Integrative Immunogen Design and Testing

综合免疫原设计和测试

• 批准号: 10328121
• 负责人: Erica Ollmann Saphire
• 金额: $ 262.89万
• 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/10328121
• 关键词: 2019-nCoV; Animal Disease Models; Animal Model; Animals; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Chiroptera; Coronavirus; Coronavirus Infections; Coronavirus spike protein; Detection; Development; Diagnostic; Disease Outbreaks; Dissociation; 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; Severe Acute Respiratory Syndrome; Structure; T-Lymphocyte; Testing; Vaccinated; Vaccines; Variant; Virion; Virus; Zoonoses; cold temperature; combat; coronavirus vaccine; cross reactivity; cross-species transmission; design; efficacy evaluation; glycosylation; human coronavirus; immunogenicity; improved; innovation; neutralizing antibody; novel; novel coronavirus; particle; pressure; programs; receptor binding; response; thermostability; tool; transmission process; 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 冠状病毒很可能仍然是对人类健康的持续威胁。然而，下一步是否意义重大 疾病暴发将由一种已知的冠状病毒、另一种新的冠状病毒或持续激增的 SARS-CoV-2的变种(S)未知。这个项目的目标是开发新的、改进的免疫原来 诱导更广泛的抗冠状病毒免疫，从结构上评估所产生的泛冠状病毒或广谱冠状病毒 抗体，并评估广泛的冠状病毒疫苗在动物模型中的效果。我们将从小说开始 与早期版本相比，第三代峰值更好地保留在融合前的四元组中 文献中所描述的钉状物。这些新的尖峰蛋白被称为VFLIP，保留了一个三聚体 即使在没有外源三聚基序的情况下，构象也抵抗热变性， 具有更好地反映正宗病毒粒子上的糖结构并提供受体结合结构域位置的特征糖结构 构象也更好地反映了天然病毒粒子上的构象。这些分子的“关闭”速度更慢。 广泛的抗冠状病毒抗体的比率。在这个项目中，我们将从 这些改进的尖峰单独存在，并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的B细胞和T细胞免疫反应的能力。到时候我们会的 评价最佳候选免疫原在小鼠和仓鼠感染模型中的疗效 相关冠状病毒。该项目代表了协作、迭代循环的开始和结束 免疫基因的设计和评估。深入评估和迭代的周期将引领疫苗努力 针对冠状病毒构成的日益增长的威胁提供广泛的保护。