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总结 冠状病毒可能仍然对人类健康构成持续威胁。然而，下一个重大事件是否 疾病爆发将由一种已知的冠状病毒、另一种新型冠状病毒或来自其他国家的持续激增引起 SARS-CoV-2 的变种尚不清楚。该项目的目标是开发新型、改进的免疫原 引发更广泛的抗冠状病毒免疫力，从结构上评估由此产生的泛冠状病毒或广泛冠状病毒 抗体，并评估广泛的冠状病毒疫苗在动物模型中的功效。我们将从小说开始 相对于早期版本，第三代尖峰更好地保留在融合前的四元组件中 文献中已描述过的尖峰。这些新型刺突蛋白被称为“VFLIP”，保留了三聚体 即使没有外源三聚化基序，构象也能抵抗热变性， 具有更好地反映真实病毒粒子上的聚糖结构并提供受体结合结构域位置的特征 和构象也更好地反映了天然病毒粒子的构象。这些分子还具有较慢的“关闭”速度 多种抗冠状病毒抗体的比率。在这个项目中，我们将开发新的免疫原 这些改进的尖峰单独存在，并且作为创新多聚体疫苗颗粒的一部分。我们的合作项目 将评估这些免疫原引发广泛 B 和 T 细胞免疫反应的能力。我们随后将 使用多种方法评估最佳候选免疫原在小鼠和仓鼠感染模型中的功效 相关的冠状病毒。该项目代表了协作、迭代循环的开始和结束 免疫原设计和评估。深入评估和迭代的周期将引导疫苗工作 广泛的保护措施，抵御冠状病毒造成的日益严重的威胁。