Lassa fever is a substantial health burden in west Africa. We evaluated the safety, tolerability, and immunogenicity of a recombinant, live-attenuated, measles-vectored Lassa fever vaccine candidate (MV-LASV). This first-in-human phase 1 trial—consisting of an open-label dose-escalation stage and an observer-blinded, randomised, placebo-controlled treatment stage—was conducted at a single site at the University of Antwerp, Antwerp, Belgium, and involved healthy adults aged 18–55 years. Participants in the dose-escalation stage were sequentially assigned to a low-dose group (two intramuscular doses of MV-LASV at 2 × 10 times the median tissue culture infectious dose) or a high-dose group (two doses at 1 × 10 times the median tissue culture infectious dose). Participants in the double-blinded treatment stage were randomly assigned in a 2:2:1 ratio to receive low dose, high dose, or placebo. The primary endpoint was the rate of solicited and unsolicited adverse events up to study day 56 and was assessed in all participants who received at least one dose of investigational product. The trial is registered with , , and the European Union Drug Regulating Authorities Clinical Trials Database, 2018-003647-40, and is complete. Between Sept 26, 2019, and Jan 20, 2020, 60 participants were enrolled and assigned to receive placebo (n=12) or MV-LASV (n=48). All 60 participants received at least one study treatment. Most adverse events occurred during the treatment phase, and frequencies of total solicited or unsolicited adverse events were similar between treatment groups, with 96% of participants in the low-dose group, 100% of those in the high-dose group, and 92% of those in the placebo group having any solicited adverse event (p=0·6751) and 76% of those in the low-dose group, 70% of those in the high-dose group, and 100% of those in the placebo group having any unsolicited adverse event (p=0·1047). The only significant difference related to local solicited adverse events, with higher frequencies observed in groups receiving MV-LASV (24 [96%] of 25 participants in the low-dose group; all 23 [100%] participants in the high-dose group) than in the placebo group (6 [50%] of 12 participants; p=0·0001, Fisher-Freeman-Halton test). Adverse events were mostly of mild or moderate severity, and no serious adverse events were observed. MV-LASV also induced substantial concentrations of LASV-specific IgG (geometric mean titre 62·9 EU/ml in the low-dose group and 145·9 EU/ml in the high-dose group on day 42). MV-LASV showed an acceptable safety and tolerability profile, and immunogenicity seemed to be unaffected by pre-existing immunity against the vector. MV-LASV is therefore a promising candidate for further development. Coalition for Epidemic Preparedness Innovations.

中文翻译：

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重组麻疹载体拉沙热疫苗的免疫原性、安全性和耐受性：一项随机、安慰剂对照、首次人体试验

拉沙热是西非的一个重大健康负担。我们评估了重组、减毒、麻疹载体拉沙热候选疫苗 (MV-LASV) 的安全性、耐受性和免疫原性。这项首次人体 1 期试验在比利时安特卫普大学的一个地点进行，包括开放标签剂量递增阶段和观察者盲法、随机、安慰剂对照治疗阶段。参与者为 18-55 岁的健康成年人。剂量递增阶段的参与者被依次分配到低剂量组（两次肌肉注射 MV-LASV，剂量为中位组织培养感染剂量的 2 × 10 倍）或高剂量组（两次剂量为 1 × 10 倍）。组织培养感染剂量中位数）。双盲治疗阶段的参与者以 2:2:1 的比例随机分配接受低剂量、高剂量或安慰剂。主要终点是截至研究第 56 天的主动和主动不良事件发生率，并在接受至少一剂研究产品的所有参与者中进行评估。该试验已在 、 和欧盟药物监管机构临床试验数据库注册，2018-003647-40，并已完成。2019 年 9 月 26 日至 2020 年 1 月 20 日期间，共有 60 名参与者入组并分配接受安慰剂 (n=12) 或 MV-LASV (n=48)。所有 60 名参与者都接受了至少一种研究治疗。大多数不良事件发生在治疗阶段，治疗组之间总的引起或非引起的不良事件发生频率相似，低剂量组为 96%，高剂量组为 100%，而高剂量组为 92%。安慰剂组中出现任何不良事件的比例 (p=0·6751)，低剂量组中 76%，高剂量组中 70%，安慰剂组中 100%发生任何未经请求的不良事件 (p=0·1047)。唯一显着差异与局部引起的不良事件有关，在接受 MV-LASV 的组中观察到的频率较高（低剂量组 25 名参与者中的 24 名 [96%]；高剂量组中所有 23 名参与者 [100%] ）高于安慰剂组（12 名参与者中的 6 名 [50%]；p=0·0001，Fisher-Freeman-Halton 检验）。不良事件大多为轻度或中度严重性，未观察到严重不良事件。MV-LASV 还诱导了高浓度的 LASV 特异性 IgG（第 42 天低剂量组的几何平均滴度为 62·9 EU/ml，高剂量组的几何平均滴度为 145·9 EU/ml）。MV-LASV 显示出可接受的安全性和耐受性，并且免疫原性似乎不受预先存在的针对该载体的免疫力的影响。因此，MV-LASV 是进一步开发的有希望的候选者。流行病防范创新联盟。