R21 is a novel malaria vaccine, composed of a fusion protein of the malaria circumsporozoite protein and hepatitis Bsurface antigen. Following favourable safety and immunogenicity in a phase 1study, we aimed to assess the efficacy of R21 administered with Matrix-M (R21/MM) against clinical malaria in adults from the UK who were malaria naive in a controlled human malaria infection study. In this open-label, partially blinded, phase 1-2A controlled human malaria infection study undertaken inOxford, Southampton, and London, UK, we tested five novel vaccination regimens of R21/MM. Astandard three-dose regimen (groups 1and 6) was compared with a reduced (fractional) third dose (groups 2and 5) of R21/MM, concomitant administration with viral vectors ChAd63-MVA expressing ME-TRAP (group 3), and a two-dose R21/MM regimen (group 7). Controlled Human Malaria Infection (CHMI) was delivered by mosquito bite at Imperial College London, London, UK, 3-4 weeks after final vaccination (or 18months after final vaccination for group 6) alongside unvaccinated controls (groups 4A and 4B). The primary outcome measures were to assess safety of the vaccines in healthy malaria-naive volunteers and the efficacy (occurrence of blood-stage malaria infection) of the different vaccine regimens compared with non-vaccinated controls after CHMI. The trial was registered with ClinicalTrials.gov (NCT02905019). 66volunteers were enrolled with 59undergoing subsequent CHMI. All vaccination schedules were well tolerated. The highest level of protection against CHMI was observed in participants receiving the standard three-dose regimen of R21/MM (group 1, nine of 11volunteers protected) with protection maintained in three of five volunteers re-challenged by CHMI 7·5months later. Protection against malaria was also seen in group 2, group 3, and group 5compared with unvaccinated control participants. Total IgG antibody responses to the NANP repeat region of circumsporozoite protein peaked after the third dose of R21/MM in all volunteers and were well maintained to 90days after challenge. Reducing the third dose did not affect protection or antibody concentrations. Our study shows that R21/MM elicits high-level efficacy against clinical malaria in a controlled human infection model of malaria in adults who are malaria naive. These data supported the evaluation of R21/MM in field efficacy trials in the target population of young children in malaria-endemic areas. EU Horizon 2020, the UK Medical Research Council, the European Commission, the UK National Institute of Health Research, the Imperial NIHR Clinical Research Facility, the Oxford NIHR Biomedical Research Centre, and the Wellcome Trust.
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