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

通过 DNA 发射的纳米粒子和基因佐剂快速、单剂量冠状病毒疫苗，以实现持久的抗冠状病毒免疫力

• 批准号: 10328141
• 负责人: DAVID B. WEINER
• 金额: $ 110.71万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328141
• 关键词: 2019-nCoV; ACE2; Acute; Adjuvant; Aging; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Response; Antigens; B-Lymphocytes; Biological Assay; Biological Models; CCL27 gene; Cells; Cellular Immunity; Clinic; Collaborations; Coronavirus; DNA; DNA delivery; Data; Development; Dose; Environment; Epitopes; Event; Flow Cytometry; Formulation; Fostering; Frequencies; Generations; Genetic; Goals; HIV; Half-Life; Human; Immune; Immunity; Immunization; Immunoglobulin A; Immunologic Adjuvants; Infection; Influenza; Interleukin-12; Label; Laboratories; Longevity; Measures; Mediating; Memory; Memory B-Lymphocyte; Middle East Respiratory Syndrome; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Nucleic Acids; Particle Size; Pathogenicity; Phenotype; Physiologic pulse; Plasma Cells; Play; Population; Production; Protocols documentation; Public Health; Reporting; Risk; Role; Selection Criteria; Series; Site; Structure of germinal center of lymph node; Surface; System; T cell response; T memory cell; T-Lymphocyte; Translations; Vaccination; Vaccines; Viral; Virus; Work; adenosine deaminase; aged; aging population; antigen-specific T cells; base; coronavirus vaccine; cross reactivity; cytokine; cytotoxic CD8 T cells; design; effector T cell; experimental study; immunogenic; immunogenicity; improved; in vivo; insight; lymph nodes; mortality; mouse model; nanoparticle; nanoparticle delivery; neutralizing antibody; next generation; novel; novel coronavirus; older patient; pandemic coronavirus; pre-clinical; programs; response; severe COVID-19; synthetic construct; synthetic protein; transmission process; universal coronavirus vaccine; vaccine development; vaccine formulation; vaccine platform; vaccine response; vaccinology

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.

项目2摘要 迫切需要开发疫苗，以诱导对当前和长期的 新出现的致病冠状病毒(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 有可能发生人类传播，老年患者的发病率和死亡率增加，强调 需要预先设计的下一代疫苗接种平台，具有稳健的临床前数据，表明 针对结构相关的CoV的效力和广度。该团队最近描述了这项设计和研究 体内自组装纳米颗粒用于产生更有效和更快速的体液和细胞反应 在艾滋病毒和流感模型中都是如此。在这里，我们建议应用此原则证明免疫设计 战略在机动车模型系统中。在这个计划下，我们将开发和表征一系列结构上的 经过基因调整、合成DNA(SynDNA)发射的纳米颗粒(DLNP)免疫原，基于 我们最近设计的SARS-CoV-2刺突抗原。我们之前曾报道过DLNPs诱导 与传统的合成DNA和蛋白质佐剂疫苗配方相比，具有强大的免疫力。在协作中 在项目1中，我们将评估这些免疫原培养有效和持久免疫的能力 SARS-CoV-2及相关病毒。总而言之，这个项目的目标是定义操纵的效果 自组装DLNP疫苗的表位效价、大小和佐剂环境的大小， 小鼠和老年小鼠模型的功能性和反应半衰期。这些实验将提供 对表位操纵对疫苗诱导反应的影响的机械性洞察并定义 诱导稳健持久的抗冠状病毒免疫的参数。