Venkatraman Navin, Silman Daniel, Bellamy Duncan, Stockdale Lisa, Bowyer Georgina, Edwards Nick J, Griffiths Oliver, Lopez Fernando Ramos, Powlson Jonathan, Mair Catherine, Folegatti Pedro M, Datoo Mehreen S, Morter Richard, Minassian Angela M, Poulton Ian, Collins Katharine A, Brod Florian, Angell-Manning Philip, Berrie Eleanor, Brendish Nathan, Glenn Greg, Fries Louis, Baum Jake, Blagborough Andrew M, Roberts Rachel, Lawrie Alison M, Angus Brian, Lewis David J M, Faust Saul N, Ewer Katie J, Hill Adrian V S
Jenner Institute, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK; Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK.
Jenner Institute, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK.
Lancet Microbe. 2025 Mar;6(3):100867. doi: 10.1016/S2666-5247(24)00083-1. Epub 2025 Jan 10.
R21 is a novel malaria vaccine, composed of a fusion protein of the malaria circumsporozoite protein and hepatitis B surface antigen. Following favourable safety and immunogenicity in a phase 1 study, 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 in Oxford, Southampton, and London, UK, we tested five novel vaccination regimens of R21/MM. A standard three-dose regimen (groups 1 and 6) was compared with a reduced (fractional) third dose (groups 2 and 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 18 months 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).
66 volunteers were enrolled with 59 undergoing 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 11 volunteers protected) with protection maintained in three of five volunteers re-challenged by CHMI 7·5 months later. Protection against malaria was also seen in group 2, group 3, and group 5 compared 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 90 days 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.
R21是一种新型疟疾疫苗，由疟疾环子孢子蛋白和乙肝表面抗原的融合蛋白组成。在1期研究显示出良好的安全性和免疫原性之后，我们旨在评估在一项受控人体疟疾感染研究中，给来自英国且未曾感染过疟疾的成年人接种R21并联合使用基质-M（R21/MM）预防临床疟疾的效果。
在英国牛津、南安普顿和伦敦进行的这项开放标签、部分设盲的1-2A期受控人体疟疾感染研究中，我们测试了R21/MM的五种新型疫苗接种方案。将标准三剂方案（第1组和第6组）与R21/MM的减量（分剂）第三剂方案（第2组和第5组）、与表达ME-TRAP的病毒载体ChAd63-MVA同时接种（第3组）以及两剂R21/MM方案（第7组）进行比较。在英国伦敦帝国理工学院，最终接种疫苗后3-4周（第6组为最终接种疫苗后18个月），通过蚊虫叮咬对受试者进行受控人体疟疾感染（CHMI），同时设置未接种疫苗的对照组（第4A组和第4B组）。主要结局指标是评估疫苗在健康且未曾感染过疟疾的志愿者中的安全性，以及与CHMI后未接种疫苗的对照组相比，不同疫苗方案的有效性（血期疟疾感染的发生率）。该试验已在ClinicalTrials.gov注册（NCT02905019）。
66名志愿者入组，其中59人接受了后续的CHMI。所有疫苗接种方案的耐受性均良好。在接受R21/MM标准三剂方案的参与者（第
