Shigellosis
Conditions
Brief summary
In this challenge study, the bioconjugate candidate vaccine Shigella4V2 will be tested for its ability to induce an immune response that protects healthy adult volunteers from infection with a wild-type Shigella sonnei strain compared to participants receiving placebo.
Detailed description
The tetravalent Shigella4V2 bioconjugate vaccine candidate will be tested for safety and preliminary efficacy in a Phase 2b controlled human infection model (CHIM) study at three sites in the United States. This trial will be conducted as a parallel-group, randomized, double-blind, multicenter, placebo-controlled study to evaluate the safety, immunogenicity, and efficacy of two injections of Shigella4V2 in healthy Shigella naïve participants 18-50 years of age, with the second injection administered one month before challenge with S. sonnei 53G strain. It will have two steps: 1. Step 1, a dose confirmation step, in which a first injection of Shigella4V2 (high dose or low dose, adjuvanted with Alhydrogel) will be administered alongside a placebo arm (phosphate-buffered saline) at a ratio of 2:2:1. A second injection of either Shigella4V2 low dose or placebo will be administered about 6 months after the first injection. 2. Step 2, in which participants will be randomized to the Shigella4V2 dose selected after Step 1 or to placebo at a ratio of 1:1. Participants will receive two injections, 28 days apart. One month after the second injection, they will be challenged with 1500 CFU of the virulent Shigella sonnei strain 53G.
Interventions
BIOLOGICALShigella4V2
Shigella4V2 is a tetravalent bioconjugate vaccine
BIOLOGICALPlacebo
Phosphate-buffered saline
Sponsors
LimmaTech Biologics AG
Emory University
Johns Hopkins Bloomberg School of Public Health
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
Step 1 and Step 2: 1. Age 18-50 years (inclusive). 2. In good health and stable medical condition, determined by MH, laboratory results, and physical examination during screening period. 3. Negative pregnancy test at the time of 1st injection, for participants of childbearing potential. 4. Persons of childbearing potential must agree to avoid pregnancy by use of effective contraception for 30 days prior to 1st injection and throughout the study. Participants assigned female at birth and unable to bear children must have this documented (e.g., tubal ligation or hysterectomy). 5. Willingness to participate in the study after all aspects of the protocol have been explained and written informed consent obtained. 6. Availability for the study duration, including all planned follow-up visits and phone calls. 7. Willingness to refrain from participating in other studies of investigational products until completion of the last study contact. Step 2 only: 8. Demonstrated comprehension of the protocol procedures, knowledge of Shigella- associated illness, and passing score of 70% or better on a comprehension assessment. Maximum two attempts are allowed.
Exclusion criteria
Step 1 and Step 2: 1. Participants currently pregnant, lactating, or intending to become pregnant during the study period as reported by the participant. 2. Presence of a significant medical or psychiatric condition which in the opinion of the investigator precludes participation in the study. 3. Clinically significant abnormalities in vital signs or in screening hematology / blood chemistry as determined by the investigator. 4. Presence in the serum of HIV 1/2 antibody, HBs-Ag, or HCV antibody (if confirmed positive by Hepatitis C confirmatory test, i.e., recombinant immunoblot assay (RIBA), polymerase chain reaction (PCR)). 5. Evidence of current excessive alcohol consumption or drug dependence (e.g. according to medical history). 6. Known or suspected impairment of immunological function (e.g., documented HIV infection, asplenia/splenectomy, or history of autoimmune disease or lymphoproliferative disorder). 7. BMI \< 19 or \> 35 kg/m2. 8. Recent vaccination or planned vaccination within 14 days of 1st study injection for inactivated vaccines and within 30 days for live vaccines. 9. Recent receipt of an investigational product within 30 days preceding the 1st study injection or planned during the entire study period. 10. Recent treatment with immunoglobulins or blood products within 3 months preceding the 1st study injection or planned use during the entire study period. 11. Use of any medication known to affect the immune function (e.g., systemic steroids) within 30 days preceding the 1st study injection or planned use during the entire study period. 12. Symptoms consistent with Traveler's Diarrhea concurrent with travel to countries where Shigella infection is endemic (most of the developing world). 13. Vaccination for or ingestion of Shigella. 14. Use of systemic antibiotics during the 7 days before 1st injection. 15. Serum IgG titers to S. sonnei LPS ≥ 2500. 16. Current occupation involving the handling of Shigella bacteria. 17. History of allergy to components of the study vaccine (Alhydrogel), to placebo (PBS), or to soy, or any other allergy the investigator deems to increase their risk of AEs in the study. 18. Any other criteria which, in the investigator's opinion, would compromise the ability of the participant to participate in the study, the safety of the study, or the results of the study. 19. Part of study personnel or close family member of personnel conducting the study. Step 2 only: 20. Personal history of inflammatory ReA. 21. Positive blood test for HLA-B27 antigen. 22. Personal history of IBS as defined by Rome IV criteria. 23. Regularly abnormal stool pattern (fewer than 3 per week or more than 3 per day). 24. Regular use of laxatives, antacids, or other agents to lower stomach acidity. 25. Known allergy to challenge agent components. 26. Known allergy to ciprofloxacin or trimethoprim-sulfamethoxazole. 27. Evidence of IgA deficiency (serum IgA \< 7 mg/dL or limit of detection of assay). 28. Planning to travel to Shigella endemic countries before completion of the challenge phase of the study. 29. Personal history of inflammatory bowel disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To demonstrate that the Shigella4V2 bioconjugate vaccine protects against shigellosis following challenge with the wild type S. sonnei 53G strain. | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccinees vs. placebo | The number of challenged participants with shigellosis post-challenge during the inpatient period that received vaccine compared to participants who received placebo. Shigellosis is defined as: 1. Severe diarrhea; OR 2. Moderate diarrhea AND \[fever OR ≥ 1 at least moderate constitutional/enteric symptoms OR ≥ 2 episodes of vomiting in 24 h\]; OR 3. Dysentery AND \[fever OR ≥ 1 at least moderate constitutional/enteric symptoms OR ≥ 2 episodes of vomiting in 24 h\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy - Number of participants with blood in stool as confirmed by hemoccult | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccinees vs. placebo | Occurrence of at least one stool with blood as confirmed by hemoccult post-challenge during the inpatient period |
| Safety - Solicited Local and Systemic Adverse Events (AEs) | To be evaluated after injection in vaccinees vs. placebo during the 7-day follow-up period of each injection (day of administration and 6 following days) | Number of participants with solicited AEs, including local and general post-injection |
| The number of challenged participants with shigellosis post-challenge during the inpatient period that responded to Shigella4V2 vaccine compared to participants who received placebo. | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo | Occurrence of shigellosis among the challenged participants that responded from the time of challenge until the end of the inpatient monitoring period |
| Efficacy - Number of participants with moderate-to-severe shigellosis | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Occurrence of moderate-to-severe shigellosis post-challenge during the inpatient period. Moderate-to-severe shigellosis is defined as: 1. Moderate or severe diarrhea AND \[fever OR ≥ 1 severe constitutional/enteric symptoms OR ≥ 3 episodes of vomiting in 24 h\]; OR 2. Dysentery AND \[fever OR ≥ 1 severe constitutional/enteric symptoms OR ≥ 3 episodes of vomiting in 24 h\] |
| Efficacy - Number of participants with diarrhea of any severity | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Occurrence of ≥ 2 loose stools in any 24-hour period post-challenge during the inpatient period |
| Efficacy - Number of participants with severe diarrhea | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Occurrence of ≥ 6 loose stools or more than 800 g of stool in any 24-hour period post-challenge during the inpatient period |
| Efficacy - Number of participants with moderate or severe diarrhea | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Occurrence of ≥ 4 loose stools or ≥ 400 g of stool in any 24-hour period post-challenge during the inpatient period |
| Efficacy - Number of participants with more severe diarrhea | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Occurrence of ≥ 10 loose stools or ≥ 1000 g of stool in any 24-hour period post-challenge during the inpatient period |
| Efficacy - Maximum weight of grade 3-5 stools passed in 24 h per participant | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Maximum weight of loose stools (grade 3-5) passed in any 24-hour period post-challenge during the inpatient period |
| Efficacy - Maximum number of grade 3-5 stools passed in 24 h per participant | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Maximum number of loose stools (grade 3-5) passed in any 24-hour period post-challenge during the inpatient period |
| Efficacy - Number of participants with moderate or severe constitutional enteric symptoms | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Occurrence of moderate or severe constitutional enteric symptoms post-challenge during the inpatient period |
| Efficacy - Number of participants with severe constitutional enteric symptoms | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Occurrence of severe constitutional enteric symptoms post-challenge during the inpatient period |
| Efficacy - Number of participants with fever | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Occurrence of fever post-challenge during the inpatient period |
| Efficacy - Highest recorded temperature | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Highest recorded temperature post-challenge during the inpatient period |
| Efficacy - Time from challenge to onset of diarrhea | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Time (in hours) from challenge to first loose stool that contributes to diarrhea (≥ 2 loose stools in a 24-hour period) |
| Efficacy - Time from challenge to onset of shigellosis | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Time (in hours) from challenge to first event (e.g., first loose stool, first day of fever or moderate symptom, or first episode of vomiting) that contributes to the shigellosis endpoint |
| Efficacy - Duration of diarrhea | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Duration will be calculated as the time (in hours) from the first stool that contributes to diarrhea until the last stool that contributes to diarrhea, occurring post-challenge during the inpatient period, irrespective of intermittent time without loose stools |
| Efficacy - Shigella disease severity score | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Shigella disease severity score (scale from 0 to 9) post-challenge during the inpatient period |
| Efficacy - Number of participants requiring early antibiotic therapy | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Receipt of antibiotic therapy prior to 5 days after challenge |
| Safety - Unsolicited AEs | To be evaluated after injection in vaccinees vs. placebo during the 28-day follow-up period after each injection (day of administration and 27 following days) | Number of participants with unsolicited AEs post-injection |
| Safety - All Solicited and Unsolicited AEs post-injection | To be evaluated after injection in vaccinees vs. placebo during the 28-day follow-up period after each injection (day of administration and 27 following days) | Number of participants with any AEs post-injection |
| Safety - Unsolicited AEs post-challenge | To be evaluated after challenge in vaccinees vs. placebo during the 28-day follow-up period post-challenge (day of challenge and 27 following days) | Number of participants with unsolicited AEs post-challenge |
| Safety - Medically relevant AEs post-injection | To be evaluated in vaccinees vs. placebo from 28 days post each injection until receipt of next injection, challenge, or until their study end | Number of participants with medically relevant AEs post-injection |
| Safety - Medically relevant AEs post-challenge | To be evaluated in vaccinees vs. placebo from 28 days post-challenge (Day 57) until their study end | Number of participants with medically relevant AEs post-challenge |
| Safety - Serious Adverse Events (SAEs) | To be evaluated after injection in vaccinees vs. placebo until their study end | Number of participants with SAEs |
| Safety - AEs leading to withdrawal from the trial | To be evaluated after injection in vaccinees vs. placebo until their study end | Number of participants with AEs leading to withdrawal from the trial |
| Safety - Evaluate changes in hematological and blood chemistry parameters following injection | To be evaluated at 7-days of each post-injection compared to baseline values in vaccinees vs. placebo | Number of participants with hematological and blood chemistry laboratory abnormalities |
| Immunogenicity - Geometric mean titers (GMTs) of anti-S. sonnei LPS IgGs in serum | To be evaluated in vaccinees vs. placebo from Day 1 until study end | Anti-S. sonnei LPS IgG titer in serum collected at V1, V2, V3, V4, V5/a/b, V6, V7 and V8 in Step 1, and at V1, V2, V3, V4, C-1, C8, and V6 in Step 2 |
| Immunogenicity - GMTs of anti-S. flexneri 2a LPS IgGs in serum | To be evaluated in vaccinees vs. placebo from Day 1 until study end | Anti-S. flexneri 2a LPS IgG titer in serum collected at V1, V2, V3, V4, V5/a/b, V6, V7 and V8 in Step 1, and at V1, V2, V3, V4, C-1, C8, and V6 in Step 2 |
| Immunogenicity - GMTs of anti-S. flexneri 3a LPS IgGs in serum | To be evaluated in vaccinees vs. placebo from Day 1 until study end | Anti-S. flexneri 3a LPS IgG titer in serum collected at V1, V2, V3, V4, V5/a/b, V6, V7 and V8 in Step 1, and at V1, V2, V3, V4, C-1, C8, and V6 in Step 2 |
| Immunogenicity - GMTs of anti-S. flexneri 6 LPS IgGs in serum | To be evaluated in vaccinees vs. placebo from Day 1 until study end | Anti-S. flexneri 6 LPS IgG titer in serum collected at V1, V2, V3, V4, V5/a/b, V6, V7 and V8 in Step 1, and at V1, V2, V3, V4, C-1, C8, and V6 in Step 2 |
| Immunogenicity - establish or confirm immunomarker that correlate with a reduced risk of shigellosis | To be evaluated in challenged vaccinees from Day 1 to Day 65 | Association between the primary shigellosis outcome and each of the following: * Serum anti-S. sonnei LPS IgG titer at C-1 (pre-challenge) * Maximum post-vaccination serum anti-S. sonnei LPS IgG titer through C-1 (pre-challenge) * Fold change from V1 (baseline) to C-1 (pre-challenge) in serum anti-S. sonnei LPS IgG titer |
| Immunogenicity - establish or confirm immunomarker that correlate with a reduced risk of moderate-to-severe shigellosis | To be evaluated in challenged vaccinees from Day 1 to Day 65 | Association between moderate-to-severe shigellosis and each of the following: * Serum anti-S. sonnei LPS IgG titer at C-1 (pre-challenge) * Maximum post-vaccination serum anti-S. sonnei LPS IgG titer through C-1 (pre-challenge) * Fold change from V1 (baseline) to C-1 (pre-challenge) in serum anti-S. sonnei LPS IgG titer |
| Efficacy - Number of participants requiring IV fluids | To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccine responders vs. placebo as well as vaccinees vs. placebo | Receipt of IV fluids post-challenge during the inpatient period |
| Immunogenicity - establish or confirm immunomarker that correlate with a reduced risk of solicited events | To be evaluated in challenged vaccinees from Day 1 to Day 65 | Association between the occurrence (any severity) and severity of each solicited event following challenge and each of the following: * Serum anti-S. sonnei LPS IgG titer at C-1 (pre-challenge) * Maximum post-vaccination serum anti-S. sonnei LPS IgG titer through C-1 (pre-challenge) * Fold change from V1 (baseline) to C-1 (pre-challenge) in serum anti-S. sonnei LPS IgG titer |
Countries
United States
Contacts
CONTACTTena Pham
PRINCIPAL_INVESTIGATORKawsar R Talaat, MD
Johns Hopkins Bloomberg School of Public Health
PRINCIPAL_INVESTIGATORPaulina A Rebolledo, MD
Emory University
PRINCIPAL_INVESTIGATORRobert W Frenck, Jr., MD
Children's Hospital Medical Center, Cincinnati
Outcome results
None listed