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Development of T cell antigen-based human coronavirus vaccinesagainst nAb-escaping SARS-CoV-2 variants

Science Bulletin 2024年第15期69卷 2456-2470页

作者： Hao Zhou Ping Leng Yang Wang Kaiwen Yang Chen Li David M.Ojcius Pengfei Wang shibo jiang College of Medical Technology Chengdu University of Traditional Chinese MedicineChengdu 611137China Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine Chongqing Traditional Chinese Medicine HospitalChongqing 400016China Shanghai Pudong Hospital Fudan University Pudong Medical CenterShanghai Institute of Infectious Disease and BiosecuritySchool of Life SciencesFudan UniversityShanghai 200438China Department of Biomedical Sciences University of the PacificArthur Dugoni School of DentistrySan FranciscoCA 94115USA Key Laboratory of Medical Molecular Virology of Ministry of Education/Ministry of Health/Chinese Academy of Medical Sciences Shanghai Institute of Infectious Disease and BiosecuritySchool of Basic Medical SciencesFudan UniversityShanghai 200032China

Currently approved vaccines have been successful in preventing the severity of COVID-19 and hospitalization. These vaccines primarily induce humoral immune responses;however, highly transmissible and mutated variants, such as the Omicron variant, weaken the neutralization potential of the vaccines, thus,raising serious concerns about their efficacy. Additionally, while neutralizing antibodies(nAbs) tend to wane more rapidly than cell-mediated immunity, long-lasting T cells typically prevent severe viral illness by directly killing infected cells or aiding other immune cells. Importantly, T cells are more cross-reactive than antibodies, thus, highly mutated variants are less likely to escape lasting broadly cross-reactive T cell immunity. Therefore, T cell antigen-based human coronavirus(HCoV) vaccines with the potential to serve as a supplementary weapon to combat emerging SARS-CoV-2 variants with resistance to n Abs are urgently needed. Alternatively, T cell antigens could also be included in B cell antigen-based vaccines to strengthen vaccine efficacy. This review summarizes recent advancements in research and development of vaccines containing T cell antigens or both T and B cell antigens derived from proteins of SARS-CoV-2 variants and/or other HCo Vs based on different vaccine platforms.

关键词： COVID-19 Immune escape Omicron variant SARS-CoV-2 T cell antigen-based vaccine

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Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1651-1664页

作者： Xiong Xie Qiaoshuai Lan Jinyi Zhao Sulin Zhang Lu Liu Yumin Zhang Wei Xu Maolin Shao Jingjing Peng Shuai Xia Yan Zhu Keke Zhang Xianglei Zhang Ruxue Zhang jian Li Wenhao Dai Zhen Ge Shulei Hu Changyue Yu jiang Wang Dakota Ma Mingyue Zheng Haitao Yang Gengfu Xiao Zihe Rao Lu Lu Leike Zhang Fang Bai Yao Zhao shibo jiang Hong Liu Drug Discovery and Design Center State Key Laboratory of Drug ResearchCAS Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) School of Basic Medical SciencesShanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghai 200032China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China School of Chinese Materia Medica Nanjing University of Chinese Medicine138 Xian Lin RoadJiangsu 210023 NanjingChina School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China National Clinical Research Center for Infectious Disease Shenzhen Third People's HospitalShenzhen 518112China

Respiratory disease caused by coronavirus infection remains a global health *** several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be ***-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging *** L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune ***,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and *** X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of *** showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various *** mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral ***,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in *** addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse *** 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute *** together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with anti

关键词： calpain overcome entrance

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Asialoglycoprotein receptor 1 promotes SARS-CoV-2 infection of human normal hepatocytes

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1199-1208页

作者： Xinyi Yang Xu Zheng Yuqi Zhu Xiaying Zhao Jun Liu jiangna Xun Songhua Yuan Jun Chen Hanyu Pan Jinlong Yang Jing Wang Zhimin Liang Xiaoting Shen Yue Liang Qinru Lin Huitong Liang Min Li Fei Peng Daru Lu Jianqing Xu Hongzhou Lu shibo jiang Ping Zhao Huanzhang Zhu State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology Ministry of EducationInstitute of GeneticsSchool of Life SciencesYiwu Research InstituteFudan UniversityShanghaiChina Department of Microbiology Faculty of Naval MedicineNaval Medical UniversityShanghai 200433China Scientific Research Center Shanghai Public Health Clinical CenterFudan UniversityShanghaiChina Department of Infectious Diseases and Immunology Shanghai Public Health Clinical CenterFudan UniversityShanghaiChina Changzheng Hospital Naval Medical UniversityShanghaiChina Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) Shanghai Institute of Infectious Disease and BiosecuritySchool of Basic Medical SciencesFudan UniversityShanghaiChina Department of Infectious Diseases and Nursing Research Institution National Clinical Research Center for Infectious DiseasesThe Third People’s Hospital of ShenzhenShenzhenGuangdongChina

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)causes multi-organ damage,which includes hepatic dysfunction,as observed in over 50%of COVID-19 *** I converting enzyme(peptidyl-dipeptidase A)2(ACE2)is the primary receptor for SARS-CoV-2 entry into host cells,and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2,but at extremely low ***,we asked if hepatocytes might express receptors other than ACE2 capable of promoting the entry of SARS-CoV-2 into *** address this question,we performed a genome-wide CRISPR-Cas9 activation library screening and found that Asialoglycoprotein receptor 1(ASGR1)promoted SARS-CoV-2 pseudovirus infection of HeLa *** Huh-7 cells,simultaneous knockout of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus *** the immortalized THLE-2 hepatocyte cell line and primary hepatic parenchymal cells,both of which barely expressed ACE2,SARSCoV-2 pseudovirus could successfully establish an ***,after treatment with ASGR1 antibody or siRNA targeting ASGR1,the infection rate significantly dropped,suggesting that SARS-CoV-2 pseudovirus infects hepatic parenchymal cells mainly through an ASGR1-dependent *** confirmed that ASGR1 could interact with Spike protein,which depends on receptor binding domain(RBD)and N-terminal domain(NTD).Finally,we also used Immunohistochemistry and electron microscopy to verify that SARS-CoV-2 could infect primary hepatic parenchymal *** inhibiting ASGR1 in primary hepatic parenchymal cells by siRNA,the infection efficiency of the live virus decreased ***,these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of hepatic parenchymal cells.

关键词： ACE2 infection glycoprotein

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基于重组人Ⅲ型胶原蛋白的三聚体抗原疫苗策略在新冠和流感疫苗中的应用

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合成生物学 2024年第2期5卷 385-395页

作者：刘泽众周洁朱赟陆路姜世勃复旦大学基础医学院上海200032 复旦大学药学院药理系上海201203 中国科学院生物物理研究所北京100101

新冠病毒等多种包膜病毒的糖蛋白在天然状态下呈现三聚体形式。三聚体蛋白通常较单体蛋白具有更优的免疫原性。目前使用非人蛋白来源的Foldon等三聚体基序可促使目的蛋白形成稳定三聚体,但这些基序的强免疫原性会削弱目的蛋白的免疫应答... 详细信息

新冠病毒等多种包膜病毒的糖蛋白在天然状态下呈现三聚体形式。三聚体蛋白通常较单体蛋白具有更优的免疫原性。目前使用非人蛋白来源的Foldon等三聚体基序可促使目的蛋白形成稳定三聚体,但这些基序的强免疫原性会削弱目的蛋白的免疫应答,限制了其在疫苗抗原设计中的应用。在本研究中,发现并利用重组人源化Ⅲ型胶原蛋白(Rh3C)作为新型三聚体基序,利用合成生物学方法,与新冠病毒刺头(spike)蛋白受体结合域(RBD)融合表达后促使RBD形成三聚体。这种胶原-RBD(Rh3C-RBD)三聚体蛋白在免疫小鼠后,较RBD单体蛋白诱导产生了更高滴度的结合抗体和中和抗体。此外,我们还进一步验证了该Rh3C基序与流感病毒HA1蛋白融合后,较HA1单体蛋白可在小鼠体内诱导更强效的抗体应答。因此,这种新型的Rh3C基序,有望广泛用于三聚体疫苗抗原的设计和优化。

关键词：三聚体抗原人胶原蛋白新冠病毒流感病毒疫苗设计

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The First Disease X is Caused by a Highly Transmissible Acute Respiratory Syndrome Coronavirus

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Virologica Sinica 2020年第3期35卷 263-265页

作者： shibo jiang Zheng-Li Shi Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) School of Basic Medical SciencesFudan UniversityShanghai 200032China New York Blood Center The Lindsley F.Kimball Research InstituteNew YorkNY 10065USA CAS Key Laboratory of Special Pathogens Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China

Based on the announcement of the World Health Organization(WHO) in 2018, the Wuhan pneumonia caused by an unknown etiology should be recognized as the first Disease X. Later, the pathogen was identified to be a novel coronavirus denoted 2019-nCoV, which has 79.5% and 96% whole genome sequence identify to SARS-CoV and bat SARS-related coronavirus(SARSr-CoV-RaTG13), respectively, suggesting its potential bat origin. With high human-to-human transmission rate(R0), 2019-nCoV has quickly spread in China and other countries, resulting in 34,953 confirmed cases and 725 deaths as of 8 February 2020, thus calling for urgent development of therapeutics and prophylactics. Here we suggest renaming 2019-nCoV as "transmissible acute respiratory syndrome coronavirus(TARS-CoV)" and briefly review the advancement of research and development of neutralizing antibodies and vaccines targeting the receptor-binding domain(RBD) and viral fusion inhibitors targeting the heptad repeat 1(HR1) domain in spike protein of 2019-nCoV.

关键词： Coronavirus 2019-nCoV SARS-CoV Pneumonia Acute respiratory syndrome Disease X

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Advances in the research and development of therapeutic antibodies against the Zika virus

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Cellular & Molecular Immunology 2019年第1期16卷 96-97页

作者： shibo jiang Lanying Du Lindsley F.Kimball Research Institute New York Blood CenterNew YorkNY 10065USA Key Laboratory of Medical Molecular Virology Ministries of Education and HealthShanghai Medical College and Institute of Medical MicrobiologyFudan UniversityShanghai 200032China

The Zika virus(ZIKV)is an arbovirus in the same family,Flaviviridae,as the dengue virus(DENV),the West Nile virus,the yellow fever virus,and the Japanese encephalitis *** has been a recent research focus because of its close association with severe human diseases and syndromes,particularly congenital Zika syndrome,which includes fetal microcephaly and other brain abnormalities.1 The ZIKV envelope(E)protein is a major structural protein involved in receptor binding,viral entry,and *** is arranged as a dimer,with each monomer consisting of three domains(DI,DII,and DIII),a stem region,and a transmembrane region.2 The ZIKV E protein induces the production of potent neutralizing antibodies against ZIKV and is thus a key target for the development of therapeutic ZIKV antibodies.

关键词： antibodies therapeutic diseases

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A suspicious role of interferon in the pathogenesis of SARS-CoV-2 by enhancing expression of ACE2

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1822-1823页

作者： Shan Su shibo jiang Key Laboratory of Medical Molecular Virology(MOE/MOH/CAM) School of Basic Medical SciencesFudan University130 Dong An Rd.Xuhui DistrictShanghai 200032China

Based on a number of published and unpublished single-cell RNAsequencing(scRNA-seq)datasets,a recent study identified putative specific cell subtypes targeted by SARS-CoV-2(severe acute respiratory syndrome coronavirus 2)and a possible role of interferon(IFN)in its *** rapid spread of SARS-CoV-2,the causative pathogen of COVID-19,has had global public health and economic *** molecular mechanism(s)underlying the high transmissibility of SARS-CoV-2 remain(s)***,we must follow a pragmatic and stepwise path to determine the specific target cell subsets and factors that regulate SARS-CoV-2 infection to elucidate true targets for *** a recent issue of Cell,Carly and co-workers1 identified the cell subsets targeted by SARS-CoV-2 in certain *** addition,they found that IFN-αenhanced the expression of angiotensin-converting enzyme 2(ACE2),the receptor for SARS-CoV-2,in primary human upper airway basal ***,we know that IFN is cell-type-and host speciesspecific,indicating the need for more preclinical and clinical data to clarify the role of IFN in the pathogenesis of COVID-19.

关键词： ACE2 pathogenesis interferon

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SARS-CoV-2 Omicron subvariant BA.2.86: limited potential for global spread

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Signal Transduction and Targeted Therapy 2023年第12期8卷 5581-5583页

作者： Xinling Wang Lu Lu shibo jiang Shanghai Institute of Infectious Disease and Biosecurity MOE/NHC/CAMS Key Laboratory of Medical Molecular VirologyShanghai Frontiers Science Center of Pathogenic Microorganisms and InfectionSchool of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina

In recent studies published in Nature and Lancet Infectious Diseases,1,2 SARS-CoV-2 Omicron subvariant BA.2.86 exhibited a substantial antigenic drift,enhanced receptor affinity,and less immune evasion to sera of individuals upon XBB breakthrough infection or *** findings suggest that the potential for BA.2.86 to spread globally is limited,albeit the mutated BA.2.86 sequences were detected in wastewater in various public and commercial venues before the confirmed case of BA.2.86 infection in Thailand,which raised concerns about the spread of BA.2.86 through international travel.3.

关键词： wastewater potential breakthrough

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南流江预应力连续梁式渡槽抗震性能

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南水北调与水利科技（中英文） 2024年第S1期22卷 196-203页

作者：刘惠娟赖成联姜士博谢开仲广西水利电力职业技术学院南宁530023 广西水利电力勘测设计研究院有限责任公司南宁530023 广西大学土木建筑工程学院南宁530004

预应力连续梁式渡槽具有整体受力条件好、施工工艺成熟且方便的优势,在实际工程中运用广泛,其具有良好的抗震性能是保证工程安全运行的关键。以采用预应力连续梁式渡槽形式的南流江大渡槽为例,通过Midas-civil分析软件建立有限元模型并... 详细信息

预应力连续梁式渡槽具有整体受力条件好、施工工艺成熟且方便的优势,在实际工程中运用广泛,其具有良好的抗震性能是保证工程安全运行的关键。以采用预应力连续梁式渡槽形式的南流江大渡槽为例,通过Midas-civil分析软件建立有限元模型并施加拟合生成的地震波,对渡槽的抗震性能进行研究。结果表明,在拟合生成的地震波与场地类别、分区特征周期相近的人工地震波E1、E2作用下,南流江大渡槽的顺桥向及横桥向的桥墩强度验算和变形均满足要求,具有安全可靠的抗震性能。

关键词：南流江大渡槽预应力连续梁式渡槽抗震性能数值计算水库

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Potential recombination between SARS-CoV-2 and MERSCoV:calls for the development of Pan-CoV vaccines

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1343-1345页

作者： Qiao Wang Lujia Sun shibo jiang Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) Shanghai Institute of Infectious Disease and BiosecuritySchool of Basic Medical SciencesFudan University131 Dong An RdXuhui DistrictShanghai 200032China

In a recent study published in Nature,Yan and colleagues demonstrated that NeoCoV,a potential MERS-CoV ancestor in bats,can use bat ACE2 as its entry receptor and that NeoCoV S pseudotyped virus,which contains a T510F mutation in the receptor-binding domain(RBD),enters cells expressing human ACE2(hACE2).1 The findings reveal a potential zoonotic threat that MERS-CoV could,during its evolution,be gaining the ability to use hACE2 as an entry receptor and,thus,could also coinfect ACE2-expressing cells with SARS-CoV-2.

关键词： ACE2 vaccines expressing

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