中东呼吸综合征新型人源应急救治单克隆抗体保护作用机制研究

The newly discovered Middle East Respiratory Syndrome coronavirus (MERS-CoV) is the causative agent for MERS. Administration of protective monoclonal antibodies derived from convalescent MERS patients is a potent prophylactic and therapeutic treatment against lethal MERS-CoV infection. Our group generated the first MERS mouse model (PNAS 2014) and developed the first patient derived MERS protective monoclonal antibody (PNAS 2015) previously. However, most of these antibodies target the S1 domain to the N terminal of MERS-CoV spike protein, which is prone to mutation. The S2 domain to the C terminal is relatively stable and conserved among coronaviruses. No protective antibody is developed targeting S2 domain and the possibility of S2 domain to induce cross-protective antibodies against different human respiratory coronaviruses remains unknown. Our group will optimize the EBV transformation platform and immortalize human memory B cells from periphery blood and generate novel protective monoclonal antibodies targeting S2 domain of MERS-CoV spike protein; further we will decipher the mechanism that these antibodies using to protect from lethal MERS-CoV infection, and will investigate whether S2 domain could induce cross-protective antibodies after different human respiratory coronavirus infections. These studies will help prevent and control MERS epidemic in China.

中东呼吸综合征（Middle East Respiratory Syndrome, MERS）是由新型冠状病毒MERS-coronavirus（CoV）引起的急性重症肺炎。MERS病人来源的单克隆应急救治抗体是防控重要手段。本团队前期研发了国际首个MERS小鼠动物模型（PNAS 2014）和MERS病人来源单克隆保护性抗体（PNAS 2015）。然而此抗体识别MERS-CoV Spike蛋白N端S1结构域，易于受病毒变异影响。C端S2结构域在多种冠状病毒中保守，也可诱导中和抗体产生，而识别MERS-CoV S2的保护性抗体在国际上仍空白；不同呼吸道冠状病毒感染后，S2是否诱导产生抗MERS交叉保护性抗体也不明。本项目拟基于前期研究，改良EB病毒转化人外周血记忆性B细胞技术；研发识别MERS-CoV S2应急救治抗体；阐明不同呼吸道冠状病毒感染后抗体的交叉反应性；填补国内外空白并协助疫情防控

中东呼吸综合征是由高致病性冠状病毒MERS-CoV引起的急性重症肺炎。MERS病人血清学监测分析、病人来源的单克隆应急救治抗体制备及不同时期流行MERS-CoV毒株致病性变化也是高致病性冠状病毒防控的的关键。本团队前期研发了国际首个MERS小鼠动物模型和MERS病人来源单克隆保护性抗体，然而此抗体识别MERS-CoV Spike蛋白的RBD区域，易于受病毒变异影响，非RBD区域中和抗体开发较少，但非RBD区域更为保守，也可诱导中和抗体产生，识别MERS-CoV 非RBD区域的保护性抗体研究在国际上仍存在很大空缺，此外MERS血清学变化规律及不同毒株的致病性演变目前均尚未开展，直接制约的人们对高致病性冠状病毒的了解和防控体系建立。本项目基于前期研究，改良EB病毒转化人外周血记忆性B细胞技术；研发识别MERS-CoV S2、NTD、RBD应急救治抗体；阐明不同呼吸道冠状病毒感染后抗体的交叉反应性，解析MERS早期流行株和当代流行株致病机制变化规律、随着时间延长MERS康复者血清学变化特征及抗体持续期等关键问题；填补国内外空白并协助疫情防控。