A Phase IV Parallel-Group, Open-Label, Randomized Non-Inferiority Trial Evaluating Immunogenicity of Extended Dosing Intervals for Euvichol-S Oral Cholera Vaccine, Nairobi, Kenya
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 1,071
- 试验地点
- 1
- 主要终点
- To assess and compare the immune response to Euvichol-S, measured by plasma vibriocidal geometric mean titer (GMT) two weeks after the second vaccine dose, across different dosing intervals in participants aged 1 year and older.
研究概览
简要总结
Background: Despite efforts to control cholera, outbreaks continue to occur in Kenya. Oral cholera vaccines (OCVs) are a critical tool in cholera prevention strategies. This study evaluates the immunogenicity of extended dosing intervals for Euvichol-S, a WHO-prequalified OCV, in a Phase IV non-inferiority trial.
Overview Design: This trial is a parallel-group, open-label, randomized, non-inferiority study. It aims to compare the immune response of three dosing schedules of the Euvichol-S OCV: a standard 2-week interval, a 2-month interval, and a 12-month interval. The study will enroll 1071 participants, stratified by age into three groups (1-4 years, 5-14 years, 15+ years. The primary endpoint is the plasma vibriocidal geometric mean titer (GMT) measured two weeks after the second dose.
Primary Objective: To assess and compare the immune response to Euvichol-S measured by vibriocidal GMT two weeks after the second vaccine dose across different dosing intervals.
Study Sites: The study will be conducted in the Mukuru informal settlement in Nairobi, Kenya, a high-priority cholera hotspot area. The Kenya Medical Research Institute (KEMRI) will manage the study, leveraging its established relationship with the community.
Study Population: Inclusion criteria include residents of Mukuru ≥1 year, who are healthy as determined by medical history and physical examination. Exclusion criteria include pregnant women, severe malnutrition, and non-HIV immunosuppressive conditions or severe chronic diseases.
Study Interventions: Participants will be randomized to one of three dosing arms stratified by age: a standard 2-week interval, a 3-month interval, or an annual booster interval. Participants will receive the Euvichol-S OCV according to the assigned schedule. The follow-up period for participants will be 18 months, during which they will undergo regular scheduled visits and additional unscheduled visits as needed (i.e., standard dosing arm: six scheduled visits; 3-month interval arm: 7 visits; annual booster arm: 6 visits). Blood samples will be collected at each vaccination visit and 14 days later and at 6 months, 1 year and 18 months after enrollment to measure plasma vibriocidal GMT and other immunological markers. Older children in the PBMC cohort will have two additional samples collected five days after each vaccine dose and a larger blood volume (10mls) collected at 14 days after the second dose.
Outcome Measures: Primary outcome measures include the plasma vibriocidal GMT two weeks post-second dose. Secondary outcomes include antibody seroconversion rates, longitudinal GMT changes, incidence of cholera disease, and the safety profile of the vaccine. The PBMC sub-cohort will provide detailed insights into memory B cell and plasmablast responses.
Sample Size: The study will enroll 1071 participants with equal distribution across the three dosing arms and age strata. The PBMC sub-cohort will include 240 participants (40 per arm among 5-14 years, 40 per arm 1-4 years), with detailed immunological assessments.
Data Analysis: The immunogenicity of the vaccine across different dosing schedules will be compared to determine non-inferiority. Data will be analyzed descriptively to summarize the by-grade incidence of treatment-emergent adverse events (AEs), serious adverse events (SAEs), and other safety indicators.
Impact: This trial aims to generate evidence on the optimal dosing schedule for Euvichol-S OCV, potentially informing future vaccination strategies in cholera-endemic regions and improving cholera prevention in resource-limited settings.
详细描述
Study Rationale Between October 2022 and February 2024, Kenya has experienced a cholera outbreak with over 10,000 reported cases and 166 deaths across 23 counties. Alarmingly, children under 10 years of age account for one-third of the documented cases, indicating their heightened vulnerability to the disease. In February 2023, Kenya vaccinated more than 2.2 million people with a single dose of oral cholera vaccine (OCV). However, this reactive campaign alone has proven insufficient to control the outbreak.
To address endemic cholera and prevent future outbreaks, the Kenya MoH has applied to Gavi, the Vaccine Alliance, to receive OCV for a preventive vaccination campaign in 2025 to 2028. Based on recent hotspot mapping led by partners in our consortium, the government plans to conduct mass vaccination campaigns in 94 hotspot sub-counties, reaching 19 million individuals. This campaign will mark the first national preventive campaign of OCV in East Africa. Insights gained will benefit not only Kenya but also neighbouring countries experiencing cholera outbreaks.
Studies evaluating the relative impact of campaigns utilizing two doses with extended intervals are limited. Additionally, prior studies assessing extended dosing intervals have not compared durability and immunogenicity within specific age groups, nor have they consistently included extended follow-up periods. Given the specific vulnerability of children, the Global Task Force for Cholera Control ranks research on optimal cholera vaccine schedules for children one to five years as the highest priority in the Cholera Roadmap Research Agenda.
Vaccination with OCV is a proven, effective strategy to prevent cholera outbreaks. However, the current manufacturer-recommended dosing regimen is challenging to implement programmatically and offers only short-term protection, particularly in young children, the most vulnerable population. This study aims to address this gap by generating evidence on the immunogenicity and durability of immunity across different dosing schedules. By evaluating the immune response, particularly in children, this trial will provide critical data to inform optimal dosing strategies. The findings will support the Kenyan Ministry of Health in enhancing the impact of preventive OCV campaigns and improving long-term cholera control efforts in endemic regions.
Risks and Benefits
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Health Services Research
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Residents of Mukuru, Nairobi, Kenya
- •Individuals aged 1 year and above
- •Voluntary written informed consent for study participation provided by an individual or his/her legally acceptable representative. Children aged 13 years and above will also provide assent, with parental permission required for all children.
- •Ability to comply with study requirements and attend follow-up visits during the study period.
- •Participants must be in good health, as determined by medical history, physical examination, and the clinical judgment of the investigators. Clinical judgment will consider factors such as the absence of acute illness or, uncontrolled or severe chronic conditions that may affect participation in the study.
- •Lactating women may be enrolled following clinical assessment and informed consent. The vaccine contains killed, formalin-inactivated bacteria that are not systemically absorbed and act locally in the gastrointestinal tract.
排除标准
- •Known history of hypersensitivity reactions to other vaccines.
- •Pregnant women, due to differences in immune response. A pregnancy test will be administered to all female participants who have reached menarche and are under 50 years.
- •Reported diarrhea or abdominal pain lasting 2 weeks or longer within 6 months prior to study initiation; to avoid confounding the vaccine's effects with pre-existing conditions.
- •Received a cholera vaccine in the last 24 months: Ensures that the study assesses the vaccine in question without interference from prior vaccinations.
- •History of cholera disease in the last 24 months: Recent history of cholera infection can interfere with the measurement of vaccine response.
- •Severely malnourished individuals as determined by mid-upper arm circumference (MUAC) and age-specific body mass index (BMI) measurements: malnutrition can affect immune response and vaccine efficacy. In children below 510 years, severe malnutrition will be defined as MUAC < 11.5 cm, for older children (age 5 - 17y) severe malnutrition will be defined as BMI-for-age z score < -3 (WHO Child Growth Standards), for children <10y, presence of bilateral pitting oedema will be considered indicative of severe malnutrition. For adults (18y and above), severe malnutrition will be while in older children and adults it will be defined as BMI <
- •Non-HIV/AIDS immunosuppressive condition or on immunosuppressive therapy: Such conditions can significantly alter vaccine response.
- •Presence of bleeding disorders or medical contraindication for blood draws: To ensure participant safety during blood collection.
- •Participation in another clinical trial with investigational product dosing within 6 months prior to study initiation.
- •An individual thought to have difficulty in participating in the study due to severe chronic diseases, based on the judgment of the investigator.
- •An individual thought to have difficulty participating in the study due to reasons, such as significant logistical constraints, or communication barriers, or likely to be away for a period of at least 3 consecutive months in the first 6 months of enrollment based on the judgment of the investigator.
结局指标
主要结局
To assess and compare the immune response to Euvichol-S, measured by plasma vibriocidal geometric mean titer (GMT) two weeks after the second vaccine dose, across different dosing intervals in participants aged 1 year and older.
时间窗: Plasma vibriocidal GMT measurement 2-weeks after the 2nd vaccine dose of Euvichol-S in participants 1+ years for the Comparator Arm (2nd dose at 2 weeks), Intervention Arm 1 (2nd dose at 3-months), and Intervention Arm 2 (2nd dose at 1-year)
Plasma Vibriocidal GMT Measurement: Measurement of the concentration of plasma vibriocidal GMT two weeks after administering the second dose of Euvichol-S. Vibriocidal antibodies are the best-established immune correlate of protection against cholera. The GMT, a statistical representation of the antibody levels in the study population, is an objective and quantifiable measure of the vaccine's immunogenicity. By comparing GMT values across different dosing intervals, we aim to validate the immunogenicity of extended dosing schedules, assessing if they are as effective at eliciting a protective immune response as the standard two-week interval. This assessment will be crucial in guiding future vaccination strategies, particularly in resource-limited settings where scheduling flexibility can significantly impact public health outcomes.
次要结局
- Plasma Vibriocidal GMT(Plasma vibriocidal GMT over an 18-month period: two weeks post-vaccination and also at 6, 12, and 18 months post-enrollment.)