This will be a double-blind, individually randomised trial, with 2:1 randomisation with the R21/Matrix-M malaria vaccine or a control rabies vaccine (Abhayrab). The study groups are as follows:~Standard vaccination regime, 5-36 months olds R21/Matrix-M x 3, n = 1600 Rabies vaccine x 3, n = 800~Seasonal vaccination regime, 5-36 month olds R21/Matrix-M x 3, n = 1600 Rabies vaccine x 3, n = 800~In each group, a booster (4th) dose of the same vaccine will be administered 12 months after the third dose. At certain trial sites, participants in the malaria vaccine group may be further randomised 1:1 to receive a single-vial: two-vial formulation of R21/Matrix-M.~Initial follow-up will be for two years after dose three, with a primary analysis at 12 months after dose 3.~Extension of the trial will be considered to allow for longer follow-up as indicated by the 12-month safety and efficacy data.~2400 participants will be enrolled for the standard vaccination regime in: Dande, Burkina Faso; Kilifi, Kenya; and Bagamoyo, Tanzania.~In addition, a further 2400 participants will be enrolled for the seasonal vaccination regime in Nanoro, Burkina Faso and Bougouni, Mali.~Study population~Standard vaccination regime:~5-36 month old children living permanently in the study area who are eligible.~Seasonal vaccination regime:~5-36 month old children living permanently in the study area who are eligible.~Primary study objectives~Efficacy:~To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum, in 5-36 month old children living in a malaria endemic area, 12 months after completion of the primary course (standard vaccination regime).~To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum, in 5-36 month old children living in a malaria endemic area, 12 months after completion of the primary course (seasonal vaccination regime).~Safety:~• To assess the safety and reactogenicity of R21/Matrix-M, in both vaccination regimes, of children living in a malaria endemic area, in the month following each vaccination, and 12 months after completion of the primary course.~Secondary objectives~Efficacy against clinical malaria after a booster vaccination~Efficacy against clinical malaria after the primary series and booster vaccination, regardless of vaccination regime~Efficacy against asymptomatic P. falciparum infection.~Efficacy against severe malaria disease.~Efficacy according to different transmission settings.~Efficacy against incident severe anaemia, blood transfusion requirement and malaria hospitalisation.~Safety and reactogenicity (including Serious adverse events (SAEs) and any deaths) following the booster vaccination and for the duration of the study.~Assessment of humoral immunogenicity by anti-CSP antibody concentrations measured 12 months after completion of the primary series of 3 vaccinations and 12 months after booster vaccination~Safety, immunogenicity and efficacy of a single- vial formulation of R21/Matrix-M~This trial is funded by the Serum Institute of India.
A Phase III randomized controlled multi-centre trial to evaluate the efficacy of the R21/Matrix-M vaccine in African children against clinical malaria