | 1 / 28 |
Outcome results
Primary
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).
Time frame: 7 days after challenge
Population: The decision criteria to progress to challenge with the Shigella challenge strain were no limiting adverse events (AEs) and positive immune response. These individuals were challenged with 800 colony forming units (CFU) of Shigella challenge strain, Shigella flexneri 2a strain 2457T.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 2: Controls | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Moderate diarrhea | 4 participants |
| Stage 2: Controls | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Fever | 4 participants |
| Stage 2: Controls | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Severe diarrhea | 3 participants |
| Stage 2: Controls | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Blood in stools | 4 participants |
| Stage 2: Controls | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Mild diarrhea | 1 participants |
| Stage 2: Immunized | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Blood in stools | 5 participants |
| Stage 2: Immunized | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Mild diarrhea | 0 participants |
| Stage 2: Immunized | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Moderate diarrhea | 4 participants |
| Stage 2: Immunized | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Severe diarrhea | 3 participants |
| Stage 2: Immunized | Post-challenge Diarrhea, Fever, and Blood in Stool Adverse Events by Study Group | Fever | 5 participants |
Secondary
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).
Time frame: 56 days post-vaccination in stage 1
Population: This analysis is limited to groups A-C only and subjects receiving at least 2 doses of S. flexneri 2a Invaplex 50 or LPS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 2: Controls | Number of Subjects Exhibiting an Immune Response to Invaplex 50 and/or LPS | 3 participants |
| Stage 2: Immunized | Number of Subjects Exhibiting an Immune Response to Invaplex 50 and/or LPS | 2 participants |
| Stage 1: Group C, Dolphin 690 µg | Number of Subjects Exhibiting an Immune Response to Invaplex 50 and/or LPS | 7 participants |
Secondary
Post-challenge Loose Stool Sample Durations by Study Group
Time frame: 7 days after challenge
Population: One subject in each group had diarrhea continuing at discharge so measured stool output likely an underestimate.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Stage 2: Controls | Post-challenge Loose Stool Sample Durations by Study Group | Hours to first loose stool | 59.7 hours |
| Stage 2: Controls | Post-challenge Loose Stool Sample Durations by Study Group | Diarrhea duration | 32.3 hours |
| Stage 2: Immunized | Post-challenge Loose Stool Sample Durations by Study Group | Hours to first loose stool | 75.9 hours |
| Stage 2: Immunized | Post-challenge Loose Stool Sample Durations by Study Group | Diarrhea duration | 47.4 hours |
Secondary
Post-challenge Loose Stool Samples Occurrences by Study Group
Time frame: 7 days after challenge
Population: One subject in each group had diarrhea continuing at discharge so measured stool output likely an underestimate.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Stage 2: Controls | Post-challenge Loose Stool Samples Occurrences by Study Group | Number of loose stools | 6.5 loose stools |
| Stage 2: Controls | Post-challenge Loose Stool Samples Occurrences by Study Group | Maximum number in 24 hours period | 4.0 loose stools |
| Stage 2: Immunized | Post-challenge Loose Stool Samples Occurrences by Study Group | Number of loose stools | 8.0 loose stools |
| Stage 2: Immunized | Post-challenge Loose Stool Samples Occurrences by Study Group | Maximum number in 24 hours period | 5.0 loose stools |
Secondary
Post-challenge Loose Stool Sample Volumes by Study Group
Time frame: 7 days after challenge
Population: One subject in each group had diarrhea continuing at discharge so measured stool output likely an underestimate.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Stage 2: Controls | Post-challenge Loose Stool Sample Volumes by Study Group | Total volume | 540.5 mL |
| Stage 2: Controls | Post-challenge Loose Stool Sample Volumes by Study Group | Maximum volume loose stools in 24 hour period | 422.0 mL |
| Stage 2: Immunized | Post-challenge Loose Stool Sample Volumes by Study Group | Total volume | 706.0 mL |
| Stage 2: Immunized | Post-challenge Loose Stool Sample Volumes by Study Group | Maximum volume loose stools in 24 hour period | 492.0 mL |
Secondary
S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group
Time frame: 56 days post-challenge
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Flatulence | 6 participants |
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Nausea | 4 participants |
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Headache | 7 participants |
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Abdominal pain/cramps | 7 participants |
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Lightheadedness | 1 participants |
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Bloating | 3 participants |
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Constipation | 0 participants |
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Malaise | 5 participants |
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Abdominal tenderness | 2 participants |
| Stage 2: Controls | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Vomiting | 2 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Abdominal tenderness | 1 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Nausea | 4 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Vomiting | 2 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Abdominal pain/cramps | 8 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Bloating | 6 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Flatulence | 5 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Headache | 6 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Lightheadedness | 0 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Constipation | 0 participants |
| Stage 2: Immunized | S. Flexneri 2a Related Non-diarrheal Clinical Outcomes by Study Group | Malaise | 5 participants |