Shigella
Conditions
Brief summary
The purpose of this study is to determine whether SF2a-TT15 (a monovalent synthetic carbohydrate-based conjugate Shigella vaccine) is safe and effective in the prevention of Shigella infection.
Detailed description
The purpose of this study is to determine whether SF2a-TT15 (a monovalent synthetic carbohydrate-based conjugate Shigella vaccine) is safe and effective in the prevention of Shigella infection. This will be a phase 2b, double-blind, placebo-controlled, single-center study, involving a vaccination phase and a challenge phase. The vaccination phase will consist of study participants that will be 1:1 randomized to receive either the vaccine or placebo. Two doses of blinded study product will be given by intramuscular route of administration, separated by approximately 4 weeks. The challenge phase will consist of an inpatient stay of approximately 12 days during which eligible study participants will ingest an oral inoculum of wild-type S flexneri 2a strain 2457T and then be monitored for illness and treated with antibiotics when the primary endpoint is reached or upon 5 days post-challenge, whichever comes first, or when deemed necessary. Upon satisfying discharge criteria, study participants will complete outpatient clinic follow-up visits through \ 7 months after last dose of blinded study product (Day 237). The efficacy study will be enrolled through three cohorts of participants, each cohort consisting of approximately 30 subjects that will be involved in the vaccination phase and 22 subjects that will proceed with the challenge phase. There will be a fourth cohort of participants, consisting of 12 subjects, that will receive the vaccine in an open-label design-this cohort will provide serum samples which are intended to be used for generating serum standards for laboratory assays, as a part of ongoing and future clinical development of Shigella vaccines.
Interventions
BIOLOGICALSF2a-TT15 Shigella Vaccine
0.5 mL of the vaccine is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29.
OTHERPlacebo
0.5 mL of normal saline is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29.
BIOLOGICALS. flexneri 2a strain 2457T Challenge Agent
Each participant will drink 120 mL of sodium bicarbonate buffer solution. Approximately 1 to 2 minutes later, the participant will ingest approximately 1500 cfu of S. flexneri 2a strain 2457T suspended in 30 mL of the bicarbonate buffer solution.
Sponsors
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female of age 18-45 years * Provides written informed consent * Healthy, based on history, exam, and medications * Documented acceptable screening laboratory work, including: WBC, ANC, Hg, Platelets Creatinine, ALT, Bili Serum IgA HIV, HBsAg, HCV Negative for HLA-B27 (this criterion does not apply to cohort 4) Stool culture urinalysis * Passing score on Comprehension Assessment Tool (greater than or equal to 70 percent correct answers) * Agrees not to participate in another interventional clinical trial during the study period * For females of child-bearing potential, must agree to acceptable birth control, 4 weeks before enrollment and through 4 weeks after last vaccination or challenge * Available for a 12-day inpatient stay (this criterion does not apply to cohort 4)
Exclusion criteria
* Positive pregnancy test at screening or within 24 hours of study product dosing * Poor venous access, as defined by inability to obtain venous blood after 3 venipuncture attempts (this criterion does not apply to cohort 4) * Abnormal vital signs, defined as: Systolic BP greater than 150 mmHg or Diastolic BP greater than 90 mmHg Resting heart rate greater than 100 Oral temperature greater than or equal to 100.4 degrees F * Persons with IgA deficiency (serum IgA less than 70 mg per dL * Serum S. flexneri 2a LPS igG titer greater than or equal to 2500 * Received prior vaccines or had prior infection (natural or challenge) with ETEC or Shigella, within 5 years prior to enrollment * Symptoms of Traveler's diarrhea associated with travel to countries where Shigella or other enteric infections are endemic (most of the developing world) within 3 years prior to enrollment * History of chronic gastrointestinal illness, including sever dyspepsia, lactose intolerance, or other significant gastrointestinal tract disease * Use of antimicrobials within 2 weeks of each dose of vaccine or the challenge * Regular use (greater than or equal to weekly) of laxatives, anti-diarrheal agents, anti-constipation agents, or antacid therapies * History of major gastrointestinal surgery (uncomplicated laparoscopic appendectomy or cholecystectomy greater than 1 year prior is permitted) * Abnormal bowel pattern, defined by less than 3 stools per week or greater than 2 stools per day in the past 6 months * Use of oral, parenteral or high-dose inhaled steroids within 30 days of each dose of vaccine or the challenge * Use of any medication which might affect immune function within 30 days of each dose of vaccine or the challenge * Current medical condition which requires daily or weekly prescribed medications for control (as medication use is limited during the inpatient stay), may be an exclusion criterion if in the judgement of the investigator the potential for missed doses could represent a significant risk to the subject's health * History of reactive arthritis * Diagnosis of schizophrenia or other major psychiatric disease * History of seizure disorder within the last 5 years * History of alcohol or drug abuse within the last 5 years * Presence of immunosuppression * Known significant allergy (i.e., anaphylaxis) to ciprofloxacin, trimethoprim-sulfamethoxazole (Bactrim), or a tetanus-containing vaccine * 12-lead electrocardiogram with pathologic abnormalities (this criterion does not apply to cohort 4) * Occupation in food handling industry, living with, or care of very young children (less than 5 years old), elderly (greater than 65 years), or immunocompromised (this criterion does not apply to cohort 4) * Having any known legal obligations, court appearances, professional meetings, vacations, planned events, or other reasons which might interfere with a person's availability for a 12-day inpatient stay. (this criterion does no apply to cohort 4) * Any other criteria which, in the investigator's opinion, would compromise the safety of the study, the ability of a subject to participate, or the results of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Moderate-Severe Shigellosis Illness, With Challenge | 10 days after challenge | Count of participants with primary endpoint (Moderate-Severe Shigellosis) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Meeting Other Case Definitions and Endpoint Definitions | 10 days after challenge | — |
| Number of Participants With Anti-LPS Serum IgG ELISA Response | Days 29, 57 and 85 | Anti-LPS serum IgG ELISA response, by response rates (proportion of 4-fold increases from baseline, Day 1) |
| Anti-LPS Serum IgG ELISA Response, by Titer | Days 1, 29, 57 and 85 | — |
| Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Days 29, 57 and 85 | — |
| Serum Bactericidal Activity Response, by Titer | Days 1, 29, 57 and 85 | — |
Countries
United States
Participant flow
Pre-assignment details
Cohort 4 was eliminated prior to the start of Cohort 4 enrollment. Cohorts 1-3 are pooled and reported by vaccine vs. placebo recipients.
Participants by arm
| Arm | Count |
|---|---|
| Vaccine 1:1 randomization to investigational Shigella vaccine or placebo (n=30). The majority of participants will then receive the Shigella challenge (n=22).
SF2a-TT15 Shigella Vaccine: 0.5 mL of the vaccine is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29. | 29 |
| Placebo 1:1 randomization to investigational Shigella vaccine or placebo (n=30). The majority of participants will then receive the Shigella challenge (n=22).
Placebo: 0.5 mL of normal saline is administered via an intramuscular injection into the deltoid muscle on Study Day 1 and Study Day 29. | 29 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Vaccination Phase | Withdrawal prior to challenge | 2 | 3 |
Baseline characteristics
| Characteristic | Vaccine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 29 Participants | 58 Participants |
| Age, Continuous | 32 years | 32 years | 32 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 27 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) White | 20 Participants | 20 Participants | 40 Participants |
| Region of Enrollment United States | 29 participants | 29 participants | 58 participants |
| Sex: Female, Male Female | 15 Participants | 10 Participants | 25 Participants |
| Sex: Female, Male Male | 14 Participants | 19 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 29 | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 18 / 29 | 21 / 29 | 0 / 22 | 0 / 22 |
| serious Total, serious adverse events | 0 / 29 | 0 / 29 | 0 / 22 | 0 / 22 |
Outcome results
Primary
Number of Participants With Moderate-Severe Shigellosis Illness, With Challenge
Count of participants with primary endpoint (Moderate-Severe Shigellosis)
Time frame: 10 days after challenge
Population: All participants that were randomized to vaccine or placebo and were challenged
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Shigella Vaccine | Number of Participants With Moderate-Severe Shigellosis Illness, With Challenge | 14 Participants |
| Placebo | Number of Participants With Moderate-Severe Shigellosis Illness, With Challenge | 17 Participants |
Secondary
Anti-LPS Serum IgG ELISA Response, by Titer
Time frame: Days 1, 29, 57 and 85
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Shigella Vaccine | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-dose 1 (Day 29) | 17441.38 titer | Standard Deviation 21018.59 |
| Shigella Vaccine | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-challenge (Day 85) | 18755.56 titer | Standard Deviation 14338.9 |
| Shigella Vaccine | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD pre-vaccination (Day 1) | 1020.69 titer | Standard Deviation 1143.11 |
| Shigella Vaccine | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-dose 2 (Day 57) | 15318.52 titer | Standard Deviation 13574.1 |
| Placebo | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD pre-vaccination (Day 1) | 662.07 titer | Standard Deviation 638.87 |
| Placebo | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-challenge (Day 85) | 5850 titer | Standard Deviation 6204.14 |
| Placebo | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-dose 1 (Day 29) | 965.52 titer | Standard Deviation 1549.03 |
| Placebo | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-dose 2 (Day 57) | 965.38 titer | Standard Deviation 1285.91 |
| Vaccine Challenged | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD pre-vaccination (Day 1) | 800 titer | Standard Deviation 489.9 |
| Vaccine Challenged | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-challenge (Day 85) | 21345.45 titer | Standard Deviation 14537.76 |
| Vaccine Challenged | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-dose 2 (Day 57) | 16327.27 titer | Standard Deviation 14392.93 |
| Vaccine Challenged | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-dose 1 (Day 29) | 18190.91 titer | Standard Deviation 22253.3 |
| Placebo Challenged | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-challenge (Day 85) | 6940 titer | Standard Deviation 6251.27 |
| Placebo Challenged | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-dose 1 (Day 29) | 1172.73 titer | Standard Deviation 1734.02 |
| Placebo Challenged | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD post-dose 2 (Day 57) | 1081.82 titer | Standard Deviation 1368.57 |
| Placebo Challenged | Anti-LPS Serum IgG ELISA Response, by Titer | Mean ±SD pre-vaccination (Day 1) | 772.73 titer | Standard Deviation 696.37 |
Secondary
Number of Participants Meeting Other Case Definitions and Endpoint Definitions
Time frame: 10 days after challenge
Population: Participants randomized to vaccine or placebo and were challenged
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Shigella Vaccine | Number of Participants Meeting Other Case Definitions and Endpoint Definitions | Count of participants with any diarrhea endpoint | 15 Participants |
| Shigella Vaccine | Number of Participants Meeting Other Case Definitions and Endpoint Definitions | Count of participants with any dysentery endpoint | 4 Participants |
| Shigella Vaccine | Number of Participants Meeting Other Case Definitions and Endpoint Definitions | Count of participants with any fever endpoint | 12 Participants |
| Shigella Vaccine | Number of Participants Meeting Other Case Definitions and Endpoint Definitions | Count of participants with any combination of diarrhea, dysentery, and/or fever | 16 Participants |
| Placebo | Number of Participants Meeting Other Case Definitions and Endpoint Definitions | Count of participants with any combination of diarrhea, dysentery, and/or fever | 19 Participants |
| Placebo | Number of Participants Meeting Other Case Definitions and Endpoint Definitions | Count of participants with any diarrhea endpoint | 18 Participants |
| Placebo | Number of Participants Meeting Other Case Definitions and Endpoint Definitions | Count of participants with any fever endpoint | 15 Participants |
| Placebo | Number of Participants Meeting Other Case Definitions and Endpoint Definitions | Count of participants with any dysentery endpoint | 12 Participants |
Secondary
Number of Participants With Anti-LPS Serum IgG ELISA Response
Anti-LPS serum IgG ELISA response, by response rates (proportion of 4-fold increases from baseline, Day 1)
Time frame: Days 29, 57 and 85
Population: Enrolled participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Shigella Vaccine | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-dose 1 (Day 29) | 27 Participants |
| Shigella Vaccine | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-challenge (Day 85) | 26 Participants |
| Shigella Vaccine | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-dose 2 (Day 57) | 26 Participants |
| Placebo | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-dose 1 (Day 29) | 1 Participants |
| Placebo | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-challenge (Day 85) | 17 Participants |
| Placebo | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-dose 2 (Day 57) | 1 Participants |
| Vaccine Challenged | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-dose 2 (Day 57) | 21 Participants |
| Vaccine Challenged | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-dose 1 (Day 29) | 20 Participants |
| Vaccine Challenged | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-challenge (Day 85) | 22 Participants |
| Placebo Challenged | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-dose 1 (Day 29) | 1 Participants |
| Placebo Challenged | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-challenge (Day 85) | 17 Participants |
| Placebo Challenged | Number of Participants With Anti-LPS Serum IgG ELISA Response | Count of participants with serum IgG ELISA response rates, post-dose 2 (Day 57) | 1 Participants |
Secondary
Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1)
Time frame: Days 29, 57 and 85
Population: Enrolled participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Shigella Vaccine | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-dose 1 (Day 29) | 21 Participants |
| Shigella Vaccine | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-challenge (Day 85) | 23 Participants |
| Shigella Vaccine | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-dose 2 (Day 57) | 22 Participants |
| Placebo | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-dose 1 (Day 29) | 2 Participants |
| Placebo | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-challenge (Day 85) | 12 Participants |
| Placebo | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-dose 2 (Day 57) | 1 Participants |
| Vaccine Challenged | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-dose 2 (Day 57) | 17 Participants |
| Vaccine Challenged | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-dose 1 (Day 29) | 17 Participants |
| Vaccine Challenged | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-challenge (Day 85) | 19 Participants |
| Placebo Challenged | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-dose 1 (Day 29) | 2 Participants |
| Placebo Challenged | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-challenge (Day 85) | 12 Participants |
| Placebo Challenged | Serum Bactericidal Activity Response, by Response Rates (Proportion of 4-fold Increases From Baseline, Day 1) | Count post-dose 2 (Day 57) | 1 Participants |
Secondary
Serum Bactericidal Activity Response, by Titer
Time frame: Days 1, 29, 57 and 85
Population: Enrolled participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Shigella Vaccine | Serum Bactericidal Activity Response, by Titer | Mean ±SD pre-vaccination (Day 1) | 1131.48 titer | Standard Deviation 2542.76 |
| Shigella Vaccine | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-dose 1 (Day 29) | 11973.15 titer | Standard Deviation 38813.69 |
| Shigella Vaccine | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-dose 2 (Day 57) | 8553.7 titer | Standard Deviation 19417.73 |
| Shigella Vaccine | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-challenge (Day 85) | 8479.63 titer | Standard Deviation 19301.06 |
| Placebo | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-challenge (Day 85) | 2345.83 titer | Standard Deviation 3228.33 |
| Placebo | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-dose 2 (Day 57) | 745.19 titer | Standard Deviation 1723.18 |
| Placebo | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-dose 1 (Day 29) | 1856.73 titer | Standard Deviation 5465.05 |
| Placebo | Serum Bactericidal Activity Response, by Titer | Mean ±SD pre-vaccination (Day 1) | 399.04 titer | Standard Deviation 723.1 |
| Vaccine Challenged | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-dose 2 (Day 57) | 9147.73 titer | Standard Deviation 21379.99 |
| Vaccine Challenged | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-challenge (Day 85) | 9420.45 titer | Standard Deviation 21232.07 |
| Vaccine Challenged | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-dose 1 (Day 29) | 13729.55 titer | Standard Deviation 42920.28 |
| Vaccine Challenged | Serum Bactericidal Activity Response, by Titer | Mean ±SD pre-vaccination (Day 1) | 1229.55 titer | Standard Deviation 2752.74 |
| Placebo Challenged | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-dose 1 (Day 29) | 2006.82 titer | Standard Deviation 5923.36 |
| Placebo Challenged | Serum Bactericidal Activity Response, by Titer | Mean ±SD pre-vaccination (Day 1) | 279.55 titer | Standard Deviation 466.6 |
| Placebo Challenged | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-challenge (Day 85) | 2448.75 titer | Standard Deviation 3326.45 |
| Placebo Challenged | Serum Bactericidal Activity Response, by Titer | Mean ±SD post-dose 2 (Day 57) | 547.73 titer | Standard Deviation 1388.06 |