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InvaplexAR-Detox and dmLT Adjuvant in the Netherlands and Zambia (SUNSHINE)

Primary Purpose

Shigellosis, Bacillary Dysentery

Status
Not yet recruiting
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
2.5 μg InvaplexAR-Detox
10 μg InvaplexAR-Detox
0.1 μg of dmLT
Placebo
Sponsored by
Leiden University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Shigellosis focused on measuring Vaccine, Invaplex, dmLT, Shigella

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Healthy adult, male or female, aged 18 to 50 years (inclusive) at the time of inclusion (=vaccination). Provide written informed consent before initiation of any study procedures. Available to complete all study visits and procedures. Negative stool PCR test for Shigella. Women of childbearing potential: negative pregnancy test at screening and before each study vaccine administration. Women are considered not of childbearing potential if they are postmenopausal (no menses for 12 months without an alternative medical cause), or if they have no uterus or no ovaries. Women of childbearing potential must agree to use continuous adequate contraception to avoid pregnancy during the study, for at least 4 weeks before the first vaccination and for 3 months following the last vaccine dose. Adequate methods of contraception for this study include: hormonal contraception combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal) progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable) intrauterine device (IUD) intrauterine hormone-releasing system (IUS) bilateral tubal occlusion/litigation procedure vasectomized partner (the vasectomized partner should be the sole male sexual partner for that participant). sexual abstinence (defined as refraining from heterosexual intercourse from signing the informed consent until 3 months after the last vaccine dose). Exclusion Criteria: Chronic medical conditions such as psychiatric conditions, diabetes mellitus, hypertension (treated by medication), autoimmune disorders, cardiovascular, renal disease or inflammatory bowel disease. Use of immunosuppressive medications or immunosuppressive illness, including a history of immunoglobulin A (IgA) deficiency. Antihistamines and corticosteroids for topical use or inhalation are no exclusion criteria. Women who are pregnant or planning to become pregnant during the study period plus 3 months beyond the last vaccine dose and currently nursing women. Participation in research involving another investigational product (defined as receipt of an investigational product or exposure to an invasive investigational device) 30 days before the first vaccination or anytime through the last in-clinic study safety visit. Positive blood test for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Clinically significant abnormalities on basic laboratory screening tests. Systemic antimicrobial treatment (i.e., topical treatments are not an exclusion criterion) within 1 week before the first vaccine dose (temporary exclusion). Known hypersensitivity to compounds in the vaccine or adjuvant or other known drug allergies that may increase the risk of adverse events. 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 inflammatory arthritis. Proven allergy to any substance in the InvaplexAR-Detox vaccine or dmLT or history of anaphylactic reaction to any other vaccine. Exclusionary skin disease history/findings that would confound assessment or prevent appropriate local monitoring of AEs, or possibly increase the risk of local AEs. Recent (<3 moths) history of gastroenteritis. Received previous licensed or experimental Shigella vaccine, dmLT or live Shigella challenge. Any severe medical condition that might place the participant at increased risk of adverse events according to the clinical judgment of the study clinicians in consultation with the PI. Any planned vaccination within 14 days before the start of the trial until the end of the trial, with the exception of SARS-CoV-2 vaccines or influenza vaccines.

Sites / Locations

  • Leiden University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

A1 - Low dose vaccine (Netherlands)

A2 - Low dose vaccine + adjuvant (Netherlands)

B1/C1 - High dose vaccine (Netherlands & Zambia)

B2/C2 - High dose vaccine + adjuvant (Netherlands & Zambia)

A3/B3/C3 - Placebo (Netherlands & Zambia)

Arm Description

10 Dutch participants who receive three 2.5 μg doses of the vaccine without adjuvant at a 28-day interval in Cohort A.

10 Dutch participants who receive three 2.5 μg dose of the vaccine with 0.1 μg of adjuvant at a 28-day interval in Cohort A.

10 Dutch participants who receive three 10 μg vaccine doses without adjuvant at a 28-day interval in Cohort B and 15 Zambian participants who receive three 10 μg vaccine doses without adjuvant at a 28-day interval in Cohort C.

10 Dutch participants that receive three 10 μg vaccine doses with 0.1 μg of adjuvant at a 28-day interval in Cohort B and 15 Zambian participants that receive three 10 μg vaccine doses with 0.1 μg of adjuvant at a 28-day interval in Cohort C.

5 Dutch participants who receive three placebo vaccinations at a 28-day interval in Cohort A, another 5 Dutch participants who receive three placebo vaccinations at a 28-day interval in Cohort B and 5 Zambian participants who receive three placebo vaccinations at a 28-day interval in Cohort C.

Outcomes

Primary Outcome Measures

Occurence of solicited adverse events
Occurrence of solicited adverse events considered to be (possibly, probably or definitely) related to vaccination according to the International Classification of Diseases version 11 (ICD-11) compared to the placebo group. Local solicited adverse events include pain/tenderness, erythema, induration/swelling, pruritus, and ipsilateral axillary lymphadenopathy. Systemic solicited adverse events include fever, chills, headache, fatigue, malaise, nausea/vomiting, painful/swollen joints, myalgia, diarrhea, and abdominal pain. Only symptoms with an onset after a vaccination until the 7th subsequent day after that vaccination will be considered solicited.
Occurence of unsolicited adverse events
Occurrence of unsolicited adverse events considered to be (possibly, probably or definitely) related to vaccination, according to the ICD-11 classification.

Secondary Outcome Measures

Geometric mean titers of serum immunoglobulin A antibodies to Invaplex antigens
Serum GMTs of anti-LPS, anti-IpaB and anti-IpaC IgA
Geometric mean titers of serum immunoglobulin G antibodies to Invaplex antigens
Serum GMTs of anti-LPS, anti-IpaB and anti-IpaC IgG
Proportion of participants with immunoglobulin A seroconversion (> 4-fold rise in titer over baseline)
Percentage of participants wit a ≥ 4-fold increase in serum anti-LPS, anti-IpaB and anti-IpaC IgA titer from baseline
Proportion of participants with immunoglobulin G seroconversion (> 4-fold rise in titer over baseline)
Percentage of participants wit a ≥ 4-fold increase in serum anti-LPS, anti-IpaB and anti-IpaC IgG titer from baseline
Serum bactericidal assay response to S. flexneri 2a, strain 2457T in geometric mean titers
Proportion of participants with serum bactericidal assay responses (≥ 4-fold rise over baseline) to S. flexneri 2a, strain 2457T
Geometric mean titers of α4β7 antibodies in lymphocyte supernatant.
B cell memory responses to Invaplex antigens
B cell memory responses to the LPS and IpaB and IpaC antigens.
T cell memory responses to Invaplex antigens
T cell memory responses to the LPS and IpaB and IpaC antigens.

Full Information

First Posted
July 5, 2023
Last Updated
October 16, 2023
Sponsor
Leiden University Medical Center
Collaborators
Centre for Infectious Disease Research in Zambia, PATH, Walter Reed Army Institute of Research (WRAIR), Göteborg University, European Vaccine Initiative, European and Developing Countries Clinical Trials Partnership (EDCTP)
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1. Study Identification

Unique Protocol Identification Number
NCT05961059
Brief Title
InvaplexAR-Detox and dmLT Adjuvant in the Netherlands and Zambia
Acronym
SUNSHINE
Official Title
Phase Ia/b Double-blind, Placebo-controlled, Dose Escalating Safety Study of Detoxified Shigella Flexneri 2a Artificial Invasin Complex (InvaplexAR-Detox) Vaccine Formulated With and Without dmLT Adjuvant Given Intramuscularly to Healthy Adults in the Netherlands and Zambia
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
November 2023 (Anticipated)
Primary Completion Date
October 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Leiden University Medical Center
Collaborators
Centre for Infectious Disease Research in Zambia, PATH, Walter Reed Army Institute of Research (WRAIR), Göteborg University, European Vaccine Initiative, European and Developing Countries Clinical Trials Partnership (EDCTP)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this clinical trial is to test a new Shigella vaccine (InvaplexAR-DETOX) in combination with a new adjuvant (dmLT) in healthy participants. The main questions it aims to answer are: Is the new Shigella vaccine (with and without the new adjuvant) safe and well tolerated? How wel does the new Shigella vaccine stimulate the immune system in combination with the new adjuvant, and without the new adjuvant? Participants will receive three vaccinations at 28-day intervals. Researchers will compare the results of participants vaccinated with the vaccine in combination with the adjuvant to the results of participants vaccinated with the vaccine only and to the results of participants vaccinated with a placebo (fake vaccine).
Detailed Description
Rationale: Shigella remains endemic in many places and occurs in epidemics that cause considerable morbidity and mortality. Vaccines are an attractive and potentially highly cost-effective tool for the prevention of shigellosis and can fill current gaps in effective prevention strategies. A challenge to effective Shigella vaccine development has been the reduced immunogenicity and protective efficacy of candidate Shigella vaccines in infants and children less than 3 years of age. The potential impact of including an adjuvant in candidate parenteral Shigella vaccine formulations needs to be evaluated. InvaplexAR-Detox is an injectable Shigella vaccine that uses a novel combination of conserved invasion plasmid antigen proteins with a serotype-specific bacterial lipopolysaccharide attenuated for safe intramuscular administration. The adjuvant dmLT has been shown to significantly enhance Shigella immune responses in mice and has safely been administered intramuscularly in healthy volunteers in combination with other antigens in phase I trials. Objective: to evaluate the safety and immunogenicity of two strength formulations of a candidate Shigella vaccine (2.5 or 10 μg Sfl2a InvaplexAR-Detox) given with and without adjuvant (0.1 μg dmLT). Study design: this is a phase Ia/b dose escalation, randomized, double-blind, placebo-controlled trial assessing the safety, tolerability and immunogenicity of three vaccinations given 4 weeks apart of Sfl2a InvaplexAR-Detox vaccine alone or in combination with the dmLT adjuvant in the Leiden University Medical Center in the Netherlands and at the Centre for Infectious Disease Research in Zambia (CIDRZ). The study will be initiated with the low vaccine dose in the Netherlands (Cohort A) and will not proceed to the high vaccine dose in the Netherlands (Cohort B) before the safety data of Cohort A has been reviewed by the Safety Monitoring Committe (SMC). The SMC will also review the safety data of Cohort B before the high vaccine dose will be administered in Zambian adults (Cohort C). Study population: a total of 50 healthy Dutch and 35 healthy Zambian adults aged 18-50 years. Intervention: a 2.5 μg or 10 μg intramuscular dose of the candidate Shigella vaccine Sfl2a InvaplexAR-Detox given with and without double mutant (LT R192G/L211A) enterotoxigenic Escherichia coli heat labile toxin adjuvant (0.1 μg dmLT) given at day 1, day 29 and day 57 compared to a placebo (saline). Main study endpoints: Primary endpoint measures are the occurrence of solicited and unsolicited adverse events considered to be related to vaccination. Secondary outcome measures are humoral and cellular immune responses to vaccination with and without adjuvant compared to placebo.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Shigellosis, Bacillary Dysentery
Keywords
Vaccine, Invaplex, dmLT, Shigella

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Factorial Assignment
Model Description
A phase Ia/b dose escalation, randomized, double-blind, placebo-controlled clinical trial
Masking
ParticipantCare ProviderInvestigator
Masking Description
Double blind
Allocation
Randomized
Enrollment
85 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
A1 - Low dose vaccine (Netherlands)
Arm Type
Experimental
Arm Description
10 Dutch participants who receive three 2.5 μg doses of the vaccine without adjuvant at a 28-day interval in Cohort A.
Arm Title
A2 - Low dose vaccine + adjuvant (Netherlands)
Arm Type
Experimental
Arm Description
10 Dutch participants who receive three 2.5 μg dose of the vaccine with 0.1 μg of adjuvant at a 28-day interval in Cohort A.
Arm Title
B1/C1 - High dose vaccine (Netherlands & Zambia)
Arm Type
Experimental
Arm Description
10 Dutch participants who receive three 10 μg vaccine doses without adjuvant at a 28-day interval in Cohort B and 15 Zambian participants who receive three 10 μg vaccine doses without adjuvant at a 28-day interval in Cohort C.
Arm Title
B2/C2 - High dose vaccine + adjuvant (Netherlands & Zambia)
Arm Type
Experimental
Arm Description
10 Dutch participants that receive three 10 μg vaccine doses with 0.1 μg of adjuvant at a 28-day interval in Cohort B and 15 Zambian participants that receive three 10 μg vaccine doses with 0.1 μg of adjuvant at a 28-day interval in Cohort C.
Arm Title
A3/B3/C3 - Placebo (Netherlands & Zambia)
Arm Type
Placebo Comparator
Arm Description
5 Dutch participants who receive three placebo vaccinations at a 28-day interval in Cohort A, another 5 Dutch participants who receive three placebo vaccinations at a 28-day interval in Cohort B and 5 Zambian participants who receive three placebo vaccinations at a 28-day interval in Cohort C.
Intervention Type
Biological
Intervention Name(s)
2.5 μg InvaplexAR-Detox
Intervention Description
2.5 μg intramuscular dose of Sfl2a InvaplexAR-Detox.
Intervention Type
Biological
Intervention Name(s)
10 μg InvaplexAR-Detox
Intervention Description
10 μg intramuscular dose of Sfl2a InvaplexAR-Detox.
Intervention Type
Biological
Intervention Name(s)
0.1 μg of dmLT
Intervention Description
0.1 μg intramuscular dose of double mutant (LT R192G/L211A) enterotoxigenic Escherichia coli heat labile toxin (dmLT).
Intervention Type
Biological
Intervention Name(s)
Placebo
Intervention Description
Placebo vaccination with commercially available saline solution.
Primary Outcome Measure Information:
Title
Occurence of solicited adverse events
Description
Occurrence of solicited adverse events considered to be (possibly, probably or definitely) related to vaccination according to the International Classification of Diseases version 11 (ICD-11) compared to the placebo group. Local solicited adverse events include pain/tenderness, erythema, induration/swelling, pruritus, and ipsilateral axillary lymphadenopathy. Systemic solicited adverse events include fever, chills, headache, fatigue, malaise, nausea/vomiting, painful/swollen joints, myalgia, diarrhea, and abdominal pain. Only symptoms with an onset after a vaccination until the 7th subsequent day after that vaccination will be considered solicited.
Time Frame
Within 7 days following vaccination (day of vaccination and 7 subsequent days).
Title
Occurence of unsolicited adverse events
Description
Occurrence of unsolicited adverse events considered to be (possibly, probably or definitely) related to vaccination, according to the ICD-11 classification.
Time Frame
Within 28 days following each vaccination (day of vaccination and 28 subsequent days).
Secondary Outcome Measure Information:
Title
Geometric mean titers of serum immunoglobulin A antibodies to Invaplex antigens
Description
Serum GMTs of anti-LPS, anti-IpaB and anti-IpaC IgA
Time Frame
Study days 1 (baseline), 29, 57, 64, 85 and 225.
Title
Geometric mean titers of serum immunoglobulin G antibodies to Invaplex antigens
Description
Serum GMTs of anti-LPS, anti-IpaB and anti-IpaC IgG
Time Frame
Study days 1 (baseline), 29, 57, 64, 85 and 225.
Title
Proportion of participants with immunoglobulin A seroconversion (> 4-fold rise in titer over baseline)
Description
Percentage of participants wit a ≥ 4-fold increase in serum anti-LPS, anti-IpaB and anti-IpaC IgA titer from baseline
Time Frame
Study days 1 (baseline), 29, 57, 64, 85 and 225.
Title
Proportion of participants with immunoglobulin G seroconversion (> 4-fold rise in titer over baseline)
Description
Percentage of participants wit a ≥ 4-fold increase in serum anti-LPS, anti-IpaB and anti-IpaC IgG titer from baseline
Time Frame
Study days 1 (baseline), 29, 57, 64, 85 and 225.
Title
Serum bactericidal assay response to S. flexneri 2a, strain 2457T in geometric mean titers
Time Frame
Study days 1 (baseline), 29, 57, 64, and 85.
Title
Proportion of participants with serum bactericidal assay responses (≥ 4-fold rise over baseline) to S. flexneri 2a, strain 2457T
Time Frame
Study days 1 (baseline), 29, 57, 64, and 85.
Title
Geometric mean titers of α4β7 antibodies in lymphocyte supernatant.
Time Frame
Study days 1 (baseline), 8, 36, and 64
Title
B cell memory responses to Invaplex antigens
Description
B cell memory responses to the LPS and IpaB and IpaC antigens.
Time Frame
Study days 1 (baseline), 64 and 225
Title
T cell memory responses to Invaplex antigens
Description
T cell memory responses to the LPS and IpaB and IpaC antigens.
Time Frame
Study days 1 (baseline), 64 and 225

10. Eligibility

Sex
All
Gender Based
Yes
Gender Eligibility Description
Self-identified male or female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy adult, male or female, aged 18 to 50 years (inclusive) at the time of inclusion (=vaccination). Provide written informed consent before initiation of any study procedures. Available to complete all study visits and procedures. Negative stool PCR test for Shigella. Women of childbearing potential: negative pregnancy test at screening and before each study vaccine administration. Women are considered not of childbearing potential if they are postmenopausal (no menses for 12 months without an alternative medical cause), or if they have no uterus or no ovaries. Women of childbearing potential must agree to use continuous adequate contraception to avoid pregnancy during the study, for at least 4 weeks before the first vaccination and for 3 months following the last vaccine dose. Adequate methods of contraception for this study include: hormonal contraception combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal) progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable) intrauterine device (IUD) intrauterine hormone-releasing system (IUS) bilateral tubal occlusion/litigation procedure vasectomized partner (the vasectomized partner should be the sole male sexual partner for that participant). sexual abstinence (defined as refraining from heterosexual intercourse from signing the informed consent until 3 months after the last vaccine dose). Exclusion Criteria: Chronic medical conditions such as psychiatric conditions, diabetes mellitus, hypertension (treated by medication), autoimmune disorders, cardiovascular, renal disease or inflammatory bowel disease. Use of immunosuppressive medications or immunosuppressive illness, including a history of immunoglobulin A (IgA) deficiency. Antihistamines and corticosteroids for topical use or inhalation are no exclusion criteria. Women who are pregnant or planning to become pregnant during the study period plus 3 months beyond the last vaccine dose and currently nursing women. Participation in research involving another investigational product (defined as receipt of an investigational product or exposure to an invasive investigational device) 30 days before the first vaccination or anytime through the last in-clinic study safety visit. Positive blood test for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Clinically significant abnormalities on basic laboratory screening tests. Systemic antimicrobial treatment (i.e., topical treatments are not an exclusion criterion) within 1 week before the first vaccine dose (temporary exclusion). Known hypersensitivity to compounds in the vaccine or adjuvant or other known drug allergies that may increase the risk of adverse events. 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 inflammatory arthritis. Proven allergy to any substance in the InvaplexAR-Detox vaccine or dmLT or history of anaphylactic reaction to any other vaccine. Exclusionary skin disease history/findings that would confound assessment or prevent appropriate local monitoring of AEs, or possibly increase the risk of local AEs. Recent (<3 moths) history of gastroenteritis. Received previous licensed or experimental Shigella vaccine, dmLT or live Shigella challenge. Any severe medical condition that might place the participant at increased risk of adverse events according to the clinical judgment of the study clinicians in consultation with the PI. Any planned vaccination within 14 days before the start of the trial until the end of the trial, with the exception of SARS-CoV-2 vaccines or influenza vaccines.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Meta Roestenberg, MD, PhD
Phone
+3171715262613
Email
M.Roestenberg@lumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Geert Roozen, MD
Email
G.V.T.Roozen@lumc.nl
Facility Information:
Facility Name
Leiden University Medical Center
City
Leiden
ZIP/Postal Code
2333 ZA
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data of the trial will follow the FAIR (findable, accessible, interoperable and re-usable) principles for data collection and sharing outlined by force11 and metadata will be entered in a repository which will be open access after completion of the trial.
IPD Sharing Time Frame
After completion of the trial. Specific timepoint to be decided.

Learn more about this trial

InvaplexAR-Detox and dmLT Adjuvant in the Netherlands and Zambia

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