冠状病毒
冠状病毒是单股、正链的RNA囊膜病毒，其宿主范围十分广泛。常见宿主包括宠物（猫、狗）、家畜（猪、牛）、鸟类、蝙蝠等。截至目前，共有7种冠状病毒可在人群中传播，分别为HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV（非典病毒）、MERS-CoV（中东呼吸综合征病毒）与SARS-CoV-2（新冠病毒），其中后三种对全球人民生命健康与经济发展造成了严重的损失。此外，两种动物冠状病毒Hu-PDCoV与 CCoV-HuPn-2018同样被发现能够感染人类，但并未造成传播。
在新冠肺炎疫情中，高福院士团队在党中央的坚强领导下，率先确定病原体、测序病毒全基因组、成功分离病毒，第一时间发出预警，以实际行动践行习近平总书记“公开、透明、负责任”的疫情处置重要指示精神。同时，高福院士带领团队迅速开展病毒入侵、跨种传播、病毒变异株、新型疫苗研发、生物大分子药物开发、检测试剂盒的开发六大方向的系统性研究，为抗击疫情提供科技支撑。基础研究方面，相关成果在Cell（7篇）、Science（1篇）、Nature（3篇）、Lancet（7篇）和NEJM（6篇）等国际知名期刊发表；应用方面，开发出全球首个治疗性抗体（17国获批使用）、首个重组蛋白亚单位疫苗（6国获批使用）、多种临床检测试剂盒（70余国使用）。
1. 率先确定病原体、测序病毒全基因组并第一时间共享、成功分离病毒
新冠肺炎疫情爆发初期，高福院士作为时任中国疾病预防控制中心主任，以高度的专业敏感性意识到其严重性并及时报告卫健委领导，并作为专家组成员赴武汉调查。团队于2020年1月2日接到肺炎样本，于3日获得病毒全基因组序列并完成病毒鉴定，4日成功研制出特异性核酸检测试剂，7日成功从临床样本中分离得到新冠病毒并刊发全球首个病毒电镜照片，8日同世界卫生组织沟通病毒基因组序列信息共享事宜，在国家卫生健康委指导下向世界卫生组织提交新冠病毒基因组序列信息，10日正式在全球流感共享数据库（GISAID）发布，11日统筹商品化检测试剂发放至湖北，为疫情初期的快速响应争取了时间。24-29日，先后用《新英格兰医学》《柳叶刀》等杂志平台与世界同行共享数据、公开信息、分享经验，展示了中国负责任的大国形象（Lancet, 2020a, b, c, NEJM, 2020a, b）。
2. 病毒感染机制与跨种传播研究
冠状病毒感染的第一步是通过刺突（S）蛋白结合细胞表面的特定受体，这一过程在一定程度上决定了病毒的跨种传播机制，对疫苗与抗体的设计也至关重要。自新冠疫情暴发起，高福院士团队在病毒入侵机制、生物学特征及跨种传播机制等面向世界科技前沿的重大科学问题的研究中取得了系列重要进展。
新冠疫情暴发初期，团队迅速鉴定出SARS-CoV-2利用ACE2作为受体并公开了首个新冠病毒S蛋白受体结合域（RBD）与ACE2的复合物结构（Cell, 2020a），该研究入选“Cell期刊2020年度高被引论文Top10”。随着新冠病毒的变异，团队进一步解析了重要变异株（VOC）的RBD/ACE2复合物结构，阐明了其入侵机制（Nat Commun, 2021; Cell, 2022a, b）
图1 新冠病毒RBD与受体相互作用的分子机制
为系统评估新冠病毒跨种传播潜力，高福院士团队提出了以筛查动物受体结合能力进行病毒溯源的研究新思路，对与人类生活密切相关的20余个物种ACE2进行检测，并将RaTG13、GD/1/2019、GX/P2V/2017等动物源性新冠相关冠状病毒同时纳入检测，系统阐明了新冠相关冠状病毒跨种受体识别的机制（Cell, 2021）。相关成果入选“2021年中国生命科学十大进展”
图2 新冠相关冠状病毒跨种识别谱
1. 诊防治产品开发助力疫情防控
面对突如其来的疫情，迅速开发诊防治产品，建立免疫屏障对于挽救人民生命、摆脱疫情影响至关重要。新冠病毒暴发初期，高福院士团队争分夺秒，迅速投入到了诊防治产品的开发工作中。
早在新冠疫情之前，高福院士团队在MERS-CoV的研究中提出了RBD二聚体的β冠状病毒通用疫苗设计策略并进一步优化了抗原设计获得串联的RBD二聚体。疫情暴发后，团队将该策略运用到新冠病毒，成为全球首款新冠病毒重组亚单位疫苗并与安徽智飞龙科马生物制药公司进行新冠重组蛋白疫苗开发（Cell, 2020b; New England Journal of Medicine, 2022a）。该疫苗得到中国在内的六个国家紧急使用，并在乌兹别克斯坦联合生产，被习近平总书记访乌期间发表的署名文章提及。Omicron变异株出现后，团队评估了其免疫逃逸情况并提出了优化的免疫程序（New England Journal of Medicine, 2022b, c; Lancet, 2023a, b）。此后进一步开发了基于Delta与Omicron变异株序列的二代新冠疫苗（Cell, 2022b）。
图3 β冠状病毒通用疫苗设计策略
在疫苗之外，高福院士团队利用疫情前搭建的抗体快速筛选平台，率先分离出单克隆抗体（Nature, 2020; Science, 2020）。其中JS016（CB6）与礼来公司合作开发并获得17个国家和地区的紧急使用授权。同时，团队与翰宇药业合作开发了新冠病毒鼻喷多肽抑制剂HY3000，获得临床试验批件；开发新冠病毒抗原检测试剂盒，销往70多个国家和地区。
图4 新冠病毒中和抗体Etesevimab (JS016)
新冠相关顶刊文章
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