Rapid, single-dose coronavirus vaccines via DNA-launched nanoparticles and genetic adjuvants for durable anti-coronavirus immunity

项目2摘要 迫切需要开发疫苗，其诱导针对当前和未来的免疫力的稳健和持久的免疫力。 新出现的致病性冠状病毒（CoV）。这些疫苗还必须在老年患者中具有免疫原性， 他们患上严重冠状病毒病的风险增加。许多具有大流行潜力的新型冠状病毒仍然存在 准备在人类中传播，老年患者的发病率和死亡率风险增加，强调 需要预先设计的下一代疫苗接种平台，具有可靠的临床前数据，表明 针对结构相关的CoV的效力和广度。该团队最近描述了设计和研究 体内自组装纳米颗粒，用于产生更有效和快速的体液和细胞反应 在HIV和流感模型中。在这里，我们建议应用这种证明的主要免疫设计 CoV模型系统中的策略。在这个项目下，我们将开发和表征一系列结构 调谐的、遗传佐剂化的、合成DNA（synDNA）发射的纳米颗粒（DLNP）免疫原， 我们最近设计的SARS-CoV-2刺突抗原我们先前报道了DLNPs诱导细胞凋亡的能力。 与传统的synDNA和蛋白质佐剂疫苗制剂相比，合作 在项目1中，我们将评估这些免疫原促进对以下疾病的有效和持久免疫的能力： SARS-CoV-2和相关病毒。总之，这个项目的目标是定义操纵的效果， 表位的价数、大小和佐剂环境对自组装DLNP疫苗的影响大小， 功能性，以及在年轻和老年小鼠模型中的反应半衰期。这些实验将提供 表位操作对疫苗诱导的应答的影响的机制见解，并定义 这些参数可诱导稳健和持久的抗CoV免疫力。

Project 2 Summary There is an urgent need to develop vaccines which induce robust and lasting immunity against current and emerging pathogenic coronaviruses (CoVs). These vaccines must also be immunogenic in elderly patients as they are at increased risk of severe coronavirus disease. Many novel CoVs with pandemic potential remain poised for human transmission, and elderly patients are at increased risk of morbidity and mortality, emphasizing the need for predesigned next-generation vaccination platforms with robust preclinical data indicating increased potency and breadth against structurally related CoVs. This team has recently described the design and study of in vivo self-assembling nanoparticles for generation of more potent and rapid humoral and cellular responses in both the HIV and influenza models. Here we propose to apply this proof-of-principal immunization design strategy in the CoV model system. Under this program we will develop and characterize a series of structurally tuned, genetically adjuvanted, synthetic DNA (synDNA)-launched nanoparticle (DLNP) immunogens based on our recent designs for the SARS-CoV-2 spike antigen. We previously reported on the ability of DLNPs to induce robust immunity compared to traditional synDNA and protein-in-adjuvant vaccine formulations. In collaboration with Project 1 we will evaluate the capacity of these immunogens to foster potent and durable immunity against SARS-CoV-2 and related viruses. In summary, the goal of this project is to define the effect of manipulating epitope valency, size, and adjuvant environment on self-assembling DLNP vaccine on the magnitude, functionality, and half-life of responses in young and aged mouse models. These experiments will provide mechanistic insight into the effects of epitope manipulation on vaccine-induced responses and define the parameters which induce robust and durable anti-CoV immunity.