| Study Objectives: |
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Objectives
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Endpoints
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Primary
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To identify the preferred dose of each component of the altSonflex1-2-3 vaccine (low, medium, or high) for infants 9 months of age in Africa (Stage 2).
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Anti-serotype specific Shigella lipopolysaccharide (LPS)* serum immunoglobulin G (IgG) titres as measured by reference enzymelinked immunosorbent assay (ELISA), in infants 9 months of age in Africa, 28 days after the third vaccination (Day 281).
*S. sonnei, S. flexneri 1b, S. flexneri 2a, and S. flexneri 3a serotypes will be tested.
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To evaluate the safety and reactogenicity of the altSonflex1-2-3 vaccine in all participants in Africa (Stage 2).
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Number of adults 18 to 50 years of age in Africa with solicited administration-site events during 7 days after each vaccination (study intervention administered on Day 1 and Day 85).
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Number of adults 18 to 50 years of age in Africa with solicited systemic events during 7 days after each vaccination (study intervention administered on Day 1 and Day 85).
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Number of adults 18 to 50 years of age in Africa with unsolicited AEs during 28 days after each vaccination (study intervention administered on Day 1 and Day 85).
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Number of adults 18 to 50 years of age in Africa with SAEs during their entire study participation period (from Day 1 to Day 113).
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Number of adults 18 to 50 years of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results, at 7 days after each vaccination (Day 8 and Day 92).
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Number of children 24 to 59 months of age in Africa with solicited administration-site events during 7 days after each vaccination (study intervention administered on Day 1 and Day 85).
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Number of children 24 to 59 months of age in Africa with solicited systemic events during 7 days after each vaccination (study intervention administered on Day 1 and Day 85).
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Number of children 24 to 59 months of age in Africa with unsolicited AEs during 28 days after each vaccination (study intervention administered on Day 1 and Day 85).
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Number of children 24 to 59 months of age in Africa with SAEs during their entire study participation period (from Day 1 to Day 113).
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Number of children 24 to 59 months of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results, at 7 days after each vaccination (Day 8 and Day 92).
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Number of infants 9 months of age in Africa with solicited administration-site events during 7 days after each vaccination (study intervention administered on Day 1, Day 85, and Day 253).
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Number of infants 9 months of age in Africa with solicited systemic events during 7 days after each vaccination (study intervention administered on Day 1, Day 85, and Day 253).
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Number of infants 9 months of age in Africa with unsolicited AEs during 28 days after each vaccination (study intervention administered on Day 1, Day 85, and Day 253).
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Number of infants 9 months of age in Africa with SAEs during their entire study participation period (from Day 1 to Day 281).
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Number of infants 9 months of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results, at 7 days after each vaccination (Day 8, Day 92, and Day 260).
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Secondary
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To evaluate the immunogenicity profile of the altSonflex1-2-3 vaccine in all participants in Africa (Stage 2).
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Anti-serotype specific Shigella LPS* serum IgG geometric mean titres (GMTs), in adults 18 to 50 years of age in Africa, as measured by reference ELISA, before each vaccination (Day 1 and Day 85) and 28 days after each vaccination (Day 29 and Day 113).
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Anti- serotype specific Shigella LPS* serum IgG GMTs, in children 24 to 59 months of age in Africa, as measured by reference ELISA, before each vaccination (Day 1 and Day 85) and 28 days after each vaccination (Day 29 and Day 113).
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Anti-serotype specific Shigella LPS* serum IgG GMTs, in infants 9 months of age in Africa, as measured by reference ELISA, before each vaccination (Day 1, Day 85, and Day 253) and 28 days after each vaccination (Day 29, Day 113, and Day 281).
*S. sonnei, S. flexneri 1b, S. flexneri 2a, and S. flexneri 3a serotypes will be tested.
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To further characterise the immunogenicity profile of the S. sonnei component of altSonflex1-2-3 vaccine in all participants in Africa (Stage 2).
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Number of adults in Africa 18 to 50 years of age achieving a reference ELISA level equivalent to ≥1:800* titre against S. sonnei LPS, before each vaccination (Day 1 and Day 85) and 28 days after each vaccination (Day 29 and Day 113).
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Number of children 24 to 59 months of age in Africa achieving a reference ELISA level equivalent to ≥1:800* titre against S. sonnei LPS in, before each vaccination (Day 1 and Day 85) and 28 days after each vaccination (Day 29 and Day 113).
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Number of infants 9 months of age in Africa achieving a reference ELISA level equivalent to ≥1:800* titre against S. sonnei LPS, before each vaccination (Day 1, Day 85, and Day 253) and 28 days after each vaccination (Day 29, Day 113, and Day 281).
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Number of adults in Africa 18 to 50 years of age achieving a reference ELISA level equivalent to ≥1:1600** titre against S. sonnei LPS, before each vaccination (Day 1 and Day 85) and 28 days after each vaccination (Day 29 and Day 113).
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Number of children 24 to 59 months of age in Africa achieving a reference ELISA level equivalent to ≥1:1600** titre against S. sonnei LPS in, before each vaccination (Day 1 and Day 85) and 28 days after each vaccination (Day 29 and Day 113).
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Number of infants 9 months of age in Africa achieving a reference ELISA level equivalent to ≥1:1600** titre against S. sonnei LPS, before each vaccination (Day 1, Day 85, and Day 253) and 28 days after each vaccination (Day 29, Day 113, and Day 281).
*This threshold (1:800, known as “Cohen’s Threshold”) has been previously reported to be potentially protective for Shigella [Cohen, 1988; Launay, 2017] and will be calibrated for the assay to be used in this study. The details of the equivalent threshold to be used will be reported in the Clinical Study Report (CSR).
**This threshold (1:1600, double of “Cohen’s Threshold”) will be calibrated for the assay to be used in this study. The details of the equivalent threshold to be used will be reported in the CSR.
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To evaluate seroresponse with the altSonflex1-2-3 vaccine after each vaccination in all participants in Africa (Stage 2).
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Number of adults 18 to 50 years of age in Africa showing at least a 4-fold increase in anti-serotype specific Shigella LPS* serum IgG titres, as measured by reference ELISA, at 28 days after each vaccination (Day 29 and Day 113), compared to baseline (Day 1 and Day 85).
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Number of children 24 to 59 months of age showing at least a 4-fold increase in anti-serotype specific Shigella LPS* serum IgG titres, as measured by reference ELISA, at 28 days after each vaccination (Day 29 and Day 113), compared to baseline (Day 1 and Day 85).
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Number of infants 9 months of age showing at least a 4-fold increase in anti-serotype specific Shigella LPS* serum IgG titres, as measured by reference ELISA, at 28 days after each vaccination (Day 29, Day 113, and Day 281), compared to baseline (Day 1, Day 85, and Day 253).
*S. sonnei, S. flexneri 1b, S. flexneri 2a, and S. flexneri 3a serotypes will be tested
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To evaluate the immunogenicity of co-administered MR-VAC in infants 9 months of age in Africa (Stage 2), in the dose-finding cohort.
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Anti-measles IgG concentrations, as measured by ELISA, in infants 9 months of age in Africa, in the dose-finding cohort, before the first MR-VAC (Day 1) and at 28 days after the second MR-VAC vaccination (Day 281).
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Anti-rubella IgG concentrations, as measured by ELISA, in infants 9 months of age in Africa, in the dose-finding cohort, before the first MR-VAC (Day 1) and at 28 days after the second MR-VAC vaccination (Day 281).
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Number of infants 9 months of age, in the dose-finding cohort, achieving anti-measles IgG concentrations of ≥150 mIU/mL* and ≥ 200 mIU/mL*, as measured by ELISA, at 28 days after the second MR-VAC vaccination (Day 281).
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Number of infants 9 months of age, in the dose-finding cohort, achieving anti-rubella IgG concentrations of ≥4 IU/mL* and ≥10 IU/mL*, as measured by ELISA, at 28 days after the second MR-VAC vaccination (Day 281).
*This threshold is based on the vaccine correlate of protection and World Health Organization guidelines.
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Tertiary
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To evaluate the immune response induced by the Sonflex1-2-3 vaccine in 25% of infants 9 months of age in Africa (Stage 2), in the dose-finding cohort, using the serum bactericidal assay (SBA).
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Anti-serotype specific* serum bactericidal antibody GMTs in 25% of infants 9 months of age in the dose-finding cohort, before each vaccination (Day 1, Day 85, and Day 253) and 28 days after each vaccination (Day 29, Day 113, and Day 281).
*S. sonnei, S. flexneri 1b, S. flexneri 2a, and S. flexneri 3a serotypes will be tested.
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To further explore immune responses to the altSonflex1-2-3 vaccine in 25% of adults in Europe (Stage 1) and 25% of infants 9 months of age in Africa (Stage 2), in the dose finding
cohort.
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Antibody features (subclassing, affinity, avidity) and functional properties (induction of cellular phagocytosis and cellular cytotoxicity, natural killer [NK] cell activation, eosinophil and basophil degranulation, complement deposition, neutrophil activation/ phagocytosis, dendritic cell phagocytosis, mucin binding, glycosylation, and Fc receptor alteration), as measured by systems serology analysis
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Anti-serotype serum bactericidal antibody GMTs against a panel of vaccine heterologous Shigella serotypes, as measured by SBA
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Anti-serotype serum bactericidal antibody GMTs against a panel of vaccine homologous and heterologous Shigella serotypes, as measured by opsonophagocytosis assay
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| Laymans Summary: |
Shigellosis is an infectious disease caused by a group of bacteria called Shigella. Shigellosis remains a major public health problem around the world; it is one of the leading causes of diarrheal disease in low- and middle-income countries (LMIC), particularly in young children. The Global Burden of Disease study (IHME) estimated that in 2017 Shigella caused approximately 238,000 deaths globally. In infants, in LMIC, particularly where healthcare resources are limited, shigellosis can often lead to death. There is presently no widely available vaccine against Shigella. Treatment for shigellosis is mainly supportive to keep patients stable. Shigellosis can be treated with antibiotics but many Shigella bacteria no longer respond well to or are resistant to most of the used antibiotics. Thus, a very important way to fight Shigella is through prevention with the use of vaccination.. The aim of the study is to assess how an experimental Shigella vaccine, called altSonflex1-2-3 makes the body to produce proteins that fight off the bacteria causing shigellosis and to assess the side effects the vaccine may cause. The study is being conducted in two stages. Stage 1 in Europe and stage 2 in Kericho, Kenya. In Kericho, If the vaccine is found to be safe for adults, 18-50 years old, the study will progress to include children, 24 to 59 months and then 9 months old infants who will receive one of three different dose levels of the vaccine (A [low], B[medium], and C [high]). The adults will receive either 2 injections of the Shigella vaccine or 2 injections of a control vaccine, the first with Menveo (a vaccine that prevents meningitis) followed by boostrix (a vaccine that prevents tetanus, diphtheria and whooping cough). The children will receive either 2 injections of Shigella vaccine or 2 injections of control vaccines, the first one being Menveo followed by Typhim VI (a vaccine that prevents typhoid fever) as the second one. The infants will receive either 3 injections of Shigella vaccine or 2 injections of Menveo followed by 1 injection of Infanrix (a vaccine for children that prevents diphtheria, tetanus and whooping cough). Adults and children will be followed up for 4 months while infants will be followed up for 11 months. The benefits of this study include, participants or participants’ parents may gain medical advice about their own or their children’s health status through the medical evaluations and laboratory assessments associated with the study. Vaccines administered as control and not routinely given will be provided free of charge and can provide protection against meningitis, typhoid, diphtheria, tetanus, pertussis. The children and infants who will be assigned to receive the shigella vaccine will receive menveo vaccine after the study is completed as a benefit. The results of this study will allow the selection of the most appropriate dose for further vaccine development in infants 9 months of age, which is the main target age group for this vaccine.
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| Abstract of Study: |
Shigellosis remains a major public health problem around the world; it is one of the leading causes of diarrheal disease in low- and middle-income countries (LMIC), particularly in young children. The Global Burden of Disease study (IHME) estimated that in 2017 Shigella caused approximately 238,000 deaths globally and, with 15.2%, it ranked second with regard to pathogen contributions in global diarrheal deaths. In infants, in LMIC, particularly where healthcare resources are limited, shigellosis can often lead to death. There is presently no widely available vaccine against Shigella. Treatment for shigellosis is mainly supportive to keep patients stable and restore lost electrolytes due to diarrhea. If available, specific antibiotics are sometimes used for severe cases of shigellosis.
Current drugs are under threat from the increasing rates of antibiotic resistance in Shigella serotypes around the world. Prevention of diarrheal diseases caused by Shigella, with the introduction of an efficacious vaccine is important. This is a Phase 1/2 observer-blind, controlled, self-contained, randomised, multi-country, staged, age-de-escalation study. This study will evaluate the safety and immunogenicity of a new candidate Shigella 4-component generalized modules for membrane antigens (GMMA), the altSonflex1-2-3 GMMA vaccine against S. sonnei and S. flexneri serotypes 1b, 2a, and 3a and select the dose of administration for further clinical development in the target population of infants. The candidate altSonflex1-2-3 vaccine will be administered intramuscularly first in adults 18 to 50 years in Europe (Stage 1) and, subsequently in stage 2, to adults 18 to 50 years, children 24 to 59 months, and 9 months old infants in Kericho, Kenya using three different doses of vaccine (A [low], B[medium], and C [high]). In stage 2, participants will be randomized to receive either altSonflex1-2-3 GMMA vaccine or control vaccine. The adults will receive 2 vaccinations of altSonflex1-2-3 GMMA vaccine three months apart or menveo and boostrix 3 months apart. The children will receive 2 vaccinations of altSonflex1-2-3 GMMA vaccine 3 months apart or menveo and typhim Vi 3 months apart. The infants will receive 2 vaccinations of altSonflex1-2-3 GMMA vaccine 3 months apart and a third vaccine 6 months after the 2nd vaccination or menveo 3 months apart and infanrix 6 months after the 2nd vaccination. A total of 448 (20 adults, 40 children, 388 infants) participants who meet the eligibility criteria as described in the main protocol will be enrolled at Kericho. Adults and children will be followed up for 4 months while infants will be followed up for 11 months. The results of this study will allow the selection of the most appropriate dose for further vaccine development in infants 9 months of age, which is the main target age group for this vaccine. The study findings will be shared with all authorities having oversight of this protocol including the sponsor, Kenya Medical Research Institute Scientific Ethics Review Unit, Pharmacy and Poisons Board, Walter Reed Army Institute of Research Institutional Review Board and Kenya’s Ministry of Health.
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