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微生物与传染病学

张林琦

清华大学亚博全站手机网页登录教授

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挖掘免疫保护机制,开创药物和疫苗研发

张林琦教授于1992年获得英国爱丁堡大学分子病毒学博士学位,之后在美国纽约大学和洛克菲勒大学担任助理教授和副教授。2007年全职任教于清华大学,现为清华大学亚博全站手机网页登录长聘教授,北京协和亚博全站手机网页登录兼职教授,博士生导师,清华大学艾滋病综合研究中心主任。曾获国家自然科学基金委“海外杰出青年基金”和“杰出青年科学基金”,教育部“长江学者”特聘教授。是国内外多个传染病和疫苗研究机构和组织的咨询专家。2016当选首位中国籍非洲科学院院士。 张林琦教授长期从事针对病毒感染和保护性免疫机制的研究,在疫苗的免疫原设计与优化、载体的选择和构建、保护性抗体反应的机制以及评估等方面取得了突出的成绩,发表上百篇高水平的科研论文,多个抗体和疫苗已经在国内外进入人体临床试验。

从艾滋病到新型冠状病毒肺炎,抗体药物和疫苗研究

张林琦教授的科研重点是人类重大病毒性传染病的致病机理,病毒与免疫系统相互作用关系,抗病毒药物、抗体和疫苗研发。主要研究方向包括艾滋病病毒、新型冠状病毒,中东呼吸道冠状病毒,寨卡病毒等新发突发高致病性病毒。研究团队致力于利用结构生物学和免疫学的最新手段,最大限度诱导保护性免疫反应,全方位大幅度提高疫苗的安全性和保护性。同时通过深度挖掘宿主在自然感染和疫苗接种过程中的基因和蛋白组学变化,发现“保护性免疫反应”关键分子标志物,为评估疫苗的安全性和有效性提供全面和精准的指标。

· 新冠疫苗的研发

张林琦教授团队与天津医科大学周东明教授团队合作,通过对新冠spike蛋白三聚体结构的理性设计,以黑猩猩腺病毒AdC68TS为载体进行新冠病毒疫苗的研制。利用该载体搭载新型冠状病毒S蛋白,通过滴鼻和肌肉注射的方式进行疫苗的免疫,在小鼠和恒河猴体内均产生了有效的保护性免疫反应。采用这类载体研制的疫苗使用时可降低免疫剂量,从而有效降低疫苗的毒副作用,提高抗原的免疫原性,因此这种腺病毒载体更适合在临床应用。研究团队正在与沃森生物合作,将疫苗推向临床应用。目前该疫苗已获得国家药监局IND批件,正式开展临床试验。

· 新冠抗体的研发

在抗病毒治疗方面,张林琦教授团队与深圳市第三人民医院张政团队和清华大学王新泉团队合作,从新冠康复者体内筛选获得近千株全人源单克隆抗体,其中几十株具有强效抗病毒活性的中和抗体。与腾盛华创公司合作,将其中两株最强抗体组合,以抗体鸡尾酒的方式,推进人体临床试验。该抗体组合是唯一进入美国国立卫生研究院(NIH)组织的2/3期全球平台型临床试验ACTIV的中国主导研发的抗体产品,目前已在世界多地开展3期临床试验。国内有关单药和联合用药的临床研究进展顺利,在人群中安全性良好,目前正在组织开展2期临床试验。针对已发现的多种突变株,包括英国株、南非株、巴西株以及印度突变株,该抗体组合保持高效的中和能力。

· 艾滋疫苗的研发

张林琦教授团队与香港大学李嘉誠亚博全站手机网页登录艾滋病研究所所长陈志伟教授、中国科学院广州生物医药与健康研究院陈凌教授等,合作完成了粘膜疫苗在恒河猴模型体内的临床前试验研究,这种粘膜疫苗可以大幅度提高针对艾滋病病毒的T和B淋巴細胞的免疫能力,从而可以有效地抑制艾滋病病毒在体内的复制与传播。


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10.Xu Jiuyang, Jia Wenxu, Wang Pengfei, Zhang Senyan, Shi Xuanling, Wang Xinquan, Zhang Linqi. (2019). Antibodies and vaccines against Middle East respiratory syndrome coronavirus. Emerging Microbes and Infections, 8(1), 841–856. https://doi.org/10.1080/22221751.2019.1624482

11.Wang Qian, Liu Lihong, Ren Wuze, Gettie Agegnehu, Wang Hua, Liang Qingtai, Shi Xuanling, Montefiori David C., Zhou Tongqing, Zhang Linqi. (2019). A single substitution in gp41 modulates the neutralization profile of SHIV during in vivo adaptation. Cell Reports, 27(9), 2593-2607.e5. https://doi.org/10.1016/j.celrep.2019.04.108

12.Jia Wenxu, Channappanavar Rudragouda, Zhang Chao, Li Mingxi, Zhou Haixia, Zhang Shuyuan, Zhou Panpan, Xu Jiuyang, Shan Sisi, Shi Xuanling, Wang Xinquan, Zhao Jincun, Zhou Dongming, Perlman Stanley, Zhang Linqi. (2019). Single intranasal immunization with chimpanzee adenovirus-based vaccine induces sustained and protective immunity against MERS-CoV infection. Emerging Microbes and Infections, 8(1), 760–772. https://doi.org/10.1080/22221751.2019.1620083

13.Li Guanqiao, Jiang Yan, Zhang Linqi. (2019). HIV upsurge in China’s students. Science (New York, N.Y.), 364(6442), 711. https://doi.org/10.1126/science.aay0799

14.Wang Pengfei, Zuo Yanan, Sun Jianfeng, Zuo Teng, Zhang Senyan, Guo Shichun, Shi Xuanling, Liang Mifang, Zhou Paul, Zhang Linqi, Wang Xinquan. (2019). Structural and functional definition of a vulnerable site on the hemagglutinin of highly pathogenic avian influenza A virus H5N1. Journal of Biological Chemistry, 294(12), 4290–4303. https://doi.org/10.1074/jbc.RA118.007008

15.Wang Lin, Wang Ruoke, Wang Lei, Ben Haijing, Yu Lei, Gao Fei, Shi Xuanling, Yin Chibiao, Zhang Fuchun, Xiang Ye, Zhang Linqi. (2019). Structural basis for neutralization and protection by a Zika virus-specific human antibody. Cell Reports, 26(12), 3360-3368.e5. https://doi.org/10.1016/j.celrep.2019.02.062

16.Zuo Yanan, Wang Pengfei, Sun Jianfeng, Guo Shichun, Wang Guiqin, Zuo Teng, Fan Shilong, Zhou Paul, Liang Mifang, Shi Xuanling, Wang Xinquan, Zhang Linqi. (2018). Complementary recognition of the receptor-binding site of highly pathogenic H5N1 influenza viruses by two human neutralizing antibodies. Journal of Biological Chemistry, 293(42), 16503–16517. https://doi.org/10.1074/jbc.RA118.004604

17.Zhang Senyan, Zhou Panpan, Wang Pengfei, Li Yangyang, Jiang Liwei, Jia Wenxu, Wang Han, Fan Angela, Wang Dongli, Shi Xuanling, Fang Xianyang, Hammel Michal, Wang Shuying, Wang Xinquan, Zhang Linqi. (2018). Structural definition of a unique neutralization epitope on the receptor-binding domain of MERS-CoV spike glycoprotein. Cell Reports, 24(2), 441–452. https://doi.org/10.1016/j.celrep.2018.06.041

18.Niu Peihua, Zhang Senyan, Zhou Panpan, Huang Baoying, Deng Yao, Qin Kun, Wang Pengfei, Wang Wenling, Wang Xinquan, Zhou Jianfang, Zhang Linqi, Tan Wenjie. (2018). Ultrapotent human neutralizing antibody repertoires against Middle East respiratory syndrome coronavirus from a recovered patient. Journal of Infectious Diseases, 218(8), 1249–1260. https://doi.org/10.1093/infdis/jiy311

19.Li Cui, Gao Fei, Yu Lei, Wang Ruoke, Jiang Yisheng, Shi Xuanling, Yin Chibiao, Tang Xiaoping, Zhang Fuchun, Xu Zhiheng, Zhang Linqi. (2018). A single injection of human neutralizing antibody protects against Zika virus infection and microcephaly in developing mouse embryos. Cell Reports, 23(5), 1424–1434. https://doi.org/10.1016/j.celrep.2018.04.005

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22.Zhang Qi, Gui Miao, Niu Xuefeng, He Shihua, Wang Ruoke, Feng Yupeng, Kroeker Andrea, Zuo Yanan, Wang Hua, Wang Ying, Li Jiade, Li Chufang, Shi Yi, Shi Xuanling, Gao George F., Xiang Ye, Qiu Xiangguo, Chen Ling, Zhang Linqi. (2016). Potent neutralizing monoclonal antibodies against Ebola virus infection. Scientific Reports, 6, 1–15. https://doi.org/10.1038/srep25856

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26.Wang Nianshuang, Shi Xuanling, Jiang Liwei, Zhang Senyan, Wang Dongli, Tong Pei, Guo Dongxing, Fu Lili, Cui Ye, Liu Xi, Arledge Kelly C., Chen Ying Hua, Zhang Linqi, Wang Xinquan. (2013). Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Research, 23(8), 986–993. https://doi.org/10.1038/cr.2013.92

27.Sun Caijun, Chen Zhiwei, Tang Xian, Zhang Yinfeng, Feng Liqiang, Du Yanhua, Xiao Lijun, Liu Li, Zhu Weijun, Chen Ling, Zhang Linqi. (2013). Mucosal priming with a replicating-vaccinia virus-Based vaccine elicits protective immunity to simian immunodeficiency virus challenge in rhesus monkeys. Journal of Virology, 87(10), 5669–5677. https://doi.org/10.1128/jvi.03247-12

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29.Guo Dongxing, Shi Xuanling, Arledge Kelly C., Song Dingka, Jiang Liwei, Fu Lili, Gong Xinqi, Zhang Senyan, Wang Xinquan, Zhang Linqi. (2012). A single residue within the V5 region of HIV-1 envelope facilitates viral escape from the broadly neutralizing monoclonal antibody VRC01. Journal of Biological Chemistry, 287(51), 43170–43179. https://doi.org/10.1074/jbc.M112.399402

30.Zuo Teng, Shi Xuanling, Liu Zhonghua, Guo Linlin, Zhao Qing, Guan Tianxia, Pan Xianming, Jia Na, Cao Wuchun, Zhou Boping, Goldin Mark, Zhang Linqi. (2011). Comprehensive analysis of pathogen-specific antibody response in vivo based on an antigen library displayed on surface of yeast. Journal of Biological Chemistry, 286(38), 33511–33519. https://doi.org/10.1074/jbc.M111.270553

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37.Poles Michael A., Barsoum Shady, Yu Wenjie, Yu Jian, Sun Patricia, Daly Jeanine, He Tian, Mehandru Saurabh, Talal Andrew, Markowitz Martin, Hurley Arlene, Ho David, Zhang Linqi. (2003). Human immunodeficiency virus type 1 induces persistent changes in mucosal and blood γδ T cells despite suppressive therapy. Journal of Virology, 77(19), 10456–10467. https://doi.org/10.1128/jvi.77.19.10456-10467.2003

38.Zhang Linqi, Chung Chris, Hu Bor Shen, He Tian, Guo Yong, Kim Alexandria J., Skulsky Eva, Jin Xia, Hurley Arlene, Ramratnam Bharat, Markowitz Martin, Ho David D. (2000). Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy. Journal of Clinical Investigation, 106(7), 839–845. https://doi.org/10.1172/JCI10565

39.Ho David D., Zhang Linqi. (2000). HIV-1 rebound after anti-retroviral therapy. Nature Medicine, 6(7), 736–737. https://doi.org/10.1038/77447

40.Zhang Linqi, Lewin Sharon R., Markowitz Martin, Lin Hsi Hsun, Skulsky Eva, Karanicolas Rose, Yuxian He, Xia Jin, Tuttleton Sarah, Vesanen Mika, Spiegel Hans, Kost Rhonda, Van Lunzen Jan, Stellbrink Hans Juergen, Wolinsky Steven, Borkowsky William, Palumbo Paul, Kostrikis Leondios G., Ho David D. (1999). Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. Journal of Experimental Medicine, 190(5), 725–732. https://doi.org/10.1084/jem.190.5.725

41.Zhang Linqi, Ramratnam Bharat, Tenner-Racz Klara, He Yuxian, Vesanen Mika, Lewin Sharon, Talal Andrew, Racz Paul, Perelson Alan S., Korber Bette T., Markowitz Martin, Guo Yong, Duran Margarita, Hurley Arlene, Tsay John, Huang Yu-Ching, Wang Chia-Ching, Ho David D. (1999). Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. New England Journal of Medicine, 340(21), 1605–1613. https://doi.org/10.1056/nejm199905273402101

42.Zhang Linqi, He Tian, Huang Yaoxing, Chen Zhiwei, Guo Young, Wu Sam, Kunstman Kevin J., Brown R. Clark, Phair John P., Neumann Avidan U., Ho David D., Wolinsky Steven M. (1998). Chemokine Coreceptor Usage by Diverse Primary Isolates of Human Immunodeficiency Virus Type 1. Journal of Virology, 72(11), 9307–9312. https://doi.org/10.1128/jvi.72.11.9307-9312.1998

43.Zhang Linqi, Huang Yaoxing, He Tian, Cao Yunzhen, Ho David D. (1996). HIV-1 subtype and second-receptor use. Nature, 383, 31.

44.Zhang Linqi, MacKenzie P, Cleland A, Holmes E C, Brown A J, Simmonds P. (1993). Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. Journal of Virology, 67(6), 3345–3356. https://doi.org/10.1128/jvi.67.6.3345-3356.1993

45.Zhang, Linqi; Simmonds, Peter; Ludlam, Christopher A.; Brown Andrew J. Leigh. (1991). Detection, quantification and sequencing of HIV-1 from the plasma of seropositive individuals and from factor VIII concentrates. AIDS, 5(6), 675–681.

学术荣誉与奖励

2020 清华大学抗击新冠肺炎疫情先进集体

2020 清华大学第十七届“良师益友”

2020 连续五年爱思唯尔中国高被引学者

2019 拜耳讲席教授

2016 当选为非洲科学院院士

2016 清华大学教育教学成果一等奖

2015 获国家科技进步奖二等奖

2008 国家自然科学基金杰出青年基金

2007 长江学者奖励计划特聘教授

2007 “新世纪百千万人才工程”国家级人选


开设课程

医学微生物学

高级微生物学

流行病学