奥地利默克公司子公司Themis生物科学Roland Tschismarov团队研究了重组麻疹载体的拉沙热疫苗的免疫原性、安全性和耐受性。2023年3月16日出版的《柳叶刀》杂志发表了这项成果。

拉沙热在西非是一个巨大的健康负担。研究组评估了重组、减毒、活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。

研究组在比利时安特卫普大学的单一机构进行了首次人体1期试验，由开放标签剂量递增阶段和观察者盲、随机、安慰剂对照治疗阶段组成，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（两次肌内注射MV-LASV，剂量为组织培养感染剂量中位数的2 × 10⁴倍）或高剂量组（组织培养感染剂量中位数的1 × 10⁵倍）。

双盲治疗阶段的参与者以2:2:1的比例被随机分配接受低剂量、高剂量MV-LASV或安慰剂。主要终点是截至研究第56天的设定或非设定记录不良事件发生率，并在接受至少一剂研究药物的所有参与者中进行评估。

2019年9月26日至2020年1月20日，60名参与者被招募并分配接受安慰剂（n=12）或MV-LASV（n=48）。所有60名参与者至少接受了一次研究治疗。大多数不良事件发生在治疗阶段，治疗组之间总的设定或非设定记录不良事件的发生频率相似，低剂量组96%的参与者、高剂量组100%的参与者、安慰剂组92%的参与者有任何设定记录不良事件，组间差异不显著；而低剂量组76%、高剂量组70%的患者和安慰剂组100%的患者有任何非设定记录不良事件，MV-LASV组与安慰剂组间差异显著。

唯一的显著差异与局部引起的不良事件有关，在MV-LASV组中观察到的频率更高（低剂量组25名参与者中有24名[96%]；高剂量组所有23名[100%]），而安慰剂组12名参与者中有6名（50%）。不良事件大多为轻度或中度，未观察到严重不良事件。MV-LASV还诱导了大量的LASV特异性IgG（第42天，低剂量组的几何平均滴度为62.9 EU/ml，高剂量组为145.9 EU/ml）。

研究结果表明，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对该载体的免疫影响。因此，MV-LASV是一个很有前途的进一步发展的候选疫苗。

附：英文原文

Title: Immunogenicity, safety, and tolerability of a recombinant measles-vectored Lassa fever vaccine: a randomised, placebo-controlled, first-in-human trial

Author: Roland Tschismarov, Pierre Van Damme, Clara Germain, Ilse De Coster, Mathieu Mateo, Stephanie Reynard, Alexandra Journeaux, Yvonne Tomberger, Kanchanamala Withanage, Denise Haslwanter, Katherine Terler, Sabrina Schrauf, Matthias Müllner, Erich Tauber, Katrin Ramsauer, Sylvain Baize

Issue&Volume: 2023-03-16

Abstract:

Background

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).

Methods

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 2×104 times the median tissue culture infectious dose) or a high-dose group (two doses at 1×105 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 ClinicalTrials.gov, NCT04055454, and the European Union Drug Regulating Authorities Clinical Trials Database, 2018-003647-40, and is complete.

Findings

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).

Interpretation

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.

DOI: 10.1016/S0140-6736(23)00048-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00048-X/fulltext