Assessing Vaccine Effectiveness of R21/Matrix-M Across Malaria Transmission Settings (AVERT)

R21/Matrix-M has been introduced through national immunization programs, but its effectiveness under routine conditions may differ from efficacy observed in clinical trials because children may receive different numbers of doses, doses may be delayed, protection may wane, and malaria transmission and other prevention measures vary across settings.

AVERT will use a prospective test-negative case-control design at approximately 22 outpatient health facilities in moderate- to high-transmission areas of Burkina Faso and Uganda. Consecutive children younger than 5 years who meet country definitions for suspected malaria, are eligible for R21/Matrix-M vaccination, and have caregiver consent will be enrolled. All participants will undergo malaria testing as part of routine care, with study blood smear microscopy used to assign case or control status. A structured caregiver questionnaire will collect demographic, clinical, residential, socioeconomic, health-care access, and malaria-prevention information. R21/Matrix-M dose number and vaccination dates will be verified primarily from vaccination cards, individual health records, or facility vaccination registers.

Cases and controls will be matched, when feasible, by geographic area and calendar time. Conditional or standard logistic regression will estimate adjusted odds ratios comparing vaccinated and unvaccinated children, and vaccine effectiveness will be calculated as (1 - adjusted odds ratio) x 100%. Analyses will be conducted separately by country and will assess effectiveness by dose, time since vaccination, dose spacing, transmission intensity, sex, and use of seasonal malaria chemoprevention, insecticide-treated nets, and indoor residual spraying. A health-system-perspective economic evaluation will estimate incremental cost per uncomplicated clinical malaria case averted.

Inclusion criteria

• Residence in an area where R21/Matrix-M is implemented and within the catchment area of a selected study facility.
• Younger than 5 years and eligibleto receive R21/Matrix-M under the national vaccination schedule at rollout.
• Meets the country definition of suspected malaria, generally axillary temperature of at least 37.5 degrees Celsius or a history of fever within the previous 24 hours, and is undergoing malaria testing.
• Written informed consent provided by an adult caregiver aged 18 years or older.

Exclusion criteria

• Caregiver is unable or unwilling to provide informed consent.
• Severe non-malaria illness at presentation that would interfere with study participation.
• Repeat presentation within the protocol-defined exclusion window after a previous enrollment: within 14 days after a microscopy-positive visit; or more than 7 but fewer than 14 days after a microscopy-negative visit. A microscopy-negative visit followed by a positive diagnosis within 7 days will be reclassified as positive rather than treated as a new enrollment.
• Documented receipt of any RTS,S malaria vaccine dose.