Venkatraman Navin, Tiono Alfred B, Bowyer Georgina, Bellamy Duncan G, Stockdale Lisa K, Powlson Jonathan, Collins Katharine A, Coulibaly Sam, Datoo Mehreen S, Silman Daniel, Ouedraogo Alphonse, Nébié Issa, Imoukhuede Egeruan B, Brod Florian, Folegatti Pedro, Dickinson-Craig Emma, Jamieson Sophie, Bougouma Edith C, Wright Daniel, Diarra Amidou, Bliss Carly M, Morter Richard, Glenn Greg, Fries Louis F, Reimer Jenny M, Lövgren-Bengtsson Karin, Baker Megan, Poulton Ian, Moyle Sarah, Berrie Eleanor, Green Nicola, Mukhopadhyay Ekta, Viebig Nicola K, Angus Brian, Lawrie Alison, Roberts Rachel, Gilbert Sarah C, Lewis David J M, Sirima Sodiomon B, Ewer Katie J, Hill Adrian V S
Jenner Institute, University of Oxford-NIHR Oxford Biomedical Research Centre, Oxford, UK.
Centre National de Recherche et Formation sur le Paludisme (CNRFP) Research Unit, Banfora, Burkina Faso.
Lancet Microbe. 2025 Mar;6(3):100868. doi: 10.1016/S2666-5247(24)00084-3. Epub 2025 Jan 10.
Malaria remains a substantial public health burden among young children in sub-Saharan Africa and a highly efficacious vaccine eliciting a durable immune response would be a useful tool for controlling malaria. R21 is a malaria vaccine comprising nanoparticles, formed from a circumsporozoite protein and hepatitis B surface antigen (HBsAg) fusion protein, without any unfused HBsAg, and is administered with the saponin-based Matrix-M adjuvant. This study aimed to assess the safety and immunogenicity of the malaria vaccine candidate, R21, administered with or without adjuvant Matrix-M in adults naïve to malaria infection and in healthy adults from malaria endemic areas.
In this Article we report two phase 1, first-in-human trials. The first trial was a phase 1a open-label study in the UK evaluating the safety and immunogenicity of R21 administered either alone, or with 50 μg of Matrix-M. The second trial was a phase 1b randomised controlled trial in Burkina Faso. Adults had to be aged 18-50 years for enrolment in the phase 1a trial, and 18-45 years in the phase 1b trial. The phase 1a trial doses were 2 μg, 10 μg, and 50 μg R21/Matrix-M, and 50 μg R21 only. The phase 1b trial doses were 10 μg R21/Matrix-M and saline placebo. Matrix-M was always dosed at 50 μg. Phase 1b implemented block randomisation by randomisation into study groups by an independent statistician based at the University of Oxford using a randomisation code list with allocation concealment using opaque sealed envelopes. The primary objective of the phase 1a trial was to assess the safety and tolerability of R21 with and without Matrix-M. The primary objective of the phase 1b trial was to assess the safety and tolerability of R21 with Matrix-M. Both trials are registered with ClinicalTrials.gov, NCT02572388 for phase 1a and NCT02925403 for phase 1b, and are completed.
Between Oct 1, 2015, and Jan 3, 2017, 31 individuals were enrolled in the phase 1a study. Six individuals were assigned to receive 2 μg R21/Matrix-M, 11 to 10 μg R21/Matrix-M, ten to 50 μg R21/Matrix-M, and four to 50 μg R21 only. Between Aug 26, 2016, and Sept 28, 2017, 13 individuals were enrolled in the phase 1b study. Eight individuals were assigned to receive 10 μg R21/Matrix-M, and five to placebo. Vaccinations were well tolerated, and most local and systemic adverse events were mild. There were no serious adverse events deemed related to vaccination. Two serious adverse events occurred. The first in the 10 μg R21/Matrix-M group was worsening of previously undisclosed or undiagnosed palindromic rheumatism and was deemed unlikely to be related to vaccination and the second in the 2 μg R21/Matrix-M was hospital admission for an unplanned excision of a pre-existing Bartholin's cyst, also unrelated to vaccination. In the phase 1a study, a total of 21 adverse events were recorded in the 2 μg R21/Matrix-M group, 103 in the 10 μg R21/Matrix-M group, 94 in the 50 μg R21/Matrix-M group, and 21 in the 50 μg R21 alone group. In the phase 1b study, twelve adverse events were recorded in the 10 μg R21/Matrix-M group and 0 in the placebo group.
R21 with Matrix-M adjuvant has an acceptable safety profile. These data have formed the basis for efficacy testing of this vaccine.
The European Commission Framework 7 and The European & Developing Countries Clinical Trials Partnership.
疟疾仍是撒哈拉以南非洲幼儿面临的重大公共卫生负担，一种能引发持久免疫反应的高效疫苗将是控制疟疾的有用工具。R21是一种疟疾疫苗，由环子孢子蛋白和乙型肝炎表面抗原（HBsAg）融合蛋白形成的纳米颗粒组成，不含任何未融合的HBsAg，并与基于皂苷的基质-M佐剂联合使用。本研究旨在评估在未感染疟疾的成年人以及来自疟疾流行地区的健康成年人中，使用或不使用基质-M佐剂的疟疾候选疫苗R21的安全性和免疫原性。
在本文中，我们报告了两项1期人体首次试验。第一项试验是在英国进行的1a期开放标签研究，评估单独使用R21或与50μg基质-M联合使用时的安全性和免疫原性。第二项试验是在布基纳法索进行的1b期随机对照试验。1a期试验的入选成年人年龄必须在18至50岁之间，1b期试验的入选成年人年龄必须在18至45岁之间。1a期试验的剂量为2μg、10μg和50μg R21/基质-M，以及仅50μg R21。1b期试验的剂量为10μg R21/基质-M和生理盐水安慰剂。基质-M的剂量始终为50μg。1b期试验通过牛津大学的一名独立统计学家使用随机编码列表并采用不透明密封信封进行分配隐藏，将研究组随机分组，实施区组随机化。1a期试验的主要目的是评估使用和不使用基质-M时R21的安全性和耐受性。1b期试验的主要目的是评估使用基质-M时R21的安全性和耐受性。两项试验均已在ClinicalTrials.gov上注册，1a期试验注册号为NCT02572388，1b期试验注册号为NCT02925403，且均已完成。
在2015年10月1日至2017年1月3日期间，31名个体参加了1a期研究。6名个体被分配接受2μg R21/基质-M，11名接受10μg R21/基质-M，10名接受50μg R21/基质-M，4名仅接受50μg R21。在2016年8月26日至2017年9月28日期间，13名个体参加了1b期研究。8名个体被分配接受10μg R21/基质-M，5名接受安慰剂。疫苗接种耐受性良好，大多数局部和全身不良事件为轻度。没有严重不良事件被认为与疫苗接种有关。发生了两起严重不良事件。第一起发生在10μg R21/基质-M组，是先前未披露或未诊断的回纹型风湿症病情恶化，被认为不太可能与疫苗接种有关；第二起发生在2μg R21/基质-M组，是因计划外切除先前存在的巴氏腺囊肿而住院，也与疫苗接种无关。在1a期研究中，2μg R21/基质-M组共记录了21起不良事件，10μg R21/基质-M组记录了103起，50μg R21/基质-M组记录了94起，仅50μg R21组记录了21起。在1b期研究中，10μg R21/基质-M组记录了12起不良事件，安慰剂组记录了0起。
R21与基质-M佐剂联合使用具有可接受的安全性。这些数据构成了该疫苗疗效测试的基础。
欧盟委员会框架7计划以及欧洲与发展中国家临床试验合作组织。
