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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 one dose of Shigella4V2 in healthy Shigella naïve participants 18-50 years of age, administered one month before challenge with S. sonnei 53G strain. It will have two steps:

1. Step 1, a dose selection step, in which participants will receive either one of two doses of Shigella4V2 (high dose or low dose, adjuvanted with Alhydrogel) or placebo (phosphate-buffered saline) at a ratio of 2:2:1, to find the optimal immunogenic dose for Step 2; and

2. Step 2, in which participants will be randomized to either the Shigella4V2 dose selected in Step 1 or to placebo at a ratio of 1:1. One month after injection, they will be challenged with 1500 CFU of the virulent Shigella sonnei strain 53G. In order to assess the ability of Shigella4V2 to protect against infection with this strain, the attack rate of shigellosis in the group vaccinated with Shigella4V2 will be compared to the group of the participants who received placebo injections.

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
120
Inclusion Criteria

Step 1 & 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 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 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.

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Exclusion Criteria

Step 1 & 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 study injection for inactivated vaccines and within 30 days for live vaccines.

  9. Recent receipt of an investigational product within 30 days preceding the study injection or planned during the entire study period.

  10. Recent treatment with immunoglobulins or blood products within 3 months preceding the 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 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 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.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Shigella4V2 High doseShigella4V21 high dose of Shigella4V2 will be injected intramuscularly in the deltoid muscle
Shigella4V2 Low doseShigella4V21 low dose of Shigella4V2 will be injected intramuscularly in the deltoid muscle
PlaceboPlacebo1 dose of PBS will be injected intramuscularly in the deltoid muscle
Primary Outcome Measures
NameTimeMethod
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 29 through Day 37) 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 Outcome Measures
NameTimeMethod
Efficacy - Number of participants with moderate-to-severe shigellosisTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 severityTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 diarrheaTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 diarrheaTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 diarrheaTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 participantTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 participantTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 symptomsTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 symptomsTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in vaccinees vs. placebo

Occurrence of severe constitutional enteric symptoms post-challenge during the inpatient period

Efficacy - Number of participants with feverTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in vaccinees vs. placebo

Occurrence of fever post-challenge during the inpatient period

Efficacy - Highest recorded temperatureTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in vaccinees vs. placebo

Highest recorded temperature post-challenge during the inpatient period

Efficacy - Time from challenge to onset of diarrheaTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 shigellosisTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 diarrheaTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 scoreTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in 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 therapyTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in vaccinees vs. placebo

Receipt of antibiotic therapy prior to 5 days after challenge

Efficacy - Number of participants requiring IV fluidsTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) in vaccinees vs. placebo

Receipt of IV fluids post-challenge during the inpatient period

Efficacy - Number of participants with blood in stool as confirmed by hemoccultTo be evaluated post-challenge during the inpatient period (Day 29 through Day 37) 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 post-injection (day of administration and 6 following days)

Number of participants with solicited AEs, including local and general post-injection

Safety - Unsolicited AEsTo be evaluated after injection in vaccinees vs. placebo during the 28-day follow-up period post-injection (day of administration and 27 following days)

Number of participants with unsolicited AEs post-injection

Safety - All Solicited and Unsolicited AEs post-injectionTo be evaluated after injection in vaccinees vs. placebo during the 28-day follow-up period post-injection (day of administration and 27 following days)

Number of participants with any AEs post-injection

Safety - Unsolicited AEs post-challengeTo 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 AEsTo be evaluated in vaccinees vs. placebo from 28 days post-injection (Day 29) or post-challenge (Day 57) until study end

Number of participants with medically relevant AEs

Safety - Serious Adverse Events (SAEs)To be evaluated after injection in vaccinees vs. placebo until study end

Number of participants with SAEs

Safety - AEs leading to withdrawal from the trialTo be evaluated after injection in vaccinees vs. placebo until study end

Number of participants with AEs leading to withdrawal from the trial

Safety - Evaluate changes in hematological and blood chemistry parameters following injectionTo be evaluated at 7-days 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 serumTo 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 and V5 in Step 1, and at V1, V2, C-1, C8, and V4 in Step 2

Immunogenicity - GMTs of anti-S. flexneri 2a LPS IgGs in serumTo 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 and V5 in Step 1, and at V1, V2, C-1, C8, and V4 in Step 2

Immunogenicity - GMTs of anti-S. flexneri 3a LPS IgGs in serumTo 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 and V5 in Step 1, and at V1, V2, C-1, C8, and V4 in Step 2

Immunogenicity - GMTs of anti-S. flexneri 6 LPS IgGs in serumTo 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 and V5 in Step 1, and at V1, V2, C-1, C8, and V4 in Step 2

Immunogenicity - establish or confirm immunomarker that correlate with a reduced risk of shigellosisTo be evaluated in challenged vaccinees from Day 1 to Day 37

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 shigellosisTo be evaluated in challenged vaccinees from Day 1 to Day 37

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 eventsTo be evaluated in challenged vaccinees from Day 1 to Day 37

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 (1)

Hope Clinic of Emory University

🇺🇸

Atlanta, Georgia, United States

Related News

valneva.com
·

Valneva and LimmaTech Announce First Vaccination in Phase 2b Human Challenge Study ...

Valneva SE and LimmaTech Biologics AG initiated a Phase 2b controlled human infection model (CHIM) study for Shigella4V2 (S4V2), a tetravalent bioconjugate shigellosis vaccine candidate. The study aims to test S4V2's safety and efficacy in 120 healthy participants aged 18-50 in the U.S. The FDA granted Fast Track designation to S4V2, recognizing its potential to address a serious condition and fill an unmet medical need.
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