A Multi-Targeting, Nucleoside-Modified mRNA Influenza Virus Vaccine Provides Broad Protection in Mice
A Multi-Targeting, Nucleoside-Modified mRNA Influenza Virus Vaccine Provides Broad Protection in Mice
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DOI：
10.1016/j.ymthe.2020.04.018
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发表时间：
2020-07-08
影响因子：
12.4
通讯作者：
Nachbagauer, Raffael
中科院分区：
文献类型：
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作者：
Freyn, Alec W.;da Silva, Jamile Ramos;Nachbagauer, Raffael
流感病毒是引起全世界公共卫生关注的呼吸道病原体，每年造成多达65万人死亡。季节性流感病毒疫苗用于预防疾病，但效果有限。开发一种可能引起持久、广泛交叉反应性免疫反应的通用流感病毒疫苗对于降低流感病毒流行是必要的。在这项研究中，我们利用脂质纳米颗粒封装、核苷修饰的mRNA疫苗皮内递送保守的流感病毒抗原（血凝素柄、神经氨酸酶、基质-2离子通道和核蛋白），并在小鼠模型中诱导具有相当广度和效力的强免疫反应。核苷修饰的mrna -脂质纳米颗粒疫苗所赋予的免疫力，在单次免疫后提供了500倍于中位致死剂量的H1N1大流行性病毒攻击保护，而联合疫苗在每个抗原50 ng的剂量下可防止发病。单剂联合疫苗具有广泛的保护潜力，用一组1组甲型流感病毒攻毒证实了这一点。这些发现支持了核苷修饰的mrna -脂质纳米颗粒疫苗作为通用流感病毒候选疫苗的进展。
Influenza viruses are respiratory pathogens of public health concern worldwide with up to 650,000 deaths occurring each year. Seasonal influenza virus vaccines are employed to prevent disease, but with limited effectiveness. Development of a universal influenza virus vaccine with the potential to elicit long-lasting, broadly cross-reactive immune responses is necessary for reducing influenza virus prevalence. In this study, we have utilized lipid nanoparticle-encapsulated, nucleoside-modified mRNA vaccines to intradermally deliver a combination of conserved influenza virus antigens (hemagglutinin stalk, neuraminidase, matrix-2 ion channel, and nucleoprotein) and induce strong immune responses with substantial breadth and potency in a murine model. The immunity conferred by nucleoside-modified mRNA-lipid nanoparticle vaccines provided protection from challenge with pandemic H1N1 virus at 500 times the median lethal dose after administration of a single immunization, and the combination vaccine protected from morbidity at a dose of 50 ng per antigen. The broad protective potential of a single dose of combination vaccine was confirmed by challenge with a panel of group 1 influenza A viruses. These findings support the advancement of nucleoside-modified mRNA-lipid nanoparticle vaccines expressing multiple conserved antigens as universal influenza virus vaccine candidates.