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

Official title

Real-World Effectiveness of the R21/Matrix-M Malaria Vaccine in Children in Burkina Faso and Uganda

Overview

The AVERT study is a prospective observational test-negative case control study evaluating the real-world effectiveness of the R21/Matrix-M malaria vaccine among children younger than 5 years in Burkina Faso and Uganda. Children who seek outpatient care with suspected malaria and are eligible for the national R21/Matrix-M vaccination program will be enrolled. Malaria infection will be determined by blood smear microscopy. Children with a positive microscopy result will be classified as cases and children with a negative result as controls. Vaccination history, including the number and timing of doses, will be obtained primarily from vaccination cards or other written records. Vaccine effectiveness will be estimated by comparing the odds of vaccination among cases and controls.

Detailed description

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.

Interventions

• Biological R21/Matris-M Malaria vaccine
  R21/Matrix-M vaccination received through routine national immunization programs. The study will record the number and dates of doses received. Children will be classified as having received 0, 1, 2, 3, or 4 eligible doses, with prespecified grouped classifications used if individual dose categories are underpowered. Doses given fewer than 14 days before malaria testing will not count toward the primary exposure classification.

Primary outcome measures

• Dose-specific effectiveness of R21/Matrix-M against microscopy-confirmed clinical malaria [Time frame: At the enrollment illness episode, during the approximately 7- to 8-month study recruitment period]

Secondary outcome measures (6)

• Effectiveness of R21/Matrix-M by time since vaccination [Time frame: At the enrollment illness episode, during the approximately 7- to 8-month recruitment period]
• Effect modification of vaccine effectiveness by malaria transmission intensity [Time frame: At the enrollment illness episode, during the approximately 7- to 8-month recruitment period]
• Effect modification of vaccine effectiveness by sex [Time frame: At the enrollment illness episode, during the approximately 7- to 8-month recruitment period]
• Effect modification by other malaria prevention interventions [Time frame: At the enrollment illness episode, during the approximately 7- to 8-month recruitment period]
• Effectiveness according to vaccine dose timing [Time frame: At the enrollment illness episode, during the approximately 7- to 8-month recruitment period]
• Effectiveness of the fourth dose relative to the three-dose primary series [Time frame: At the enrollment illness episode, during the approximately 7- to 8-month recruitment period]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Burkina Faso · 12 centers

• Boromo urbain 1 — Boromo
• Ouahabou — Boromo
• Béréba — Houndé
• Dohoun — Houndé
• Kari — Houndé
• Déguélin — Karangasso-Vigué
• Karangasso-Vigué — Karangasso-Vigué
• Sourmousso — Karangasso-Vigué
• … and 4 more centers

Uganda · 9 centers

• Kitgum-Matidi HCIII — Kitgum
• Namokora HCIV — Kitgum
• Lalogi HCIV — Omoro
• Rwenyawawa HCIII — Kikube
• Nawaikoke HCIII — Kaliro
• Kigandalo HCIV — Mayuge
• Nadunget HCIII — Moroto
• Orum HCIV — Otuke
• … and 1 more center

Identifiers

NCT: NCT07749911 · AVERT-2026-01 · INV-097482 · 2026-06-05

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗