含有 B 细胞激活因子(BAFF)的高免疫原性流感病毒样颗粒,用于多亚型疫苗开发。

Highly immunogenic influenza virus-like particles containing B-cell-activating factor (BAFF) for multi-subtype vaccine development.

机构信息

Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.

National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan.

出版信息

Antiviral Res. 2019 Apr;164:12-22. doi: 10.1016/j.antiviral.2019.02.004. Epub 2019 Feb 6.

Abstract

Virus-like particle (VLP) technology is an attractive platform for the development of seasonal and pandemic influenza vaccines. Influenza VLPs can be obtained by the overexpression of HA, M1, NA, and/or M2 viral proteins in insect, mammalian, or plant cells. In this study, we reported to obtain highly immunogenic influenza VLPs by molecular incorporation with B-cell-activating factor (BAFF) or proliferation-inducing ligand (APRIL). Since BAFF and APRIL act as homotrimers to interact with their receptors, we engineered the VLPs by direct fusion of BAFF or APRIL to the transmembrane anchored domain of H5HA gene. Results showed that immunizations with the HA-transmembrane anchored BAFF- or APRIL-VLPs only formulated in alum but not MPL adjuvant elicited significantly higher IgG titers in sera. However, only the BAFF-VLPs formulated in alum adjuvant elicited more broadly neutralizing antibodies against the homologous and two heterologous H5N1 clade/subclade viruses and conferred protective immunity against live virus challenges. As the multi-subtype influenza vaccines containing a variety of HA subtypes can confer broader protective immunity, we also obtained multi-subtype H5H7 BAFF-VLPs and H1H5H7 BAFF-VLPs and demonstrated that these multi-subtype BAFF-VLPs were able to induce the production of neutralizing antibodies against multiple HA subtypes. Our findings provided useful information for the development of highly immunogenic, multi-subtype influenza VLP vaccines.

摘要

病毒样颗粒 (VLP) 技术是开发季节性和大流行性流感疫苗的有吸引力的平台。流感 VLPs 可以通过在昆虫、哺乳动物或植物细胞中过量表达 HA、M1、NA 和/或 M2 病毒蛋白来获得。在这项研究中,我们报告了通过与 B 细胞激活因子 (BAFF) 或增殖诱导配体 (APRIL) 的分子结合获得高度免疫原性的流感 VLPs。由于 BAFF 和 APRIL 作为三聚体相互作用与其受体,我们通过直接融合 BAFF 或 APRIL 到 H5HA 基因的跨膜锚定结构域来设计 VLPs。结果表明,仅用明矾配制的 HA 跨膜锚定 BAFF 或 APRIL-VLPs 进行免疫接种,而不是 MPL 佐剂,可在血清中引起更高的 IgG 滴度。然而,只有用明矾佐剂配制的 BAFF-VLPs 能诱导出针对同源和两种异源 H5N1 分支/亚分支病毒的更广泛中和抗体,并赋予针对活病毒挑战的保护免疫力。由于含有多种 HA 亚型的多亚型流感疫苗可提供更广泛的保护免疫力,我们还获得了多亚型 H5H7 BAFF-VLPs 和 H1H5H7 BAFF-VLPs,并证明这些多亚型 BAFF-VLPs 能够诱导针对多种 HA 亚型的中和抗体的产生。我们的研究结果为开发高免疫原性、多亚型流感 VLP 疫苗提供了有用的信息。

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