Epitope focusing to the receptor binding motif for a universal coronavirus vaccine

通用冠状病毒疫苗受体结合基序的表位

• 批准号: 10188307
• 负责人: Aaron Gregory Schmidt
• 金额: $ 39.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-22 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188307
• 关键词: 2019-nCoV; Administrative Supplement; Affect; Angiotensin Receptor; Antibodies; Antigens; Binding; Binding Sites; COVID-19; COVID-19 vaccine; Cells; Coronavirus; Cryoelectron Microscopy; Data; Development; Engineering; Epitopes; Frequencies; Future; Hemagglutinin; Immune response; Immunodominant Epitopes; Immunological Models; Influenza; Influenza Hemagglutinin; Lead; Masks; Molecular; Pathway interactions; Peptidyl-Dipeptidase A; Polysaccharides; Property; Proteins; Regimen; Research; Scaffolding Protein; Serum; Site; Structure; Surface; Testing; Vaccines; Viral; Virus; X-Ray Crystallography; base; data modeling; design; in vivo evaluation; mimicry; mouse model; neutralizing antibody; novel; novel coronavirus; pandemic disease; prevent; receptor; receptor binding; response; scaffold; theories; universal influenza vaccine; viral fitness

Project Summary There is urgent need for the development of effective countermeasures against the newly emerged novel coronavirus or “nCoV” (also known as COVID-19). The development of a “universal” coronavirus (CoV) vaccine would not only be effective against COVID-19 but, in theory, would protect against future, potential pandemic CoV strains. The pathway to such a vaccine will likely focus on the design of novel immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes, such as the receptor binding site (RBS). Here we leverage our structure-based, “resurfacing” and glycan engineering immunogen design approaches for a universal influenza vaccine and extend it to COVID-19. Our ongoing studies for influenza demonstrate that our resurfaced, heterochimeric immunogen approach substantially increased the overall frequency of elicited RBS-directed responses and our glycan engineering approach could effectively focus the immune response to a novel, conserved influenza hemagglutinin epitope; we envision that implementing comparable immunogen design approaches for COVID-19 specifically focusing to its receptor-binding interface epitope would yield similar results. We intend to use this Administrative Supplement to generate preliminary data to show the efficacy of our approach for a COVID-19 vaccine, and to optimize the vaccine regimen in the murine model; the data generated here will form the basis for future studies for a universal CoV vaccine.

项目摘要 针对新出现的小说，迫切需要制定有效的对策 冠状病毒或“nCoV”（也称为COVID-19）。“通用”冠状病毒（CoV）的发展 疫苗不仅对COVID-19有效，而且在理论上可以预防未来， 潜在的大流行性冠状病毒株。这种疫苗的途径可能会集中在设计新的疫苗上。 免疫原，其引发针对保守病毒表位的广泛中和抗体，如受体 结合位点（RBS）。在这里，我们利用基于结构的“表面重塑”和聚糖工程 通用流感疫苗的免疫原设计方法，并将其扩展到COVID-19。我们正在进行的 对流感的研究表明，我们的表面重塑的异源嵌合免疫原实质上 增加了引发RBS导向反应的总体频率， 可以有效地将免疫反应集中于一种新的、保守的流感血凝素表位;我们 设想实施针对COVID-19的类似免疫原设计方法， 关注其受体结合界面表位将产生类似的结果。我们打算利用这个 行政补充，以产生初步数据，以显示我们的方法的有效性， COVID-19疫苗，并在小鼠模型中优化疫苗方案;此处生成的数据 将为未来的通用冠状病毒疫苗研究奠定基础。