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

项目2总结 迫切需要开发疫苗，以诱导针对当前和未来的强大而持久的免疫力。 新出现的致病性冠状病毒（CoV）。这些疫苗还必须对老年患者具有免疫原性，因为 他们患严重冠状病毒疾病的风险增加。许多具有大流行潜力的新型冠状病毒仍然存在 已做好人际传播的准备，老年患者的发病和死亡风险增加，强调 需要预先设计的下一代疫苗接种平台，该平台具有可靠的临床前数据，表明增加 针对结构相关的冠状病毒的效力和广度。该团队最近描述了设计和研究 体内自组装纳米粒子，用于产生更有效、更快速的体液和细胞反应 在艾滋病毒和流感模型中。在这里我们建议应用这种原理证明免疫设计 冠状病毒模型系统中的策略。根据该计划，我们将开发并表征一系列结构 调整的、基因佐剂的、合成 DNA (synDNA) 发射的纳米颗粒 (DLNP) 免疫原，基于 我们最近针对 SARS-CoV-2 刺突抗原的设计。我们之前报道过 DLNP 诱导的能力 与传统的 synDNA 和蛋白佐剂疫苗配方相比，具有更强的免疫力。合作中 通过项目 1，我们将评估这些免疫原培养有效且持久的免疫力的能力 SARS-CoV-2 和相关病毒。总之，该项目的目标是定义操纵的效果 表位效价、大小和佐剂环境对自组装 DLNP 疫苗的影响程度， 年轻和老年小鼠模型中反应的功能和半衰期。这些实验将提供 深入了解表位操作对疫苗诱导反应的影响，并定义 诱导强大且持久的抗冠状病毒免疫力的参数。

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.