A Human Challenge Study to Assess Protection of a Shigella Tetravalent Bioconjugate Vaccine

Phase 2

Recruiting

• Conditions: Shigellosis
• Interventions: Biological: Shigella4V2; Biological: Placebo

• Registration Number: NCT06615375
• Lead Sponsor: LimmaTech Biologics AG

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.

Study Timeline

• Study First Submitted: 2024-09-20
• Study First Submitted QC: 2024-09-24
• Study First Posted: 2024-09-26
• Study Start: 2024-11-12
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-08
• Last Update Posted: 2025-05-13
• Primary Completion: 2026-02
• Study Completion: 2026-07

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Shigella4V2 High dose	Shigella4V2	1 injection of high dose Shigella4V2 and 1 injection of low dose Shigella4V2 will be injected intramuscularly in the deltoid muscle
Shigella4V2 Low dose	Shigella4V2	2 injections of low dose of Shigella4V2 will be injected intramuscularly in the deltoid muscle
Placebo	Placebo	2 injections of PBS will be injected intramuscularly in the deltoid muscle

Primary Outcome Measures

Name	Time	Method
To demonstrate that the Shigella4V2 bioconjugate vaccine protects vaccine responders 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 vaccine responders vs. placebo	The number of challenged participants with shigellosis post-challenge during the inpatient period that responded to Shigella4V2 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 Outcome Measures

Name	Time	Method
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
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
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
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
The number of challenged participants with shigellosis post-challenge during the inpatient period that received vaccine compared to participants who received placebo.	To be evaluated post-challenge during the inpatient period (Day 56 through Day 65) in vaccinees vs. placebo	Occurrence of shigellosis among the challenged participants from the time of challenge until the end of the inpatient monitoring period.
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
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
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
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

Trial Locations

Locations (3)

Johns Hopkins Center for Immunization Research; 🇺🇸 Baltimore, Maryland, United States

Hope Clinic of Emory University; 🇺🇸 Atlanta, Georgia, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States