Integrative Immunogen Design and Testing

综合免疫原设计和测试

• 批准号: 10842890
• 负责人: Erica Ollmann Saphire
• 金额: $ 206.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10842890
• 关键词: 2019-nCoV; Animal Disease Models; Animal Model; Animals; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Chiroptera; Collaborations; Coronavirus; Coronavirus Infections; Coronavirus spike protein; Detection; Development; Disease Outbreaks; Dissociation; Ebola; Engineering; Ensure; Epitopes; Evaluation; Generations; Genetic Variation; Goals; HIV-2; Hamsters; Hand; Health; Human; Immune Targeting; Immune response; Immunity; Infection; Literature; Measures; Mediating; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Modeling; Molecular Conformation; Mus; Mutation; Pathogenicity; Pattern; Polysaccharides; Positioning Attribute; Proteins; Resistance; SARS coronavirus; SARS-CoV-2 transmission; SARS-CoV-2 variant; Structure; T-Lymphocyte; Testing; Vaccinated; Vaccines; Variant; Virion; Virus; Zoonoses; cold temperature; combat; coronavirus vaccine; cross immunity; cross reactivity; cross-species transmission; design; diagnostic tool; efficacy evaluation; glycosylation; human coronavirus; immunogenicity; improved; innovation; neutralizing antibody; novel; novel coronavirus; particle; pressure; programs; receptor binding; response; thermostability; vaccine candidate; viral fitness

Project 3 Summary Coronaviruses will likely remain a persistent threat to human health. However, whether the next significant disease outbreak will be caused by a known coronavirus, another novel coronavirus, or continued surges from variant(s) of SARS-CoV-2 is unknown. The goal of this project is to develop novel, improved immunogens to elicit broader anti-coronavirus immunity, to structurally evaluate resulting pan-coronavirus or broad-coronavirus antibodies, and to evaluate efficacy of broad coronavirus vaccines in animal models. We will begin with novel third-generation spikes that better remain in a pre-fusion quaternary assemblies relative to earlier versions of spike that have been described in the literature. These novel spike proteins, termed “VFLIP”, retain a trimeric conformation even in the absence of exogenous trimerization motifs, are resistant to thermal denaturation, feature glycan structures that better reflect those on authentic virions and offer receptor-binding domain positions and conformation that also better reflect those on native virions. These molecules further feature slower “off” rates for a wide panel of anti-coronavirus antibodies. In this program, we will develop novel immunogens from these improved spikes alone and as part of innovative multimeric vaccine particles. Our collaborating projects will evaluate these immunogens for their ability to elicit broad B- and T-cell immune responses. We will then evaluate the efficacy of the best candidate immunogens in mouse and hamster models of infection using multiple relevant coronaviruses. This project represents the beginning and end of the collaborative, iterative circle of immunogen design and evaluation. Cycles of in-depth evaluation and iteration will shepherd vaccine efforts for broad protection against the growing threat posed by coronaviruses.

项目3摘要 冠状病毒可能仍然是对人类健康的持续威胁。但是，下一个重要 疾病爆发将是由已知的冠状病毒，另一种新型冠状病毒引起的 SARS-COV-2的变体未知。该项目的目的是开发新颖的，改进的免疫原剂 引起更广泛的抗癌症免疫学，从结构上评估产生的泛氧化病毒或广泛的核心管病毒 抗体，并评估动物模型中广泛的冠状病毒疫苗的效率。我们将从小说开始 相对于早期版本 文献中描述的尖峰。这些新颖的尖峰蛋白称为“ vflip”，保留了三聚体 即使在没有外源三烯基序的情况下，构象也对热变性具有抵抗力， 特征聚糖结构，可以更好地反映正宗病毒体并提供受体结合域位置的结构 和构象，也可以更好地反映出本地病毒体的构象。这些分子进一步具有较慢的“关闭” 一系列抗科罗纳病毒抗体的速率。在这个程序中，我们将开发从 这些单独改善了尖峰，也是创新的多媒体真空颗粒的一部分。我们的协作项目 将评估这些免疫原的能力，其能够引起广泛的B和T细胞免疫反应。然后我们会 使用多种 相关冠状病毒。该项目代表了协作，迭代圈的开始和结束 免疫原设计和评估。深入评估和迭代的循环将使疫苗为 对冠状病毒构成的日益严重威胁的广泛保护。