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，从而诱导强大和持久的免疫力，以防当前和 新兴的致病性冠状病毒（COVS）。这些疫苗还必须在老年患者中具有免疫原性 它们的风险增加了严重的冠状病毒疾病。许多具有大流行潜力的新型COV仍然存在 准备人类传播，老年患者的发病率和死亡风险增加，强调 使用强大的临床前数据的预先设计的下一代疫苗接种平台的需求表明增加 对与结构相关的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的产生，以产生更有效和快速的体液和细胞反应 在艾滋病毒和流感模型中。在这里，我们建议采用这种主要免疫证明 COV模型系统中的策略。在此程序下，我们将开发并在结构上进行一系列特征 根据基于基于基于的，遗传佐剂的合成DNA（SynDNA）启动的纳米颗粒（DLNP）免疫原子 我们最近针对SARS-COV-2尖峰抗原的设计。我们以前报告了DLNP诱导的能力 与传统的syndna和亚辅助疫苗配方相比，可靠的免疫力。合作 使用项目1，我们将评估这些免疫原子的能力，以促进有效和耐用的免疫力 SARS-COV-2和相关病毒。总而言之，该项目的目的是定义操纵的效果 自组装DLNP疫苗的表位价，大小和辅助环境，大小为 年轻小鼠模型中的功能，以及响应的半衰期。这些实验将提供 机械洞察表位操纵对疫苗诱导的反应的影响并定义 诱导强大而耐用的抗COV免疫力的参数。