Overview

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.

Eligibility

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

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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.