Project 3: Nucleoside-modified mRNA-LNP vaccine platform

项目3：核苷修饰mRNA-LNP疫苗平台

• 批准号: 10842504
• 负责人: Barton F. Haynes
• 金额: $ 93.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10842504
• 关键词: 2019-nCoV; Address; Adjuvant; Adverse event; Age; Animal Model; Animals; Antibody Response; Antigens; B-Lymphocytes; COVID-19 pandemic; COVID-19 vaccine; Cell Surface Proteins; Cessation of life; Collaborations; Communicable Diseases; Coronavirus; Coronavirus Infections; Country; Data; Development; Disease; Disease Outbreaks; Ebola virus; Elderly; Encapsulated; Epidemic; Epithelial Cells; Evaluation; Ferritin; Future; Generations; Glycoproteins; Goals; Helper-Inducer T-Lymphocyte; Human; Human Herpesvirus 2; Immune; Immune response; Infection; Length; Malignant Neoplasms; Mediating; Membrane; Mesocricetus auratus; Messenger RNA; Middle East Respiratory Syndrome Coronavirus; Modeling; Modification; Morbidity - disease rate; Nucleosides; Pathology; Phase III Clinical Trials; Pre-Clinical Model; Production; Proteins; Pulmonary Pathology; Risk; SARS coronavirus; Structure of germinal center of lymph node; T cell response; T-Cell Development; T-Lymphocyte; Testing; Vaccines; Viral; Virus; Virus Diseases; Zika Virus; betacoronavirus; betacoronavirus vaccine; clinical development; coronavirus pandemic; design; effector T cell; expectation; flexibility; future outbreak; immunogenic; immunogenicity; influenzavirus; innovation; lipid nanoparticle; mortality; mouse model; nanoparticle; neutralizing antibody; new outbreak; novel coronavirus; novel vaccines; pandemic disease; pandemic potential; pandemic preparedness; particle; pathogen; pathogenic virus; phase III trial; preclinical study; prevent; programs; protective efficacy; receptor binding; research clinical testing; response; universal coronavirus vaccine; vaccine candidate; vaccine development; vaccine platform; zoonotic coronavirus

ABSTRACT - Project 3 Coronaviruses havethe potential to cause significant morbidity andmortality as demonstrated by the ongoing SARS-CoV-2 pandemic. The purpose of this program project is to develop safe and broadly-protective group 2b and 2c betacoronavirus (panbetaCoV) vaccines capable of inducing protective immune responses and evaluate them in animal challenge models. The fact that there has been 3 major CoV outbreaks (SARS-CoV-1, MERS and SARS-CoV-2) in less than 20 years strongly supports the idea of generation of broadly protective panbetaCoV vaccines that can significantly contribute to global pandemic preparedness against future CoV epidemics and pandemics. Coronaviruses (CoVs) have significant pandemic potential, as illustrated by the outbreaks of SARS-CoV-1, MERS and SARS-CoV-2 in less than 20 years. The outbreak of a novel CoV, SARS- CoV-2, has resulted in at over 85 million infections and 1.8 million deaths. Thus, development of panbetaCoV vaccines is essential to preventing a future outbreaks due to an emerging new zoonotic CoV. Messenger RNA/LNP-based vaccines have proved to be highly effective against cancer and infectious diseases and one of the most effective platforms comprises nucleoside-modified mRNA (mod mRNA) encapsulated in LNPs. Two of the leading COVID-19 vaccines in phase 3 clinical trials by Moderna and Pfizer/BioNTech use our nucleoside-modified mRNA-LNP vaccine platform and are 95% protective in Phase 3 trials. Besides potency, mRNA/LNPs can undergo rapid, scalable production and induced durable immune responses. In Project 3, we propose to develop cross-protective and safe mod mRNA-LNP vaccines against animal and human betaCoVs and evaluate their immunogenicity and protective efficacy in preclinical studies. We hypothesize that mod mRNA-LNP vaccines encoding CoV immunogens capable of inducing broadly protective and broadly cross-protective B and T cell responses will effectively provide protection against future outbreaks of zoonotic CoVs.. We propose the following Specific Aims: Aim 1) Development of neutralizing antibody panbetaCoV vaccines using mod mRNA-LNP. Aim 2) Development of T cell vaccines using mod mRNA-LNP. In summary, this proposal aims to develop panbetaCoV vaccines that are safe, easy-to-produce and can induce protective immune responses in animal challenge models. The data generated will be capable of moving this panbetaCoV vaccine approach to clinical development.

摘要 - 项目 3 正在进行的研究表明，冠状病毒有可能导致显着的发病率和死亡率 SARS-CoV-2 大流行。该计划项目的目的是开发安全且具有广泛保护性的组 2b 和 2c β 冠状病毒 (panbetaCoV) 疫苗能够诱导保护性免疫反应并评估 他们在动物挑战模型中。事实上，已经发生了 3 次重大 CoV 爆发（SARS-CoV-1、MERS 和 SARS-CoV-2）在不到 20 年的时间里强烈支持了产生广泛保护性病毒的想法 panbetaCoV 疫苗可以极大地促进全球针对未来 CoV 的大流行防范 流行病和流行病。正如以下数据所示，冠状病毒 (CoV) 具有显着的大流行潜力 SARS-CoV-1、MERS 和 SARS-CoV-2 在不到 20 年的时间内爆发。新型冠状病毒（SARS）的爆发 CoV-2 已导致超过 8500 万人感染和 180 万人死亡。因此，panbetaCoV 的开发 疫苗对于预防未来因新出现的人畜共患冠状病毒而爆发至关重要。 基于信使 RNA/LNP 的疫苗已被证明对癌症和传染病非常有效 核苷修饰 mRNA (mod mRNA) 是最有效的平台之一 封装在 LNP 中。 Moderna 和 正在进行 3 期临床试验的两种领先的 COVID-19 疫苗 辉瑞/BioNTech 使用我们的核苷修饰 mRNA-LNP 疫苗平台，在第 3 阶段具有 95% 的保护率 试验。除了效力之外，mRNA/LNP 还可以进行快速、可扩展的生产并诱导持久的免疫 回应。在项目3中，我们建议开发交叉保护且安全的mod mRNA-LNP疫苗 动物和人类 betaCoV 并在临床前研究中评估其免疫原性和保护功效。 我们假设编码 CoV 免疫原的 mod mRNA-LNP 疫苗能够广泛诱导 保护性和广泛交叉保护性 B 和 T 细胞反应将有效提供针对未来的保护 人畜共患冠状病毒的爆发。我们提出以下具体目标： 目标 1) 使用 mod mRNA-LNP 开发中和抗体 panbetaCoV 疫苗。 目标 2) 使用 mod mRNA-LNP 开发 T 细胞疫苗。 综上所述，该提案旨在开发安全、易于生产且可用于生产的泛β冠状病毒疫苗。 在动物挑战模型中诱导保护性免疫反应。生成的数据将能够移动 这种 panbetaCoV 疫苗的临床开发方法。