Neutralizing Monoclonal Antibodies against the Gn and the Gc of the Andes Virus Glycoprotein Spike Complex Protect from Virus Challenge in a Preclinical Hamster Model
Neutralizing Monoclonal Antibodies against the Gn and the Gc of the Andes Virus Glycoprotein Spike Complex Protect from Virus Challenge in a Preclinical Hamster Model
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DOI：
10.1128/mbio.00028-20
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发表时间：
2020-03-01
期刊：
影响因子：
6.4
通讯作者：
Krammer, Florian
中科院分区：
文献类型：
--
作者：
Duehr, James;McMahon, Meagan;Krammer, Florian
汉坦病毒是肾综合征出血热（HFRS）和汉坦病毒心肺综合征（HCPS）的病原体。后者与30%至50%的病死率有关。HCPS病例很罕见，在美洲每年约有300例。最近，在阿根廷西南部丘布特州的Epuyen及其周围地区发生了前所未有的HCPS爆发。自2018年11月以来，至少有29例病例得到实验室确认，并怀疑人与人之间的传播。尽管对公众健康构成重大威胁，但汉坦病毒病没有治疗方法或疫苗。在这里，我们描述了一个努力，以确定，表征，并开发中和和保护性抗体对糖蛋白复合物（Gn和Gc）的安第斯山脉病毒（ANDV），病原体的Epuyen爆发。使用鼠杂交瘤技术，我们产生了19种不同的抗ANDV GnGc的单克隆抗体（MAbs）。当针对表达安第斯山脉糖蛋白（GP）的重组水泡性口炎病毒（VSV-ANDV）进行中和试验时，在抗体依赖性细胞毒性报告基因测定中，12种单克隆抗体显示出有效的中和作用，8种单克隆抗体显示出活性。逃逸突变体分析显示，中和单克隆抗体靶向Gn和Gc。选择结合不同表位的四种单克隆抗体进行临床前研究，发现在ANDV感染的叙利亚仓鼠模型中对致死性具有100%的保护作用。这些数据表明汉坦病毒GnGc上存在广泛的中和抗体表位，具有独特的性质和作用机制。重要信息新世界汉坦病毒感染与高病死率相关，并且没有特定的疫苗或治疗方案存在。此外，汉他病毒GnGc复合物的生物学、其抗原性和其融合机制知之甚少。抗GnGc的保护性单克隆抗体有可能发展成为抗汉他病毒病的治疗药物，也是阐明糖蛋白复合物生物学的重要工具。
Hantaviruses are the etiological agent of hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The latter is associated with case fatality rates ranging from 30% to 50%. HCPS cases are rare, with approximately 300 recorded annually in the Americas. Recently, an HCPS outbreak of unprecedented size has been occurring in and around Epuyen, in the southwestern Argentinian state of Chubut. Since November of 2018, at least 29 cases have been laboratory confirmed, and human-to-human transmission is suspected. Despite posing a significant threat to public health, no treatment or vaccine is available for hantaviral disease. Here, we describe an effort to identify, characterize, and develop neutralizing and protective antibodies against the glycoprotein complex (Gn and Gc) of Andes virus (ANDV), the causative agent of the Epuyen outbreak. Using murine hybridoma technology, we generated 19 distinct monoclonal antibodies (MAbs) against ANDV GnGc. When tested for neutralization against a recombinant vesicular stomatitis virus expressing the Andes glycoprotein (GP) (VSV-ANDV), 12 MAbs showed potent neutralization and 8 showed activity in an antibody-dependent cellular cytotoxicity reporter assay. Escape mutant analysis revealed that neutralizing MAbs targeted both the Gn and the Gc. Four MAbs that bound different epitopes were selected for preclinical studies and were found to be 100% protective against lethality in a Syrian hamster model of ANDV infection. These data suggest the existence of a wide array of neutralizing antibody epitopes on hantavirus GnGc with unique properties and mechanisms of action.IMPORTANCE Infections with New World hantaviruses are associated with high case fatality rates, and no specific vaccine or treatment options exist. Furthermore, the biology of the hantaviral GnGc complex, its antigenicity, and its fusion machinery are poorly understood. Protective monoclonal antibodies against GnGc have the potential to be developed into therapeutics against hantaviral disease and are also great tools to elucidate the biology of the glycoprotein complex.