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).
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
85
2.5 μg intramuscular dose of Sfl2a InvaplexAR-Detox.
10 μg intramuscular dose of Sfl2a InvaplexAR-Detox.
0.1 μg intramuscular dose of double mutant (LT R192G/L211A) enterotoxigenic Escherichia coli heat labile toxin (dmLT).
Placebo vaccination with commercially available saline solution.
Leiden University Medical Center
Leiden, Netherlands
RECRUITINGOccurence 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.
Time frame: Within 7 days following vaccination (day of vaccination and 7 subsequent days).
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.
Time frame: Within 28 days following each vaccination (day of vaccination and 28 subsequent days).
Geometric mean titers of serum immunoglobulin A antibodies to Invaplex antigens
Serum GMTs of anti-LPS, anti-IpaB and anti-IpaC IgA
Time frame: Study days 1 (baseline), 29, 57, 64, 85 and 225.
Geometric mean titers of serum immunoglobulin G antibodies to Invaplex antigens
Serum GMTs of anti-LPS, anti-IpaB and anti-IpaC IgG
Time frame: Study days 1 (baseline), 29, 57, 64, 85 and 225.
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
Time frame: Study days 1 (baseline), 29, 57, 64, 85 and 225.
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
Time frame: Study days 1 (baseline), 29, 57, 64, 85 and 225.
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.
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.
Geometric mean titers of α4β7 antibodies in lymphocyte supernatant.
Time frame: Study days 1 (baseline), 8, 36, and 64
B cell memory responses to Invaplex antigens
B cell memory responses to the LPS and IpaB and IpaC antigens.
Time frame: Study days 1 (baseline), 64 and 225
T cell memory responses to Invaplex antigens
T cell memory responses to the LPS and IpaB and IpaC antigens.
Time frame: Study days 1 (baseline), 64 and 225
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