Nucleoside-Modified mRNA Vaccines Protect IFNAR(-/-) Mice against Crimean-Congo Hemorrhagic Fever Virus Infection.
Nucleoside-Modified mRNA Vaccines Protect IFNAR(-/-) Mice against Crimean-Congo Hemorrhagic Fever Virus Infection.
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DOI：
10.1128/jvi.01568-21
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发表时间：
2022-02-09
影响因子：
5.4
通讯作者：
Mirazimi A
中科院分区：
文献类型：
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作者：
Appelberg S;John L;Pardi N;Végvári Á;Bereczky S;Ahlén G;Monteil V;Abdurahman S;Mikaeloff F;Beattie M;Tam Y;Sällberg M;Neogi U;Weissman D;Mirazimi A
克里米亚-刚果出血热(CCHF)是由克里米亚-刚果出血热病毒(CCHFV)引起的，被列入世界卫生组织的优先疾病和病原体名单。CCHF分布全球，病死率高，没有批准的疫苗或有效的治疗方法，对全球健康构成威胁。在目前的研究中，我们证明了编码猪瘟病毒核蛋白(N)或糖蛋白(GcGn)的核苷修饰的信使核糖脂纳米粒免疫−/−小鼠可以保护小鼠免受致死性猪瘟病毒的感染。此外，我们发现m RNA-LNP在IFNAR−/−和免疫活性小鼠中都能诱导强烈的体液和细胞免疫反应，中和抗体不是保护所必需的。在评估CCHFV gC和Gn抗原等免疫应答时，我们发现gC蛋白比Gn蛋白更具免疫原性。肝损伤在CCHF中普遍存在，并与人类疾病的严重性和死亡率有关。因此，为了了解CCHFV感染后肝脏的免疫反应和疫苗的潜在作用，我们对接种疫苗的小鼠和感染CCHFV后的对照小鼠的肝脏样本进行了蛋白质组学分析。与对人类的观察相似，接种疫苗影响了代谢途径。综上所述，本研究表明，基于病毒核蛋白或糖蛋白的CCHFV mRNA-LNP疫苗对CCHFV诱导的疾病具有中介保护作用。因此，基因免疫是预防CCHFV引起的疾病的一种有吸引力的方法，我们相信我们有必要的证据将这个疫苗平台带入下一步针对CCHFV感染的疫苗的开发。重要意义克里米亚-刚果出血热病毒(CCHFV)是引起克里米亚-刚果出血热(CCHF)的人畜共患病原体，是一种严重的发热疾病。CCHFV分布广泛，在世界多个地区流行。在新的地区也报告了CCHF病例，这表明该疾病正在扩大，令人高度关切。疾病的扩散、高死亡率和没有批准的疫苗使CCHF对全球健康构成威胁。因此，疫苗的开发非常重要。在这里，我们显示了100%保护致死性CCHFV感染用编码不同CCHFV蛋白的mRNA-LNP免疫的小鼠。疫苗接种表现出很强的体液免疫和细胞免疫。MRNA-LNP疫苗结合了诱导有效免疫反应的能力、瞬时携带者的安全性和基因疫苗的灵活性。这一结果和我们目前的研究结果支持了基于mRNA-LNP的CCHFV疫苗的开发。
Crimean-Congo hemorrhagic fever (CCHF), caused by Crimean-Congo hemorrhagic fever virus (CCHFV), is on the World Health Organizations’ list of prioritized diseases and pathogens. With global distribution, high fatality rate, and no approved vaccine or effective treatment, CCHF constitutes a threat against global health. In the current study, we demonstrate that vaccination with nucleoside-modified mRNA-lipid nanoparticles (mRNA-LNP), encoding for the CCHFV nucleoprotein (N) or glycoproteins (GcGn) protect IFNAR−/− mice against lethal CCHFV infection. In addition, we found that both mRNA-LNP induced strong humoral and cellular immune responses in IFNAR−/− and immunocompetent mice and that neutralizing antibodies are not necessary for protection. When evaluating immune responses induced by immunization including CCHFV Gc and Gn antigens, we found the Gc protein to be more immunogenic compared with the Gn protein. Hepatic injury is prevalent in CCHF and contributes to the severity and mortality of the disease in humans. Thus, to understand the immune response in the liver after infection and the potential effect of the vaccine, we performed a proteomic analysis on liver samples from vaccinated and control mice after CCHFV infection. Similar to observations in humans, vaccination affected the metabolic pathways. In conclusion, this study shows that a CCHFV mRNA-LNP vaccine, based on viral nucleo- or glycoproteins, mediate protection against CCHFV induced disease. Consequently, genetic immunization is an attractive approach to prevent disease caused by CCHFV and we believe we have necessary evidence to bring this vaccine platform to the next step in the development of a vaccine against CCHFV infection. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic pathogen causing Crimean-Congo hemorrhagic fever (CCHF), a severe fever disease. CCHFV has a wide distribution and is endemic in several areas around the world. Cases of CCHF are also being reported in new areas, indicating an expansion of the disease, which is of high concern. Dispersion of the disease, high fatality rate, and no approved vaccine makes CCHF a threat to global health. The development of a vaccine is thus of great importance. Here we show 100% protection against lethal CCHFV infection in mice immunized with mRNA-LNP encoding for different CCHFV proteins. The vaccination showed both robust humoral and cellular immunity. mRNA-LNP vaccines combine the ability to induce an effective immune response, the safety of a transient carrier, and the flexibility of genetic vaccines. This and our results from the current study support the development of a mRNA-LNP based vaccine against CCHFV.