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.

项目摘要在2019年12月 2）。 SARS-COV-2在全球范围内迅速传播，导致大流行疾病称为冠状病毒病 2019（Covid-19）。有超过8000万的感染和近200万人死亡。迄今为止。 SARS-COV-2是人畜共患病的第三个β冠状病毒，引起人类流行病。这是相似的至但与中东呼吸道综合征冠状病毒（MERS-COV）和急性急性呼吸道综合征病毒1（SARS-COV-1），两者都引起了本世纪的爆发。而几个候选人 SARS-COV-2的疫苗最近已获得紧急使用授权，疫苗诱导的寿命响应，SARS-COV-2菌株中突变的持续紧急紧急以及不成比例的发病率老年患者人群的死亡率面临控制SARS-COV-2的持续挑战。因此，可以解决SARS-COV-2疫苗这些挑战的疫苗方式，并允许针对非常需要同时使用多种潜在的大流行冠状病毒。创新的疫苗可以对已知和新出现的人类冠状病毒产生广泛的免疫力，这是场地。抗原表位多样性，密度，价值，抗原可用性持续时间和佐剂的影响在疫苗诱导的回复剂的效力和广度上诱导的细胞因子环境尚不清楚。纳米颗粒疫苗配方可以操纵这些变量。我们已经产生了自我组装合成DNA-LAENANET的纳米颗粒疫苗（DLNP），该疫苗表现出增加的免疫原性与匹配的合成DNA相比，发射的单体疫苗或蛋白质中的制剂。我们确定合成DNA发射的纳米颗粒会增加细胞和体液反应。人们认为，重组纳米颗粒疫苗可以通过持续存在于与蛋白质抗原相比卵泡树突状细胞并增加生发中心的形成和体液免疫。细胞介导的对纳米颗粒疫苗的反应尚不清楚，但类似的机制可能正在发挥作用。我们将利用我们创建的用于操纵这些变量和确定它们对年轻和老年模型中COV抗原的急性和长期反应的影响。