Comparison of Two Strategies for Administering the R21-Matrix M Vaccine in a Context of Seasonal Malaria Transmission in Chad (COSAV-R21)

Cluster Randomised Non-inferiority Trial Comparing Malaria Incidence When Implementing R21/Matrix-M Synchronized With Seasonal Malaria Chemoprevention Distribution Versus R21/Matrix-M Given Routinely Through the EPI in Two Health Districts in Chad (CoSAV-R21)

This is a two-arm, cluster-randomised, phase IV trial conducted in Chad to assess the protective efficacy and impact in real-life conditions of a new strategy for administering the R21/MM malaria vaccine, synchronized within a seasonal malaria chemoprevention (SMC) campaign, among children living in areas of high seasonal malaria transmission.

In this study, a cluster is defined as the catchment area of a primary care health centre. In Chad, each catchment area is known as a 'zone of responsibility' (French: Zone de Responsibilité' [ZR]).

Twenty-six (26) of the total 27 ZRs in the districts of Moïssala and Dembo will be randomized in a 1:1 ratio to receive a 4-dose (3 primary doses + 1 booster) R21/MM schedule either (1) integrated into the routine EPI vaccination program (the "Routine" control arm), or (2) synchronized with an annual seasonal malaria chemoprevention (SMC) campaign (the "Synchronized" intervention arm).

Malaria incidence: R21/MM effectiveness will be assessed using the incidence of biologically confirmed clinical malaria (trial primary endpoint). The incidence of clinical malaria will be determined through enhanced surveillance of malaria cases in health centres and hospitals over a 17-month period (August 2025 - December 2026).

Coverage surveys: Cross-sectional surveys (cluster sampling) will be carried out to measure R21/MM vaccine coverage, SMC coverage, coverage of other malaria prevention measures, and coverage of other EPI vaccines.

Nested case-control study: A sub-sample of children admitted to Moïssala District Hospital with severe clinical malaria will be offered the opportunity to participate in a nested case-control study designed to estimate the individual protective efficacy of R21/MM against severe malaria.

Aditionnaly, the INTEGREVAC ancillary study's objective is to evaluate the cost-effectiveness, acceptability and feasibility of the synchronised vaccination strategy in the context of the ongoing COSAV-R21 trial, to inform policy decisions for the effective deployment of malaria vaccines in SMC implementation areas.

Methodology and planned work:

(i) A qualitative study using in-depth interviews (IDIs) and group discussions with key stakeholders at the national, health facility, and community levels, including caregivers of children eligible for vaccination, in Chad, at several points during the trial. We will explore stakeholders' and beneficiaries' perceptions and experiences of the synchronised SMC vaccination strategy (trial intervention arm) compared to age-based vaccine administration under the routine immunisation programme (trial control arm), as well as considerations for implementing these strategies. Interviews with healthcare providers, including those administering R21 and SMC, and community members will assess the feasibility of implementing the integrated vaccination strategy via SMC.

(ii) An economic evaluation including a cost-effectiveness analysis and a nested equity analysis will be conducted. The economic evaluation will include a cost analysis to carefully identify and measure the additional costs associated with adding malaria vaccination to the EPI delivery platform and, separately, to the SMC delivery channel. Analysis of key cost drivers will enable us to identify potential efficiency savings, provide evidence for country funding requests (e.g., to GAVI and the Global Fund) and for the malaria vaccine strategy budgeting/planning process. Cost-effectiveness and equity analyses of each vaccine delivery strategy will provide evidence to help national programmes plan future malaria vaccine delivery and inform global guidance and on methods of delivering these vaccines, while providing valuable evidence on the real-world cost-effectiveness of malaria vaccination.

(iii) Impact modelling will estimate the costs, impact, and cost-effectiveness of scaling up the intervention approach to the whole of Chad, under different temporal and spatial scenarios.

Study Overview

• Status: Recruiting
• Conditions: Malaria Vaccines; Malaria Infection
• Intervention / Treatment: Other: "Synchronised" arm (intervention)

• Study Type: Interventional
• Enrollment (Estimated): 70000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: San Maurice OUATTARA; Phone Number: +235 85 15 76 18; Email: San-Maurice.OUATTARA@epicentre.msf.org
• Study Contact Backup: Name: Jessica SAYYAD, Dr; Phone Number: +331 40 21 55 55; Email: jessica.sayyad@epicentre.msf.org

Study Locations

• Chad
  • Mandoul Region
    • Moïssala, Mandoul Region, Chad
      • Recruiting
      • Medecin sans Frontières
      • Contact: Ouattara San Maurice; Phone Number: +235 85 15 76 18; Email: San-Maurice.OUATTARA@epicentre.msf.org
      • Principal Investigator: Jessica Sayyad Hilario
      • Principal Investigator: Ouattara San Maurice
      • Sub-Investigator: Dabsou Guidaoussou
      • Sub-Investigator: Antoinette Mbailamen Demian
      • Sub-Investigator: Mahamat Saleh Issakha DIAR
      • Sub-Investigator: Cédric Benodji Djerabé

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• • Routine arm

  1. Aged 6 to 11 months at the time of the first R21/MM vaccination (dose 1).
  2. Residing in a village participating in the study and randomized to the routine arm.

  3. Oral consent provided by the child's parent/guardian.

     • Synchronised arm
  1. Aged 6 to 59 months at the time of the first R21/MM vaccination (dose 1) during the first 3 rounds of SMC (2025).
  2. Residing in a village participating in the study and randomized to the synchronized arm.
  3. Oral consent provided by the child's parent/guardian.

Exclusion Criteria:

• Exclusion criteria for both arms according to Chad national EPI guidelines

Malaria vaccine is not recommended for children with known severe hypersensitivity:

• To a previous dose of a malaria vaccine
• To a previous dose of hepatitis B vaccine
• One of the components of the R21/MM vaccine

Mild illness - including respiratory tract infections, mild diarrhoea and fever below 38.5° C - is not a contraindication to R21/MM vaccination. Malnutrition and being HIV-seropositive are also not contraindications to R21/MM vaccination.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: "Routine" arm (control); primary series (3 doses) of R21/Matrix M administered throughout the year as part of the routine Expanded Programme on Immunisation (EPI), followed by a single booster six months after the 3rd dose.
Experimental: "Synchronised" arm (intervention); primary series (3 doses) of R21/MatrixM synchronized with a seasonal malaria chemoprevention (SMC) campaign, followed by a single booster 12 months after 1st dose was introduced.	Other: "Synchronised" arm (intervention); Vaccines received together with CPS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Malaria incidence in children who were aged 6-11 months when receiving their first dose R21/MM	To assess whether the R21/MM vaccine synchronized with SMC is non-inferior in preventing malaria (based on malaria incidence) compared to R21/MM administered as part of routine EPI in children who were aged 6-11 months when receiving their first dose R21	From enrollment to Month 17 (Aug 2025- december 2026)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Malaria incidence	Incidence of clinical malaria (biologically confirmed by RDT) in each study arm among children aged 6-59 months, irrespective of R21/MM vaccination status	from enrolment to Month 17 (Aug 2025- Dec 2026)
R21/MM vaccination coverage	Proportion of children having received the appropriate number of doses for their age	from enrolment to Month 17 (Aug 2025- Dec 2026)
Coverage of other malaria prevention measures	Proportion of children possessing, and proportion of children using, a long-lasting insecticidal net (LLIN) on the day before completing the coverage survey questionnaire	from enrolment to Month 17 (Aug 2025- Dec 2026)
Coverage of other EPI antigens	o Proportion of age-eligible children vaccinated against measles-1 and measles-2.	from enrolment to Month 17 (Aug 2025- Dec 2026)
Protective efficacy against severe malaria	Protective efficacy of vaccination with R21/MM will be measured at the individual level against severe malaria confirmed by RDT and microscopy. The protective efficacy will be calculated from the relative risk (RR) of developing severe malaria in vaccinated and unvaccinated children.	From enrollment to Month 17 (Aug 2025- december 2026)
Proportional morbidity	o Proportion of all-cause morbidity registered at health centres attributed to uncomplicated malaria	From enrollment to Month 17 (Aug 2025- december 2026)
Coverage of other malaria prevention measures	SMC coverage: average number of doses received per child and proportion of children receiving 0 and 5 doses	From enrolment to month 17 (Aug 2025- Dec 2026)
R21/MM safety	Frequency of reported serious adverse events (SAEs), adverse events following immunization (AEFI), Serious AEFIs and reported adverse events of special interest (AESIs) following R21/MM vaccination	From enrollment to Month 17 (Aug 2025- december 2026)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptability of the synchronized strategy	Acceptability of R21 vaccination synchronized with SMC together with factors that promote or hinder the completeness of the R21 schedule. Views of policy makers, healthcare providers and caregivers collected through in-depth interviews and focus group discussions.	from month 6 to month 24
Feasibility of the synchronized strategy	Feasibility of administering 4 doses of R21 via SMC vs. the EPI platform assessed through qualitative interviews and focus group discussions	from Month 6 to Month 24
Cost-effectiveness	Costs to beneficiaries : Unit costs borne by beneficiaries (children and their guardians/parents) for R21 vacicnation, SMC, treatment of malaria episodes if the child has suffered one, per study arm (total cost of malaria prevention and treatment). Provider-related costs (including the health system, the research project and implementation partners) incurred in R21 vaccination by study arm. Differential cost-effectiveness ratio (ICER) per malaria case prevented by the intervention (malaria vaccination via SMC) compared to the control (R21 vaccination via EPI. The ratio of these total costs per unit of effectiveness (malaria case averted, Disavility-adjusted life year) defines cost-effectiveness.	From first enrolment to 24 months
Fidelity of implementation of R21 vaccine delivery	We will document how the R21 vaccine administration was implemented in practice. Factors considered will include vaccine availability, accessibility of vaccination sites, staff training, community engagement efforts, adherence to vaccination schedules, quality and satisfaction with services, and any adaptations made. Data will be collected through desk review of programmatic documents, quantitative questionnaires and qualitative interviews.	From 6 months to 24 months
Equity	Explore the equity of each strategy from the perspective of wealth/poverty status and gender/sex- of vaccinated (or unvaccinated) children in Dembo and Moïssala R21 vaccination coverage (including children who have not received any doses and children who are fully vaccinated) will be presented by wealth quintile and separately by sex/gender between study arms Questions on assets and household composition will be asked during the cross-sectional household coverage surveys	from enrolment to Month 17 (Aug 2025- Dec 2026)
Impact modelling	Assess, over time and based on historical data, the impact of malaria vaccination and SMC on the malaria burdeb at the district level in Moïssala and at the subnational level, using mathematical models parameterised with data obtained during the CoSAV-R21 trial.	From Month 18 to Month 36

Collaborators and Investigators

• Sponsor: Epicentre
• Collaborators: Epicentre, Paris, France.; Liverpool School of Tropical Medicine; EXPERTISE FRANCE, Paris France; MSF Médecins Sans Frontières France; Chad Ministry of Public Health Expanded Programme on Immunisation (EPI); Chad Ministry of Public Health National Malaria Control Programme (NMCP)

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: June 3, 2025
• First Submitted That Met QC Criteria: June 17, 2025
• First Posted (Actual): June 26, 2025

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Children; Malaria; Vaccine; Pediatric; prevention; prevalence; incidence; cost effectiveness; coverage; Implementation strategy; mixed methods; qualitative; Seasonal Malaria Chemoprevention; synchronized
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; Protozoan Infections; Parasitic Diseases; Malaria; Investigative Techniques; Methods
• Other Study ID Numbers: COSAV-R21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No