Development of Viral Vaccines against Sarbecoviruses and Merbecoviruses

Sarbecoviruses和Merbecoviruses病毒疫苗的研制

基本信息

批准号：
10420516
负责人：
Michael S Diamond
金额：
$ 216.11万
依托单位：
WASHINGTON UNIVERSITY
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：
2022-09-02 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10420516
关键词：
2019-nCoV ACE2 Adenovirus Vector Animals Antibodies Antibody Response Antigens Attenuated B-Lymphocytes Binding Blocking Antibodies C-terminal CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell membrane Cell surface Cells Cellular Immunity Chad Coronavirus Coronavirus spike protein Coupled Development Diamond Disease Outbreaks Dose Engineering Epitopes Evaluation Event Family Formulation Future GTP-Binding Proteins Genes Geography Goals Hamsters Human Humoral Immunities Immune Immune response Immunity Individual Infection Intramuscular Intramuscular Injections Laboratories Length Link Merbecovirus Messenger RNA Middle East Respiratory Syndrome Coronavirus Mucosal Immunity Mus Nonstructural Protein Pan Genus Pfizer-BioNTech COVID-19 vaccine Population Proteins RNA vaccine Regimen SARS coronavirus Sarbecovirus Serology System T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Transgenic Mice Transmembrane Domain Vaccinated Vaccines Vesicular stomatitis Indiana virus Viral Vaccines Viral Vector Virus Zoonoses base betacoronavirus cellular transduction coronavirus vaccine cross reactivity design experience global health high risk human coronavirus immunogenic immunogenicity member pandemic disease product development receptor receptor binding response seasonal coronavirus universal coronavirus vaccine vaccine development vaccine efficacy vaccine platform vector vector vaccine

项目摘要

Project Summary Over the past twenty years, six coronaviruses (CoV) have emerged or expanded their geographic range. The emergent human CoVs with the greatest global impact (SARS-CoV-1, SARS-CoV-2, and MERS-CoV) belong to the Sarbecovirus and Merbecovirus subgenera within the Betacoronavirus genus of the Coronaviridae family. Many zoonotic high-risk Sarbecoviruses and Merbecoviruses are poised for human emergence events because they can bind human ACE2 and DPP4 entry receptors and infect human cells in culture. Given the historical outbreaks of CoVs, coupled with the recent emergence of SARS-CoV-2 and its destabilizing consequence on global health and economy, there is an urgent need to develop vaccines capable of broad protection against existing and future Sarbecoviruses and Merbecoviruses. Thus, the overarching goal of this P01 proposal is to generate viral-vectored vaccines that induce broad cross-protective humoral and cellular immunity to Sarbecoviruses and Merbecoviruses with pandemic potential, especially those viruses at high risk for zoonotic emergence into human populations. Project 3 will use antigen and epitope designs from Projects 1 and 2 to create vaccine platforms that generate cross-reactive immune responses against Sarbecoviruses and Merbecoviruses with pandemic potential. We will use several spike (S), RBD, and non-structural protein antigens that can be administered as part of a polyvalent formulation to induce broad B and T cell immunity. Project 3 will perform parallel and iterative engineering of an intranasally delivered chimpanzee adenoviral vectored virus (ChAd) and an intramuscularly delivered live-attenuated vesicular-stomatitis virus (VSV) displaying or producing optimized antigens. Antigens and vaccines that show immune responses of the highest magnitude and greatest cross-reactivity (determined with Core A) will be tested in in naïve, virus-immune, and mRNA vaccinated mice to determine how pre-existing immunity to SARS-CoV-2 impacts the immunogenicity of our more broadly targeting CoV vaccines. Vaccines showing optimal B and T cell immunogenicity (breadth, magnitude, and function) will be prioritized for mouse and hamster challenge studies in Core B with multiple Sarbecoviruses and Merbecoviruses. Our proposal is a proof-of-principle for product development. We envision generating at least one vaccine that induces broad-spectrum immunity to multiple CoV of concern.

项目概要在过去的二十年里，已经出现了六种冠状病毒（CoV）或扩大了它们的地理范围。对全球影响最大的新出现的人类冠状病毒（SARS-CoV-1、SARS-CoV-2 和 MERS-CoV）属于冠状病毒科β冠状病毒属中的Sarbecovirus 和Merbecovirus 亚属。许多人畜共患高风险 Sarbecovirus 和 Merbecovirus 已准备好应对人类出现事件，因为鉴于历史，它们可以结合人类 ACE2 和 DPP4 进入受体并感染培养的人类细胞。冠状病毒的爆发，加上最近出现的 SARS-CoV-2 及其对稳定的影响全球健康和经济，迫切需要开发能够广泛预防的疫苗因此，本 P01 提案的首要目标是产生病毒载体疫苗，诱导广泛的交叉保护性体液和细胞免疫具有大流行潜力的 Sarbecoviruses 和 Merbecoviruses，特别是那些具有人畜共患高风险的病毒项目 3 将使用项目 1 和 2 的抗原和表位设计。创建疫苗平台，产生针对 Sarbecoviruses 的交叉反应性免疫反应，我们将使用几种具有大流行潜力的 Merbecoviruses、RBD 和非结构蛋白抗原。可以作为多价制剂的一部分施用，以诱导广泛的 B 和 T 细胞免疫项目 3。将对鼻内递送的黑猩猩腺病毒载体病毒进行并行和迭代工程 (ChAd) 和肌肉注射的减毒活水泡性口炎病毒 (VSV) 展示或产生优化的抗原和疫苗表现出最高程度和最大的免疫反应。交叉反应性（用 Core A 测定）将在幼稚小鼠、病毒免疫小鼠和 mRNA 小鼠中进行测试以确定预先存在的 SARS-CoV-2 免疫力如何影响我们更广泛的免疫原性具有最佳 B 和 T 细胞免疫原性（广度、强度和免疫原性）的疫苗。功能）将优先用于 Core B 中多种 Sarbecoviruses 的小鼠和仓鼠攻击研究，并且我们的建议是产品开发的原理验证。一种疫苗可以诱导针对多种关注的冠状病毒的广谱免疫。