In vivo Testing of Universal Influenza Vaccine Candidates at the Duke Regional Biocontainment Laboratory

杜克大学地区生物防护实验室对候选通用流感疫苗进行体内测试

基本信息

批准号：
10627011
负责人：
Mihai Luchian Azoitei
金额：
$ 56.9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-20 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627011
关键词：
Address Affinity Animal Model Animals Antibodies Antigens Award Binding Binding Sites Biological Assay Collaborations Data Development Disease Engineering Epitopes Ferrets Flu virus Formulation Funding Goals Gold Head Hemagglutinin Human Immune Immune response Immunity Immunization Immunodominant Epitopes Individual Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Laboratories Libraries Methods Modeling Molecular Monoclonal Antibodies Mosaicism Mus Parents Pathology Polysaccharides Protein Engineering Proteins Regimen Resources Site Surface Testing Vaccines Viral Virus Virus Diseases Work base cross reactivity design experimental study glycosylation immunogenicity in vivo in vivo Model in vivo evaluation influenza infection influenza virus strain influenza virus vaccine influenzavirus mouse model nanoparticle novel novel vaccines pressure response screening stem sugar transmission process universal influenza vaccine vaccine candidate vaccine development vaccine trial

Address Affinity Animal Model Animals Antibodies Antigens Award Binding Binding Sites Biological Assay Collaborations Data Development Disease Engineering Epitopes Ferrets Flu virus Formulation Funding Goals Gold Head Hemagglutinin Human Immune Immune response Immunity Immunization Immunodominant Epitopes Individual Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Laboratories Libraries Methods Modeling Molecular Monoclonal Antibodies Mosaicism Mus Parents Pathology Polysaccharides Protein Engineering Proteins Regimen Resources Site Surface Testing Vaccines Viral Virus Virus Diseases Work base cross reactivity design experimental study glycosylation immunogenicity in vivo in vivo Model in vivo evaluation influenza infection influenza virus strain influenza virus vaccine influenzavirus mouse model nanoparticle novel novel vaccines pressure response screening stem sugar transmission process universal influenza vaccine vaccine candidate vaccine development vaccine trial

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项目摘要

Abstract The main goal of the parent award related this supplement is to develop and test in vivo novel vaccine candidates towards the development of a universal influenza vaccine. By employing computational protein design and high-throughput library screening methods, we aim to generate novel immunogens that preferentially elicit broadly cross-reactive antibodies against diverse influenza viruses. As part of the parent award, we proposed to engineer and test in vivo two hemagglutinin (HA) head-based immunogens with the goal of eliciting broadly immune responses that target the HA head trimer interface. This HA region is conserved across many influenza subtypes and is engaged by multiple broadly cross-reactive antibodies. We have already tested in mice the immunogenicity of two engineered HA head immunogens and found that they elicit antibodies that cross-react with multiple influenza subtypes, unlike the WT HA head template that they were based on. Based on these results, we request funds in this application to further optimize and test HA head-based immunogens for the elicitation of HA head trimer interface antibodies. This supplement will provide resources to test additional immunogens than those planned in the parent award, and will make available more biologically relevant animal models for in vivo immunogen testing through a collaboration with the Duke Regional Biocontainment Laboratory (RBL). The Duke RBL has developed multiple mouse and ferret viral challenge models with diverse influenza strains that will now become accessible to us through this supplement. This proposal will therefore augment the work of the parent award, by providing the resources to further develop and rigorously test in vivo HA head derived immunogens with the final goal of discovering a universal influenza vaccine.

抽象的父母奖相关的主要目标这种补充是在体内开发和测试小说疫苗候选人开发普遍的流感疫苗。通过使用计算蛋白设计和高通量图书馆筛选方法，我们旨在生成新颖的免疫原子优先引起针对多种流感病毒的广泛交叉反应抗体。作为父母的一部分奖项，我们建议在体内进行工程和测试两个hemagglutinin（ha）头部基于头部的免疫原子。引发针对HA头夹子界面的广泛免疫反应的目标。这个HA地区是在许多流感亚型中保守，并由多种广泛的交叉反应抗体参与。我们已经在小鼠中测试了两种工程HA头免疫的免疫原性，发现它们引起与多种流感亚型交叉反应的抗体，与WT HA头模板不同基于。基于这些结果，我们要求在本申请中的资金进一步优化和测试HA 基于头部的免疫原，用于促进HA头三聚体界面抗体。这种补充将提供测试额外免疫原的资源比父母奖中计划的免疫原分，并将提供更多通过与公爵的合作，用于体内免疫原子测试的生物学相关动物模型区域生物疗养实验室（RBL）。公爵RBL开发了多个小鼠和雪貂病毒具有多种流感菌株的挑战模型，现在可以通过这种补充剂来获得我们的挑战。因此，该建议将通过提供资源来进一步提高父母奖的工作开发和严格测试体内HA头部衍生的免疫原子，其最终目标是发现通用流感疫苗。