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 冠状病毒的潜力可能引起明显的发病率和尸体性 SARS-COV-2大流行。该计划项目的目的是开发安全且广泛保护的组2B 和2C Betacoronavirus（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。发生了3次主要COV爆发的事实（SARS-COV-1，MERS 和SARS-COV-2）在不到20年的时间内，强烈支持了广泛保护的想法 Panbetacov疫苗，可以显着有助于全球大流行准备对未来的COV 流行病和大流行病。冠状病毒（COVS）具有显着的大流行潜力，如 在不到20年的时间里，SARS-COV-1，MERS和SARS-COV-2爆发。小说CoV的爆发，Sars- COV-2导致超过8500万感染和180万死亡。因此，Panbetacov的发展 疫苗对于防止新的人畜共患病COV引起的未来爆发至关重要。 事实证明，基于Messenger RNA/LNP的疫苗对癌症和感染力非常有效 疾病和最有效的平台之一包括核苷改性mRNA（MOD mRNA） 封装在LNP中。现代和 辉瑞/Biontech使用我们的核苷修饰的mRNA-LNP疫苗平台，在第3阶段具有95％的保护性 试验。除效力外，mRNA/LNP还可以快速，可扩展的产生和诱导的耐用免疫 回答。在项目3中，我们建议开发跨保护和安全的mod mRNA-LNP疫苗 动物和人类的贝塔科夫（Betacovs）在临床前研究中评估其免疫原性和保护效果。 我们假设MOD mRNA-LNP疫苗编码能够广泛诱导的COV免疫原 保护性和广泛的交叉保护B和T细胞反应将有效地保护未来 人畜共患病的爆发。我们提出了以下特定目的： 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。 总而言之，该建议旨在开发安全，易于生产的Panbetacov疫苗，并且可以 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疫苗用于临床发育。