Antibody repertoire characterization in the context of coronaviruses

冠状病毒背景下的抗体库表征

• 批准号: 10266227
• 负责人: Ivelin Georgiev
• 金额: $ 67.33万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-28 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266227
• 关键词: Address; Algorithmic Analysis; Algorithms; Antibodies; Antibody Response; Antibody Specificity; Antigens; Area; Binding; Biological; Characteristics; Collaborations; Collection; Complex; Computer Analysis; Computing Methodologies; Data; Derivation procedure; Development; Donor Selection; Economic Burden; Epitope Mapping; Epitopes; Fingerprint; Generations; Genetic; Goals; HIV; HIV Infections; HIV-1; HIV-1 vaccine; Hepatitis C; Immune system; Individual; Infection; Influenza C Virus; Knock-out; Laboratories; Least-Squares Analysis; Letters; Machine Learning; Methods; Monoclonal Antibodies; Mutation; Pattern; Phenotype; Population; Public Health; Sampling; Serum; Signal Transduction; Specificity; Structure; Techniques; Technology; United States National Institutes of Health; Vaccine Design; Validation; Variant; Virus; Work; base; cohort; health economics; improved; neutralizing antibody; next generation; novel; polyclonal antibody; prospective; response; sample collection; tool

Project Summary. SARS-CoV-2, or the 2019 novel coronavirus, is a significant pandemic threat that has resulted in hundreds of thousands of diagnosed cases and tens of thousands of mortalities as of March 2020. The development of preventive and therapeutic measures that can counteract the ongoing, and any future, coronavirus pandemics is therefore of utmost significance for public health worldwide. The S protein is the immunodominant region of coronaviruses (CoV) recognized by the immune system and serves as the target for a number of neutralizing antibodies. Passive transfer of neutralizing antibodies has been shown to prevent coronavirus infection in animal models. Further, engineered prefusion-stabilized S protein immunogens have been shown to elicit high titers of coronavirus-neutralizing antibodies in animal models, in the context of MERS. Together, this prior work establishes a strong premise for targeting the identification and characterization of neutralizing antibodies in the context of SARS-CoV-2. More generally, a better understanding of the human antibody response to the S protein of SARS-CoV-2 as well as other related CoV members can help inform therapeutic antibody optimization and accelerate vaccine design efforts. Our laboratory recently developed the LIBRA-seq technology (LInking B-cell Receptor to Antigen specificity through sequencing) for antibody discovery and characterization of antigen-specific antibody repertoires. Unlike other B cell approaches, LIBRA-seq is the first to enable the simultaneous determination of BCR sequence and antigen specificity for a large number of B cells against a theoretically unlimited number of diverse antigens, at the single-cell level. LIBRA-seq therefore provides a unique opportunity for characterizing the types and specificities of antibodies that can recognize the S protein from SARS-CoV-2, as well as other CoV viruses. Here, we propose to utilize the LIBRA-seq technology in the context of SARS-CoV-2, with two major goals: (1) To identify cross-reactive antibodies that recognize multiple antigen variants associated with human coronavirus infection, including SARS-CoV-2, SARS-CoV-1, and MERS-CoV, and (2) To evaluate the ability of current lead CoV vaccine candidates to engage with antibody repertoires from healthy individuals. Taken together, the efforts proposed in this application will be of high potential translational/clinical impact for SARS-CoV-2 and other CoV pathogens of biomedical significance. The types of antibody repertoire characterization that we propose to develop here will also be readily generalizable to other pathogens, and as such, will have a broad and lasting impact on the development of countermeasures for established and emerging infectious diseases.

项目摘要。SARS-CoV-2或2019年新型冠状病毒是一种重大的大流行威胁， 截至2020年3月，导致数十万例确诊病例和数万例死亡。 制定预防和治疗措施，以应对正在发生的和任何未来的， 因此，冠状病毒大流行对全球公共卫生至关重要。S蛋白是 冠状病毒（CoV）的免疫优势区，由免疫系统识别并作为靶点 中和抗体中和抗体的被动转移已被证明可以防止 冠状病毒感染的动物模型。此外，工程化的融合前稳定的S蛋白免疫原具有 在MERS的背景下，在动物模型中显示出高滴度的冠状病毒中和抗体。 总之，这项先前的工作为确定和表征 中和抗体的研究进展。更广泛地说，更好地了解人类 对SARS-CoV-2的S蛋白以及其他相关CoV成员的抗体应答可以帮助了解 治疗性抗体优化和加速疫苗设计工作。 我们的实验室最近开发了LIBRA-seq技术（连接B细胞受体抗原） 特异性）用于抗体发现和抗原特异性抗体的表征 保留曲目与其他B细胞方法不同，LIBRA-seq是第一个能够同时测定 大量B细胞的BCR序列和抗原特异性针对理论上无限数量的 不同的抗原，在单细胞水平。因此，LIBRA-seq为表征提供了独特的机会 能够识别SARS-CoV-2的S蛋白的抗体的类型和特异性，以及其他 CoV病毒。 在这里，我们建议在SARS-CoV-2的背景下利用LIBRA-seq技术，其中有两个主要的 目的：（1）鉴定能识别多种抗原变异的交叉反应性抗体， 冠状病毒感染，包括SARS-CoV-2，SARS-CoV-1和MERS-CoV，以及（2）评估 目前领先的CoV候选疫苗与健康个体的抗体库结合。 总之，本申请中提出的努力将具有很高的转化/临床潜力。 对SARS-CoV-2和其他具有生物医学意义的CoV病原体的影响。抗体库的类型 我们在这里提出的特征也将很容易推广到其他病原体， 这将对制定既定的反措施产生广泛和持久的影响， 新出现的传染病

项目成果

Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1.

• DOI: 10.1038/s41591-018-0042-6
• 发表时间: 2018-06
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Xu K;Acharya P;Kong R;Cheng C;Chuang GY;Liu K;Louder MK;O'Dell S;Rawi R;Sastry M;Shen CH;Zhang B;Zhou T;Asokan M;Bailer RT;Chambers M;Chen X;Choi CW;Dandey VP;Doria-Rose NA;Druz A;Eng ET;Farney SK;Foulds KE;Geng H;Georgiev IS;Gorman J;Hill KR;Jafari AJ;Kwon YD;Lai YT;Lemmin T;McKee K;Ohr TY;Ou L;Peng D;Rowshan AP;Sheng Z;Todd JP;Tsybovsky Y;Viox EG;Wang Y;Wei H;Yang Y;Zhou AF;Chen R;Yang L;Scorpio DG;McDermott AB;Shapiro L;Carragher B;Potter CS;Mascola JR;Kwong PD
• 通讯作者: Kwong PD

Envelope characteristics in individuals who developed neutralizing antibodies targeting different epitopes in HIV-1 subtype C infection.

• DOI: 10.1016/j.virol.2020.03.003
• 发表时间: 2020-07
• 期刊: Virology
• 影响因子: 3.7
• 作者: Ndlovu B;Gounder K;Muema D;Raju N;Hermanus T;Mthethwa Q;Robertson K;Walker BD;Georgiev IS;Morris L;Moore PL;Ndung'u T
• 通讯作者: Ndung'u T

Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers.

• DOI: 10.3389/fimmu.2021.670561
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Nyanhete TE;Edwards RJ;LaBranche CC;Mansouri K;Eaton A;Dennison SM;Saunders KO;Goodman D;Janowska K;Spreng RL;Zhang L;Mudrak SV;Hope TJ;Hora B;Bradley T;Georgiev IS;Montefiori DC;Acharya P;Tomaras GD
• 通讯作者: Tomaras GD

A Neutralizing Antibody Recognizing Primarily N-Linked Glycan Targets the Silent Face of the HIV Envelope.

• DOI: 10.1016/j.immuni.2018.02.013
• 发表时间: 2018-03-20
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Zhou T;Zheng A;Baxa U;Chuang GY;Georgiev IS;Kong R;O'Dell S;Shahzad-Ul-Hussan S;Shen CH;Tsybovsky Y;Bailer RT;Gift SK;Louder MK;McKee K;Rawi R;Stevenson CH;Stewart-Jones GBE;Taft JD;Waltari E;Yang Y;Zhang B;Shivatare SS;Shivatare VS;Lee CD;Wu CY;NISC Comparative Sequencing Program;Mullikin JC;Bewley CA;Burton DR;Polonis VR;Shapiro L;Wong CH;Mascola JR;Kwong PD;Wu X
• 通讯作者: Wu X

Sequence and functional characterization of a public HIV-specific antibody clonotype.

• DOI: 10.1016/j.isci.2021.103564
• 发表时间: 2022-01-21
• 期刊: iScience
• 影响因子: 5.8
• 作者: Murji AA;Raju N;Qin JS;Kaldine H;Janowska K;Fechter EF;Mapengo R;Scheepers C;Setliff I;Acharya P;Morris L;Georgiev IS
• 通讯作者: Georgiev IS