Structural vaccinology guided development of a universal CoV vaccine utilizing nucleic acid delivered nanoparticles

结构疫苗学指导利用核酸递送纳米粒子开发通用 CoV 疫苗

基本信息

批准号：
10328138
负责人：
Daniel Kulp
金额：
$ 262.68万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
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/10328138
关键词：
2019-nCoV ACE2 Acute Address Adjuvant Animal Model Animals Antibody Repertoire Antigen Presentation Antigens Automobile Driving B-Lymphocytes Binding Sites COVID-19 COVID-19 mortality COVID-19 vaccine Cells Chiroptera Combined Vaccines Coronavirus Coronavirus Infections DNA Development Disease Outbreaks Dose Emergency Situation Engineering Environment Epidemic Epitopes Event FDA Emergency Use Authorization Family Family member Follicular Dendritic Cells Formulation Genetic Goals Human Humoral Immunities Immune response Immunity Immunization Immunologic Memory Immunologics In Vitro Infection Kinetics Longevity Mediating Middle East Respiratory Syndrome Coronavirus Modality Modeling Molecular Morbidity - disease rate Mucous Membrane Mus Mutation Names Nucleic Acids Peripheral Play Point Mutation Population Production Proteins Publishing Recombinants Respiratory Mucosa Role SARS coronavirus SARS-CoV-2 infection Serotyping Structure Structure of germinal center of lymph node Surface Syndrome T cell response T-Lymphocyte Vaccines Virus Virus Diseases Wild Type Mouse Zoonoses aged base betacoronavirus clinically relevant coronavirus receptor coronavirus vaccine cytokine density design human coronavirus immunogenic immunogenicity in vivo innovation lymph nodes monomer mortality nanoparticle nanoparticle delivery nanovaccine next generation novel novel coronavirus older patient pandemic coronavirus pandemic disease patient population programs receptor respiratory response synthetic construct transmission process universal coronavirus vaccine vaccine candidate vaccine development vaccine formulation vaccine response vaccine trial vaccine-induced immunity vaccinology zoonotic coronavirus

项目摘要

Project Summary In December 2019 a novel coronavirus, named sudden acute respiratory syndrome coronavirus-2 (SARS-CoV- 2). SARS-CoV-2 rapidly spread around the globe causing a pandemic disease termed coronavirus disease of 2019 (COVID-19). There have been more than 80 million infections and close to two million deaths from COVID- 19 to date. SARS-CoV-2 is the third beta coronavirus of zoonotic origin to cause human epidemics. It is similar to, but distinct from, Middle East respiratory syndrome coronavirus (MERS-CoV) and sudden acute respiratory syndrome virus-1 (SARS-CoV-1), both of which have caused outbreaks this century. While several candidate vaccines for SARS-CoV-2 have recently received emergency use authorization, the longevity of vaccine-induced responses, the continued emergency of mutation within SARS-CoV-2 strains, and the disproportionate morbidity and mortality among elderly patient populations present continued challenges to control of SARS-CoV-2. Thus, vaccine modalities which can address these challenges for SARS-CoV-2 vaccines and allow for targeting of multiple potentially pandemic coronaviruses simultaneously are greatly needed. Innovative vaccines which can develop broad immunity against known and newly emergent human coronavirus is a key goal in the field. The effects of antigen epitope diversity, density, valency, duration of antigen availability, and adjuvant- induced cytokine environment on the potency and breadth of vaccine-induced Reponses remains unclear. Nanoparticle vaccine formulations allow the ability to manipulate these variables. We have generated self- assembling synthetic DNA-launched nanoparticle vaccines (DLNPs) which displayed increased immunogenicity compared to matched synthetic DNA launched monomer vaccines or protein-in-adjuvant formulations. We determined that synthetic DNA launched nanoparticles increased both cellular and humoral responses. Recombinant nanoparticle vaccines are thought to mediate their increased immunogenicity by persisting in the lymph nodes for extended periods compared to protein antigens, promoting enhanced antigen presentation by follicular dendritic cells and increasing germinal center formation and humoral immunity. Cell-mediated responses to nanoparticle vaccines are less well understood but similar mechanisms may be at play. We will capitalize on the novel in vivo assembling synDLNP platform we have created to manipulate these variables and determine their effects on acute and long-term responses to CoV antigens in young and aged models.

项目概要 2019 年 12 月，一种新型冠状病毒被命名为突发急性呼吸综合征冠状病毒-2（SARS-CoV- 2）。 SARS-CoV-2 在全球范围内迅速传播，引发了一种名为冠状病毒病的大流行病 2019 年（新冠肺炎 (COVID-19)）。已有超过 8000 万人感染新冠病毒，近 200 万人死亡迄今为止 19 名。 SARS-CoV-2 是第三种引起人类流行病的人畜共患 β 冠状病毒。是类似的属于但不同于中东呼吸综合征冠状病毒 (MERS-CoV) 和突发急性呼吸道疾病综合征病毒-1 (SARS-CoV-1)，这两种病毒都在本世纪引起了疫情的爆发。虽然几位候选人 SARS-CoV-2 疫苗最近获得紧急使用授权，疫苗诱导的寿命延长反应、SARS-CoV-2 毒株内持续出现的紧急突变以及不成比例的发病率老年患者群体的死亡率和死亡率对控制 SARS-CoV-2 提出了持续的挑战。因此，可以解决 SARS-CoV-2 疫苗的这些挑战并允许靶向的疫苗模式非常需要同时检测多种潜在大流行的冠状病毒。创新疫苗能够对已知和新出现的人类冠状病毒产生广泛的免疫力是该研究的一个关键目标场地。抗原表位多样性、密度、效价、抗原可用性持续时间和佐剂的影响诱导的细胞因子环境对疫苗诱导反应的效力和广度的影响仍不清楚。纳米颗粒疫苗制剂能够操纵这些变量。我们已经产生了自我组装合成 DNA 发射纳米颗粒疫苗 (DLNP)，其免疫原性增强与匹配的合成 DNA 启动单体疫苗或佐剂蛋白制剂相比。我们确定合成 DNA 发射的纳米粒子增加了细胞和体液反应。重组纳米颗粒疫苗被认为通过持续存在来介导其增强的免疫原性。与蛋白质抗原相比，淋巴结的作用时间更长，从而促进抗原呈递增强滤泡树突状细胞并增加生发中心形成和体液免疫。细胞介导对纳米颗粒疫苗的反应尚不清楚，但类似的机制可能在发挥作用。我们将利用我们创建的新型体内组装 synDLNP 平台来操纵这些变量确定它们对年轻和老年模型中冠状病毒抗原的急性和长期反应的影响。