Structure based design of trimer interface epitope focused universal influenza vaccines
基于三聚体界面表位的通用流感疫苗的结构设计
基本信息
- 批准号:10576343
- 负责人:
- 金额:$ 121.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-12 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AffinityAntibodiesAntibody RepertoireAntigen PresentationAntigensB-LymphocytesBindingBinding SitesBiologicalBiological ProductsBlood CellsCellsComplexComputer ModelsCrystallographyDevelopmentElectron MicroscopyEngineeringEpitope MappingEpitopesExperimental ModelsExposure toGenerationsGenesGlycoproteinsGoalsHandHeadHemagglutininHumanImmuneImmune responseImmunityIn VitroIndividualInfectionInfluenzaInfluenza HemagglutininInfluenza vaccinationKnowledgeLaboratoriesLinear ProgrammingMachine LearningMass Spectrum AnalysisMemory B-LymphocyteMethodsModelingNaturePolysaccharidesPopulationProteinsReactionResearchResearch Project GrantsRoentgen RaysSeasonsSequence AnalysisSiteStandardizationStructureTechniquesTestingTherapeutic antibodiesVaccine AntigenVaccine DesignVaccinesValidationViralViral VaccinesVirusVirus DiseasesX-Ray Crystallographyantibody engineeringcombatcross reactivitydesigndesign verificationimmunogenicityin silicoin vivoinfluenza virus straininfluenza virus vaccineinfluenzavirusinnovationlaboratory experimentmolecular recognitionmonomermouse modelmultidisciplinarynanoparticleneutralizing antibodynext generationnext generation sequencingnovelpandemic potentialparticleprogramsprotective efficacyrational designreceptor bindingresponsescaffoldscreeningstructural biologytherapeutic vaccinetooluniversal influenza vaccinevaccine candidate
项目摘要
The “Computational Models of Immunity” projects in this application focus on development and
implementation of new structure-based design tools for influenza hemagglutinin (HA) protein
trimer interface specific antibodies or vaccine antigens. These projects will use knowledge about
the structure and function of human neutralizing antibodies to the trimer interface of the HA head
that we have in hand or will discover, in order to design new antibodies or vaccines in silico. We
have access to peripheral blood cells from a diverse panels of subjects with prior natural infection,
or exposure to experimental inoculation with vaccines encoding HA molecules with both seasonal
vaccines and unusual experimental influenza subtypes, including H3variant, H5, H6, H7, H9, and
H10 viruses. The immune B memory cell populations from these individuals are the ideal starting
materials to isolate unusual heterosubtypic antibodies. Recently, we identified the HA head trimer
interface as a major new site of vulnerability for universal influenza antibodies and candidate
vaccines. Here, we will study existing and isolate additional broadly heterosubtypic human
antibodies to the trimer interface of the HA head. We will determine the immunome of the
responding heterosubtypic clones using high-throughput next generation sequencing of antibody
gene repertoires that comprise the clonal lineages of the most heterosubtypic antibodies isolated.
Once antibodies with unusual breadth or activity are isolated, the structure of these antibodies
will be determined in complex with purified HA molecules in the Structural Core using
crystallography and single particle electron microscopy (EM) studies. Such structures will provide
the coordinates for the modeling experiments using Rosetta. We will in silico mature human
antibodies to increase affinity for the HA antigen of specific virus types and use multi-state
design to maximize breadth, i.e., create antibodies that recognize HAs of all clades,
subtypes, groups, or even types. We then will synthesize and express these novel antibodies
and determine neutralization activity, binding affinity, and competition binding groups of designed
antibodies, using a diverse HA panel and pseudotyped viruses with all type A HAs in nature. The
co-crystal structure of these human antibodies with HA will be the template for in silico design of
structurally stable epitope-focused immunogens. We will first validate these designed
immunogens by testing the interaction with the target human antibodies. Further, these
immunogens will be experimentally tested by evaluating immune responses. Then, we will use
the novel immunogens to isolate new antibodies from subjects naturally exposed to influenza, to
show that the immunogens present antigens recognized by natural immune responses.
本申请中的“免疫计算模型”项目侧重于开发和
流感病毒血凝素(HA)蛋白基于结构设计新工具的实现
三聚体界面特异性抗体或疫苗抗原。这些项目将利用有关知识,
HA头部三聚体界面的人中和抗体的结构和功能
我们已经掌握或将要发现的,以便通过计算机设计新的抗体或疫苗。我们
可以接触到来自不同组的先前有自然感染的受试者的外周血细胞,
或暴露于编码HA分子的疫苗的实验性接种,
疫苗和不常见的实验性流感亚型,包括H3变异型、H5、H6、H7、H9和
H10病毒。来自这些个体的免疫B记忆细胞群是理想的开始
分离不寻常的异亚型抗体的材料。最近,我们鉴定了HA头部三聚体,
作为通用流感抗体和候选物主要新的脆弱性位点的界面
疫苗。在这里,我们将研究现有的和分离的其他广泛的异亚型人类
抗体与HA头部的三聚体界面接触。我们将确定
使用高通量下一代抗体测序的应答异亚型克隆
包含分离的大多数异亚型抗体的克隆谱系的基因库。
一旦分离出具有异常宽度或活性的抗体,这些抗体的结构
将在结构核心中与纯化的HA分子复合,
晶体学和单粒子电子显微镜(EM)研究。这些结构将提供
使用罗塞塔进行建模实验的坐标。我们将在电脑上成熟的人类
抗体,以增加对特定病毒类型的HA抗原的亲和力,并使用多状态
设计以最大化宽度,即,产生识别所有进化枝的HA的抗体,
子类型、组甚至类型。然后我们将合成并表达这些新的抗体
并确定设计的抗体的中和活性、结合亲和力和竞争结合基团,
抗体,使用不同的HA组和具有所有A型HA的假型病毒。的
这些人抗体与HA的共晶体结构将是用于在计算机上设计HA的模板。
结构稳定的表位聚焦免疫原。我们将首先验证这些设计
通过测试与靶向人抗体的相互作用来确定免疫原。此外,这些
免疫原将通过评估免疫应答进行实验测试。然后,我们将使用
从自然暴露于流感的受试者中分离新抗体的新免疫原,
表明免疫原呈递天然免疫应答识别的抗原。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
James E Crowe其他文献
Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape
呼吸道合胞病毒预防触手可及:疫苗和单克隆抗体的现状
- DOI:
10.1016/s1473-3099(22)00291-2 - 发表时间:
2023-01-01 - 期刊:
- 影响因子:31.000
- 作者:
Natalie I Mazur;Jonne Terstappen;Ranju Baral;Azucena Bardají;Philippe Beutels;Ursula J Buchholz;Cheryl Cohen;James E Crowe;Clare L Cutland;Linda Eckert;Daniel Feikin;Tiffany Fitzpatrick;Youyi Fong;Barney S Graham;Terho Heikkinen;Deborah Higgins;Siddhivinayak Hirve;Keith P Klugman;Leyla Kragten-Tabatabaie;Philippe Lemey;Louis Bont - 通讯作者:
Louis Bont
James E Crowe的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('James E Crowe', 18)}}的其他基金
Human Monoclonal Antibodies for Encephalitic Alphaviruses
脑炎甲病毒的人单克隆抗体
- 批准号:
10539155 - 财政年份:2022
- 资助金额:
$ 121.34万 - 项目类别:
Human Monoclonal Antibodies for Encephalitic Alphaviruses
脑炎甲病毒的人单克隆抗体
- 批准号:
10669266 - 财政年份:2022
- 资助金额:
$ 121.34万 - 项目类别:
Structure based design of trimer interface epitope focused universal influenza vaccines
基于三聚体界面表位的通用流感疫苗的结构设计
- 批准号:
10361516 - 财政年份:2020
- 资助金额:
$ 121.34万 - 项目类别:
B-Cell Epitope Discovery and Mechanisms of Antibody Protection: Genetic and Structural Basis for Virus Neutralization
B 细胞表位发现和抗体保护机制:病毒中和的遗传和结构基础
- 批准号:
10021075 - 财政年份:2019
- 资助金额:
$ 121.34万 - 项目类别:
Research Project 2: Therapeutic Human Monoclonal Antibody Treatments for Filoviruses
研究项目2:丝状病毒的治疗性人单克隆抗体治疗
- 批准号:
10576280 - 财政年份:2019
- 资助金额:
$ 121.34万 - 项目类别:
Functional Antibody Repertoire Against S. aureus Leukocidins after Invasive Human Infection
人类侵袭性感染后针对金黄色葡萄球菌杀白细胞素的功能性抗体库
- 批准号:
10541163 - 财政年份:2019
- 资助金额:
$ 121.34万 - 项目类别:
B-Cell Epitope Discovery and Mechanisms of Antibody Protection: Genetic and Structural Basis for Influenza Neutralization
B 细胞表位发现和抗体保护机制:流感中和的遗传和结构基础
- 批准号:
10669544 - 财政年份:2019
- 资助金额:
$ 121.34万 - 项目类别:
B-Cell Epitope Discovery and Mechanisms of Antibody Protection: Genetic and Structural Basis for Influenza Neutralization
B 细胞表位发现和抗体保护机制:流感中和的遗传和结构基础
- 批准号:
10903692 - 财政年份:2019
- 资助金额:
$ 121.34万 - 项目类别:
Research Project 2: Therapeutic Human Monoclonal Antibody Treatments for Filoviruses
研究项目2:丝状病毒的治疗性人单克隆抗体治疗
- 批准号:
10564151 - 财政年份:2019
- 资助金额:
$ 121.34万 - 项目类别:
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 121.34万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 121.34万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 121.34万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 121.34万 - 项目类别:
Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 121.34万 - 项目类别:
Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 121.34万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 121.34万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
- 批准号:
10639161 - 财政年份:2023
- 资助金额:
$ 121.34万 - 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
- 批准号:
10752441 - 财政年份:2023
- 资助金额:
$ 121.34万 - 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
- 批准号:
10867639 - 财政年份:2023
- 资助金额:
$ 121.34万 - 项目类别: