Extended Dosing Intervals Trial for Oral Cholera Vaccine, Kenya

ConditionCholera Vaccination

Trial statusRecruiting

Trial phasePhase 4

Trial typeInterventional

Biological sexAll

Age1+

SponsorAlbert B. Sabin Vaccine Institute

About this trial

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.

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

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.

Disqualifiers

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.

Trial design

Design model

Parallel

Treatments tested in this trial

Euvichol-S Oral Cholera Vaccine
Drug
Parallel-group, phase IV, open-label, randomized, non-inferiority trial Arms: Three distinct arms, each balanced in a 1:1:1 ratio: Standard Dosing Arm (Two Weeks Interval) Extended Interval Dosing Arm (Three Months Interval) Annual Booster Dosing Arm (Twelve Months Interval) Each dosing arm will have the following three age strata: Children aged 1-4 years Children aged 5-14 years Adults aged 15 years and older

Treatment groups

1,071 Participants

are divided into 3 treatment groups

Group A: Standard Dosing Arm (Two Weeks Interval)Active comparator 1 intervention

Group B: Extended Interval Dosing Arm (Three Months Interval)Experimental treatment 1 intervention

Group C: Annual Booster Dosing Arm (Twelve Months Interval)Experimental treatment 1 intervention

Trial outcomes

Primary outcomes

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.

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.

Time frame

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)

Secondary outcomes

Plasma Vibriocidal GMT

Plasma Vibriocidal GMT Comparison: Compare the concentration of plasma vibriocidal geometric mean titer (GMT) across various dosing intervals within distinct age groups to determine whether the average antibody levels within each age strata varies by the vaccine dosing schedule. Vibriocidal Antibody Seroconversion Evaluation: Assess the proportion of vaccinees who had a 4-fold or greater rise in vibriocidal titers after vaccination, indicating the development of an immune response to the vaccine. Longitudinal GMT Changes Monitoring: Describe plasma vibriocidal GMT over an 18-month period: two weeks post-vaccination and also at 6, 12, and 18 months post-enrollment; this outcome tracks the persistence and variation of GMT by dosing interval and age to understand the duration and stability of the immune response elicited by the vaccine. Cholera Disease Incidence Comparison: Compare the incidence of cholera over 18 months across different age groups and dosing intervals.

Time frame

Plasma vibriocidal GMT over an 18-month period: two weeks post-vaccination and also at 6, 12, and 18 months post-enrollment.

Other outcomes

Exploratory Objective 1 - Anti-O-specific polysaccharide (OSP) IgA responses in plasma

Assessment of plasma Anti-OSP IgA Responses: Measure concentration of plasma levels of antibodies (IgA) against the V. cholerae O-specific polysaccharide (OSP) for insights into the specific immune response elicited by the vaccine that are known to correlate with protection. Persistence of Plasma Anti-OSP IgA: Measure how long the plasma immune response persistence. Comparative Analysis Based on Baseline Vibriocidal Titers

Time frame

Anti-OSP IgA over an 18-month period: two weeks post-vaccination and also at 6, 12, and 18 months post-enrollment.

Exploratory Objective 2 - Anti-O-specific polysaccharide (OSP) IgG responses in plasma

Assessment of plasma Anti-OSP IgG Responses: Measure concentration of plasma levels of antibodies (IgG) against the V. cholerae O-specific polysaccharide (OSP) for insights into the specific immune response elicited by the vaccine that are known to correlate with protection. Persistence of Plasma Anti-OSP IgG: Measure how long the plasma immune response persistence. Comparative Analysis Based on Baseline Vibriocidal Titers

Time frame

Anti-OSP IgG over an 18-month period: two weeks post-vaccination and also at 6, 12, and 18 months post-enrollment.

Exploratory Objective 3 - PBMC Sub-cohort: Circulating gut-homing anti-OSP memory B cells (MBCs)

Peripheral blood mononuclear cells (PBMC) Sub-cohort - Evaluate the presence and quantity of cholera-specific anti-OSP memory B cells (MBCs) specific to V. cholerae OSP at baseline and after booster doses, which are crucial for long-term immunity, as they are responsible for a quicker and more robust response upon re-exposure to the pathogen.

Time frame

MBC at baseline, 14 days after 2nd dose, and 12 months after 1st dose (1-year interval group) in sub-cohort of children 1-14 years.

Exploratory Objective 4: PBMC Sub-cohort - Mucosal Antibody Secreting Cell (ASC)

Peripheral blood mononuclear cells (PBMC) Sub-cohort - Evaluate the presence and quantity of cholera-specific mucosal gut-homing anti-OSP plasmablasts, a type of antibody-secreting cell (ASC) at baseline and after booster doses.

Time frame

Mucosal ASC at baseline and 5 days after each dose in sub-cohort of children 5-14 years.

Sponsors and contacts

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Albert B. Sabin Vaccine Institute

Lead sponsor

Kenya Medical Research Institute

Collaborator

Washington State University

Collaborator

Massachusetts General Hospital

Collaborator

Kenya Ministry of Health

Collaborator

Nairobi City County

Collaborator

Source ClinicalTrials.gov

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