Why should you do this study? Cholera is a serious disease that causes severe diarrhea and can be fatal if not treated promptly. It spreads through contaminated water and food and remains a significant health issue in many developing countries, including Kenya. This study aims to find the most effective way to use the Euvichol-S oral cholera vaccine to prevent outbreaks and save lives.

What questions are we trying to answer? We are investigating whether extending the time between doses of the Euvichol-S cholera vaccine is as effective as the standard dosing schedule. Specifically, we want to know if longer intervals between doses provide the same level of immunological protection against cholera.

Where is the study taking place? The study will be conducted in Mukuru, a large informal settlement in Nairobi, Kenya. This area is prone to cholera outbreaks, making it a good location to test the vaccine's immunogenicity.

How many participants does it involve and how will they be selected? The study will involve 1071 participants from different age groups, including children and adults. Participants will be selected from the Mukuru community and must be healthy to enroll. We will ensure a diverse age representation to evaluate the vaccine's immunogenicity across all age groups.

Who will be selected? Residents of Mukuru who are at least one year old and in good health are eligible to participate. Pregnant  women and individuals with severe health conditions will not be included in the study.

What does the study involve for those taking part? Participants will be randomly assigned to one of three groups: one group will receive the second dose of the vaccine two weeks after the first dose, another group will receive it three months later, and the last group will receive a booster dose one year after the first dose. Participants will attend several clinic visits over an 18-month period for health check-ups and blood samples. A smaller subset will provide additional blood volume to study the vaccine's impact on different parts of the immune response.

What are the risks and benefits of taking part? Risks: The vaccine might cause mild side effects such as stomach discomfort, nausea, or diarrhea. There is also a small risk of an allergic reaction. Blood sample collection may cause minor pain or bruising. Benefits: Participants will likely have a reduced risk of contracting cholera. Additionally, the study will contribute valuable information that can enhance cholera prevention efforts globally.

How will the study benefit society? This research will help identify the most effective vaccination schedule for the Euvichol-S oral cholera vaccine. The findings could lead to improved public health strategies and better protection against cholera in regions where the disease is prevalent, ultimately saving many lives.

Background: Cholera, caused by the bacterium Vibrio cholerae, remains a significant public health challenge in low-resource settings, particularly in sub-Saharan Africa. Despite efforts to control the disease, cholera outbreaks continue to occur, with Kenya experiencing several significant epidemics in recent years. 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 two-week interval, a three-month interval, and a twelve-month interval. The study will enroll 1071 participants, stratified by age into three groups: children aged 1-4 years, children aged 5-14 years, and adults aged 15 years and older. The primary endpoint is the plasma vibriocidal geometric mean titer (GMT) measured two weeks after the second dose. The trial also includes a peripheral blood mononuclear cell (PBMC) sub-cohort, focusing on younger (1-4 years) and older children (5-15 years), to assess the induction of V. cholerae OSP-specific memory B cells and specific immune responses involving gut-homing plasmablasts.

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: Key inclusion criteria include residents of Mukuru aged 1 year and above, who are healthy as determined by medical history and physical examination. Exclusion criteria include pregnant  women, individuals with severe malnutrition, and those with non-HIV immunosuppressive conditions or severe chronic diseases.

Study Interventions: Participants will be randomized to one of three dosing arms: a standard two-week interval, a three-month interval, or an annual booster interval. The arms and randomization will be stratified by age. 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. Participants in the standard dosing arm will have six scheduled visits, those in the three-month interval arm will have seven, and those in the annual booster arm will have six 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. Children in the PBMC cohort will have  two additional samples collected five days after each vaccine dose and a larger blood volume 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: A total of 1071 participants will be enrolled in the study, with equal distribution across the three dosing arms and age strata. The PBMC sub-cohort will include 360 participants (40 per arm among children 5-14y, 80 per arm among children 1-4y), who will have 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. The findings could enhance public health interventions and improve cholera prevention efforts in resource-limited settings.

Funding: The study is funded by the Wellcome Trust, with the Sabin Vaccine Institute as the sponsor.