Integrative Immunogen Design and Testing

项目3摘要 冠状病毒可能仍然是对人类健康的持续威胁。然而，下一个重要的 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 SARS-CoV-2的变种尚不清楚。该项目的目标是开发新的，改进的免疫原， 引发更广泛的抗冠状病毒免疫，以在结构上评估产生的泛冠状病毒或宽冠状病毒 抗体，并评估广泛的冠状病毒疫苗在动物模型中的效力。我们将开始与小说 第三代钉，相对于早期版本， 在文献中已经描述过的尖峰。这些新的刺突蛋白，被称为"VFLIP"，保留了三聚体结构。 即使在不存在外源三聚基序的情况下，构象也对热变性具有抗性， 特征聚糖结构，更好地反映了真实病毒体上的聚糖结构，并提供受体结合域位置 和构象也更好地反映了天然病毒体上的那些。这些分子的进一步特点是“关闭”较慢 广泛的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， 这些改进的刺突单独和作为创新的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细胞免疫应答的能力。然后我们将 使用多重免疫学方法评价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。这个项目代表了协作、迭代循环的开始和结束， 免疫原设计和评价。深入评价和反复的周期将指导疫苗工作， 针对冠状病毒带来的日益严重的威胁提供广泛的保护。

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.