A multiple-target mRNA-LNP vaccine induces protective immunity against experimental multi-serotype DENV in mice

Lihong He; Wenqiang Sun; Limin Yang; Wenjun Liu; Jing Li

doi:10.1016/j.virs.2022.07.003

October 2022

. doi: 10.1016/j.virs.2022.07.003

Citation: Lihong He, Wenqiang Sun, Limin Yang, Wenjun Liu, Jing Li. A multiple-target mRNA-LNP vaccine induces protective immunity against experimental multi-serotype DENV in mice .VIROLOGICA SINICA, 2022, 37(5) : 746-757. http://dx.doi.org/10.1016/j.virs.2022.07.003

多靶标mRNA-LNP疫苗诱导小鼠对多血清型DENV的保护性免疫力

何丽红 ^a,c ,
孙文强 ^a,b ,
杨利敏 ^a ,
刘文军 ^a,b,c,d,, ,
李晶 ^a,c,,

中国科学院微生物研究所

通讯作者： 刘文军, liuwj@im.ac.cn; 李晶, lj418@163.com
收稿日期： 2022-04-15
录用日期： 2022-07-04

摘要

登革热病毒（DENV）是一种蚊媒传播病毒，在人类的传播速度很快，是一种每年在数亿人中引起轻微到可能致命的疾病。由于该病毒的血清型众多，开发针对该病毒广谱的保护性疫苗的需求仍然没有得到满足。在此，我们构建了一种含有包膜结构域III（E-DIII）和非结构蛋白1（NS1）的mRNA疫苗，并将其包封在脂质纳米颗粒进行有效递送。这种多靶点疫苗诱发了强大的抗病毒免疫反应，增加了中和抗体滴度，在体外阻断了四种血清型的感染，且没有明显的抗体依赖性增强效应。此外，单剂量加强免疫后，针对E-DIII和NS1特异性T细胞更倾向于Th1。重要的是，通过肌肉注射免疫可抵抗DENV在小鼠体内的复制并消除组织血管渗漏。我们的研究结果表明，嵌合异源结构蛋白和非结构蛋白可以成为DENV疫苗的有效靶点。
- 登革病毒
- , mRNA疫苗
- , 包膜结构域III
- , 非结构蛋白1
- , 多血清型
- , 免疫反应

A multiple-target mRNA-LNP vaccine induces protective immunity against experimental multi-serotype DENV in mice

Lihong He ^a,c ,
Wenqiang Sun ^a,b ,
Limin Yang ^a ,
Wenjun Liu ^a,b,c,d,, ,
Jing Li ^a,c,,

a CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China;

Corresponding author: Wenjun Liu, liuwj@im.ac.cn Jing Li, lj418@163.com
Received Date: 15 April 2022
Accepted Date: 04 July 2022

Abstract

Dengue virus (DENV) is a mosquito-borne virus with a rapid spread to humans, causing mild to potentially fatal illness in hundreds of millions of people each year. Due to the large number of serotypes of the virus, there remains an unmet need to develop protective vaccines for a broad spectrum of the virus. Here, we constructed a modified mRNA vaccine containing envelope domain III (E-DIII) and non-structural protein 1 (NS1) coated with lipid nanoparticles. This multi-target vaccine induced a robust antiviral immune response and increased neutralizing antibody titers that blocked all four types of DENV infection in vitro without significant antibody-dependent enhancement (ADE). In addition, there was more bias for Th1 than Th2 in the exact E-DIII and NS1-specific T cell responses after a single injection. Importantly, intramuscular immunization limited DENV transmission in vivo and eliminated vascular leakage. Our findings highlight that chimeric allogeneic structural and non-structural proteins can be effective targets for DENV vaccine and that they can prevent the further development of congenital DENV syndrome.
- Dengue virus (DENV)
- , mRNA vaccine
- , Envelope domain III (E-DIII)
- , Non-structural protein 1 (NS1)
- , Multi-serotype
- , Immune response

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