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:10361516
- 负责人:
- 金额:$ 122.11万
- 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 RepertoireAntigensB-LymphocytesBindingBinding SitesBiologicalBiological ProductsBlood CellsCellsComplexComputer ModelsCrystallizationCrystallographyDevelopmentElectron MicroscopyEngineeringEpitopesExposure toGenerationsGenesGlycoproteinsGoalsHandHeadHemagglutininHumanImmuneImmune responseImmunityIn VitroIndividualInfectionInfluenzaInfluenza HemagglutininInfluenza vaccinationKnowledgeLaboratoriesLinear ProgrammingMachine LearningMapsMasksMass Spectrum AnalysisMemory B-LymphocyteMethodsModelingNaturePolysaccharidesPopulationProteinsResearchResearch Project GrantsRoentgen RaysSequence AnalysisSiteStandardizationStructureTechniquesTestingTherapeutic antibodiesVaccine AntigenVaccine DesignVaccinesValidationViralViral VaccinesVirusVirus DiseasesX-Ray Crystallographyantibody engineeringbasecombatcross reactivitydesignexperimental studyimmunogenicityin silicoin vivoinfluenza virus straininfluenza virus vaccineinfluenzavirusinnovationlaboratory experimentmolecular recognitionmouse modelmultidisciplinarynanoparticleneutralizing antibodynext generationnext generation sequencingnovelpandemic diseaseparticleprogramsprotective 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.
本应用程序中的“免疫计算模型”项目侧重于开发和
项目成果
期刊论文数量(0)
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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
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{{ 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:
$ 122.11万 - 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:
$ 122.11万 - 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:
10576343 - 财政年份:2020
- 资助金额:
$ 122.11万 - 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:
$ 122.11万 - 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:
$ 122.11万 - 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:
$ 122.11万 - 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:
$ 122.11万 - 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:
$ 122.11万 - 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:
$ 122.11万 - 项目类别:
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