Zhang Hui, Liu He, Wei Jing, Dang Yamei, Wang Yuan, Yang Qiqi, Zhang Liang, Ye Chuantao, Wang Bin, Jin Xiaolei, Cheng Linfeng, Ma Hongwei, Dong Yangchao, Li Yinghui, Bai Yinlan, Lv Xin, Lei Yingfeng, Xu Zhikai, Ye Wei, Zhang Fanglin
Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi' an, Shaanxi, China.
Center for Disease Control and Prevention of Shaanxi Province, Xi'an, Shaanxi, China.
NPJ Vaccines. 2024 Feb 10;9(1):28. doi: 10.1038/s41541-024-00814-2.
Hantaan virus (HTNV) is a pathogenic orthohantavirus prevalent in East Asia that is known to cause hemorrhagic fever with severe renal syndrome (HFRS), which has a high fatality rate. However, a Food and Drug Administration (FDA)-approved vaccine is not currently available against this virus. Although inactivated vaccines have been certified and used in endemic regions for decades, the neutralizing antibody (NAb) titer induced by inactivated vaccines is low and the immunization schedule is complicated, requiring at least three injections spanning approximately 6 months to 1 year. Replication-competent vesicular stomatitis virus (VSV)-based vaccines provide prolonged protection after a single injection. In this study, we successfully engineered the HTNV glycoprotein (GP) in the VSV genome by replacing the VSV-G open reading frame. The resulting recombinant (r) rVSV-HTNV-GP was rescued, and the immunogenicity of GP was similar to that of HTNV. BALB/c mice immunized with rVSV-HTNV-GP showed a high titer of NAb against HTNV after a single injection. Notably, the cross-reactive NAb response induced by rVSV-HTNV-GP against Seoul virus (an orthohantavirus) was higher than that induced by three sequential injections of inactivated vaccines. Upon challenge with HTNV, rVSV-HTNV-GP-immunized mice showed a profoundly reduced viral burden in multiple tissues, and inflammation in the lungs and liver was nearly undetectable. Moreover, a single injection of rVSV-HTNV-GP established a prolonged immunological memory status as the NAbs were sustained for over 1 year and provided long-term protection against HTNV infection. The findings of our study can support further development of an rVSV-HTNV-GP-based HTNV vaccine with a simplified immunization schedule.
汉坦病毒（HTNV）是一种在东亚流行的致病性正汉坦病毒，已知可引起具有高致死率的肾综合征出血热（HFRS）。然而，目前尚无美国食品药品监督管理局（FDA）批准的针对该病毒的疫苗。尽管灭活疫苗已在流行地区认证并使用了数十年，但灭活疫苗诱导的中和抗体（NAb）滴度较低，且免疫程序复杂，至少需要约6个月至1年的三次注射。具有复制能力的基于水疱性口炎病毒（VSV）的疫苗单次注射后可提供长期保护。在本研究中，我们通过替换VSV-G开放阅读框，成功地在VSV基因组中构建了HTNV糖蛋白（GP）。由此产生的重组（r）rVSV-HTNV-GP被拯救出来，并且GP的免疫原性与HTNV相似。用rVSV-HTNV-GP免疫的BALB/c小鼠单次注射后显示出针对HTNV的高滴度NAb。值得注意的是，rVSV-HTNV-GP诱导的针对汉城病毒（一种正汉坦病毒）的交叉反应性NAb反应高于三次连续注射灭活疫苗所诱导的反应。在用HTNV攻击后，rVSV-HTNV-GP免疫的小鼠在多个组织中的病毒载量显著降低，并且在肺和肝脏中的炎症几乎不可检测。此外，单次注射rVSV-HTNV-GP建立了长期的免疫记忆状态，因为NAb持续超过1年，并提供了针对HTNV感染的长期保护。我们的研究结果可为进一步开发具有简化免疫程序的基于rVSV-HTNV-GP的HTNV疫苗提供支持。
