Background FLU-v is a broad-spectrum influenza vaccine that induces antibodies and cell-mediated immunity. Objective To compare the safety, immunogenicity, and exploratory efficacy of different formulations and dosing regimens of FLU-v versus placebo. Design Randomized, double-blind, placebo-controlled, single-center phase 2b clinical trial. (ClinicalTrials.gov: NCT02962908; EudraCT: 2015-001932-38). Setting The Netherlands. Participants 175 healthy adults aged 18 to 60 years. Intervention 0.5-mL subcutaneous injection of 500 µg of adjuvanted (1 dose) or nonadjuvanted (2 doses) FLU-v (A-FLU-v or NA-FLU-v) or adjuvanted or nonadjuvanted placebo (A-placebo or NA-placebo) (2:2:1:1 ratio). Measurements Vaccine-specific cellular responses at days 0, 42, and 180 were assessed via flow cytometry and enzyme-linked immunosorbent assay. Solicited information on adverse events (AEs) was collected for 21 days after vaccination. Unsolicited information on AEs was collected throughout the study. Results The AEs with the highest incidence were mild to moderate injection site reactions. The difference between A-FLU-v and A-placebo in the median fold increase in secreted interferon-γ (IFN-γ) was 38.2-fold (95% CI, 4.7- to 69.7-fold; P = 0.001) at day 42 and 25.0-fold (CI, 5.7- to 50.9-fold; P < 0.001) at day 180. The differences between A-FLU-v and A-placebo in median fold increase at day 42 were 4.5-fold (CI, 2.3- to 9.8-fold; P < 0.001) for IFN-γ-producing CD4+ T cells, 4.9-fold (CI, 1.3- to 40.0-fold; P < 0.001) for tumor necrosis factor-α (TNF-α), 7.0-fold (CI, 3.5- to 18.0-fold; P < 0.001) for interleukin-2 (IL-2), and 1.7-fold (CI, 0.1- to 4.0-fold; P = 0.004) for CD107a. At day 180, differences were 2.1-fold (CI, 0.0- to 6.0-fold; P = 0.030) for IFN-γ and 5.7-fold (CI, 2.0- to 15.0-fold; P < 0.001) for IL-2, with no difference for TNF-α or CD107a. No differences were seen between NA-FLU-v and NA-placebo. Limitation The study was not powered to evaluate vaccine efficacy against influenza infection. Conclusion Adjuvanted FLU-v is immunogenic and merits phase 3 development to explore efficacy. Primary Funding Source SEEK and the European Commission Directorate-General for Research and Innovation, European Member States within the UNISEC (Universal Influenza Vaccines Secured) project.

中文翻译：

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健康成年人中独立的通用流感疫苗FLU-v的免疫原性，安全性和有效性：一项随机临床试验。

背景FLU-v是一种广谱流感疫苗，可诱导抗体和细胞介导的免疫。目的比较FLU-v与安慰剂的不同制剂和给药方案的安全性，免疫原性和探索性功效。设计随机，双盲，安慰剂对照，单中心2b期临床试验。（ClinicalTrials.gov：NCT02962908；EudraCT：2015-001932-38）。设置荷兰。参与者175名18至60岁的健康成年人。干预0.5 mL皮下注射500 µg佐剂（1剂）或非佐剂（2剂）FLU-v（A-FLU-v或NA-FLU-v）或佐剂或非佐剂的安慰剂（A-安慰剂或NA-安慰剂） ）（比例为2：2：1：1）。测量通过流式细胞术和酶联免疫吸附试验评估第0、42和180天的疫苗特异性细胞应答。接种疫苗后21天内收集了有关不良事件（AE）的主动信息。在整个研究过程中收集了未经请求的AE相关信息。结果发生率最高的不良事件为轻度至中度注射部位反应。在第42天，A-FLU-v和A-安慰剂之间的分泌干扰素-γ（IFN-γ）中位数增加倍数的差异为38.2倍（95％CI，4.7- 69.7倍； P = 0.001）和第180天时为25.0倍（CI，为5.7-50.9倍； P <0.001）。第42天，A-FLU-v和A-安慰剂之间的中位数增加差异为4.5倍（CI，2.3- -产生IFN-γ的CD4 + T细胞至9.8倍; P <0.001），肿瘤坏死因子-α（TNF-α）7.0-（4.9％（CI，1.3- 40.0倍; P <0.001））白介素2（IL-2）的折叠倍数（CI，3.5到18.0倍; P <0.001）和1.7倍（CI，0.1到4.0倍; P = 0）。004）CD107a。在第180天，IFN-γ的差异为2.1倍（CI，0.0-至6.0倍； P = 0.030），IL-2的差异为5.7倍（CI，2.0至15.0倍； P <0.001）。与TNF-α或CD107a并无差异。NA-FLU-v和NA-安慰剂之间未见差异。局限性该研究无权评估疫苗对付流感感染的功效。结论佐剂型FLU-v具有免疫原性，值得在3期开发中探索其疗效。主要资金来源SEEK和欧洲委员会研究与创新总局，UNISEC（获得通用流感疫苗担保）项目中的欧洲成员国。NA-FLU-v和NA-安慰剂之间未见差异。局限性该研究无权评估疫苗对付流感感染的功效。结论佐剂型FLU-v具有免疫原性，值得在3期开发中探索其疗效。主要资金来源SEEK和欧洲委员会研究与创新总局，UNISEC（获得通用流感疫苗担保）项目中的欧洲成员国。NA-FLU-v和NA-安慰剂之间未见差异。局限性该研究无权评估疫苗对付流感感染的功效。结论佐剂型FLU-v具有免疫原性，值得在3期开发中探索其疗效。主要资金来源SEEK和欧洲委员会研究与创新总局，UNISEC（获得通用流感疫苗担保）项目中的欧洲成员国。