Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection

Jielin Tang; Muqing Fu; Chonghui Xu; Bao Xue; Anqi Zhou; Sijie Chen; He Zhao; Yuan Zhou; Jizheng Chen; Qi Yang; Xinwen Chen

doi:10.1016/j.virs.2023.06.003

October 2023

Jielin Tang, Muqing Fu, Chonghui Xu, Bao Xue, Anqi Zhou, Sijie Chen, He Zhao, Yuan Zhou, Jizheng Chen, Qi Yang and Xinwen Chen. Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection[J]. Virologica Sinica, 2023, 38(5): 767-777. doi: 10.1016/j.virs.2023.06.003

Citation: Jielin Tang, Muqing Fu, Chonghui Xu, Bao Xue, Anqi Zhou, Sijie Chen, He Zhao, Yuan Zhou, Jizheng Chen, Qi Yang, Xinwen Chen. Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection .VIROLOGICA SINICA, 2023, 38(5) : 767-777. http://dx.doi.org/10.1016/j.virs.2023.06.003

一种新型蜱传脑炎病毒样颗粒疫苗的研发

唐婕琳 ^a,b ,
付牧青 ^c ,
许崇辉 ^b ,
薛豹 ^a,b ,
周安琪 ^d ,
陈思杰 ^d ,
赵赫 ^b ,
周缘 ^b ,
陈继征 ^a,b,e ,
杨琪 ^a,b,, ,
陈新文 ^a,b,e,,

a. 广州实验室, 广州 510005;
b. 中国科学院武汉病毒研究所, 中国科学院生物安全大科学研究中心, 武汉 430071;
c. 中国科学院广州生物医药与健康研究院, 广州 510530;
d. 广州医科大学-广州生物医药与健康研究院联合生科院, 广州, 511436;
e. 广州医科大学呼吸疾病国家重点实验室, 广州, 511436

通讯作者： 杨琪, yang_qi@gzlab.ac.cn; 陈新文, chen_xinwen@gzlab.ac.cn
收稿日期： 2023-03-12
录用日期： 2023-06-12

摘要

蜱传脑炎病毒（Tick-borne encephalitis virus, TBEV）是一种以蜱虫为传播媒介的人畜共患病原体，感染可引起脑膜炎、脑炎和脑膜脑炎等神经系统疾病症状，病死率高达10-20%。由于已批准的疫苗免疫原性相对较低、接种率不高等劣势，导致TBEV感染的患者恢复不完全。因此，开展新型、高效、安全的TBEV疫苗研发具有重要意义。本项目设计了一款在Expi293F细胞中共表达TBE结构蛋白（Core/prM/E）和非结构蛋白（NS2B/NS3Pro），通过体内自组装形成病毒样颗粒（Virus-like particles, VLPs）。通过病毒大小、形态和比对免疫VLPs小鼠血清IgG产生能力、病毒中和能力、CD4+ T细胞应答和攻毒保护实验等综合评估VLPs的功效。结果显示免疫VLPs的C57/BL6小鼠能产生高水平IgG应答，其小鼠血清也能高效中和TBEV远东亚型和欧洲亚型的感染，呈现了抗体交叉保护反应。免疫VLPs的I型干扰素受体缺失小鼠（IFNAR-/-）可免受TBEV感染。免疫VLPs小鼠病毒感染3天后，大脑和肠道组织并未检测出病毒载量，病理切片也未出现明显的病变。同时，接种VLPs小鼠脑组织中炎症因子受到明显抑制。此外，VLPs免疫诱导小鼠体内产生多细胞因子介导的抗病毒CD4+ T细胞反应，包括TNF-α+、IL-2+和IFN-γ+ T细胞。以上结果表明此种TBEV VLPs可以作为一款潜在且安全有效、用于抗蜱传脑炎病毒感染的候选疫苗。
- 蜱传脑炎病毒（TBEV）
- , 病毒样颗粒（VLP）
- , 免疫原性
- , 中和反应
- , 疫苗

Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection

Jielin Tang ^a,b ,
Muqing Fu ^c ,
Chonghui Xu ^b ,
Bao Xue ^a,b ,
Anqi Zhou ^d ,
Sijie Chen ^d ,
He Zhao ^b ,
Yuan Zhou ^b ,
Jizheng Chen ^a,b,e ,
Qi Yang ^a,b,, ,
Xinwen Chen ^a,b,e,,

a. Guangzhou National Laboratory, Guangzhou, 510005, China;
b. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China;
c. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China;
d. GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, China;
e. State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China

Corresponding author: Qi Yang, yang_qi@gzlab.ac.cn Xinwen Chen, chen_xinwen@gzlab.ac.cn
Received Date: 12 March 2023
Accepted Date: 12 June 2023

Abstract

Tick-borne encephalitis virus (TBEV) is an important tick-borne pathogen that poses as a serious public health concern. The coverage and immunogenicity of the currently available vaccines against TBEV are relatively low; therefore, it is crucial to develop novel and effective vaccines against TBEV. The present study describes a novel strategy for the assembly of virus-like particles (VLPs) by co-expressing the structural (core/prM/E) and non-structural (NS2B/NS3Pro) proteins of TBEV. The efficacy of the VLPs was subsequently evaluated in C57BL/6 mice, and the resultant IgG serum could neutralize both Far-Eastern and European subtypes of TBEV. These findings indicated that the VLP-based vaccine elicited the production of cross-subtype reactive antibodies. The VLPs provided protection to mice lacking the type I interferon receptor (IFNAR) against lethal TBEV challenge, with undetectable viral load in brain and intestinal tissues. Furthermore, the group that received the VLP vaccine did not exhibit significant pathological changes and the inflammatory factors were significantly suppressed compared to the control group. Immunization with the VLP vaccine induced the production of multiple-cytokine-producing antiviral CD4+ T cells in vivo, including TNF-α+, IL-2+, and IFN-γ+ T cells. Altogether, the findings suggest that noninfectious VLPs can serve as a potentially safe and effective vaccine candidate against diverse subtypes of TBEV.
- Tick-borne encephalitis virus (TBEV)
- , Virus-like particle (VLP)
- , Immunogenicity
- , Neutralization
- , Vaccine

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