Project 3: Nucleoside-modified mRNA-LNP vaccine platform

摘要-项目3 冠状病毒有可能导致显著的发病率和死亡率， SARS-CoV-2大流行。该项目的目的是开发安全和广泛保护的2b组 和2c乙型冠状病毒（panbetaCoV）疫苗能够诱导保护性免疫应答，并评估 在动物挑战模型中。事实上，有3个主要的冠状病毒爆发（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疫苗的想法。 泛β冠状病毒疫苗，可以大大有助于全球防范未来的冠状病毒大流行 流行病和大流行病。冠状病毒（CoV）具有重大的大流行潜力，如 在不到20年的时间里爆发了SARS-CoV-1、MERS和SARS-CoV-2。新型冠状病毒SARS的爆发- CoV-2已导致超过8500万人感染，180万人死亡。因此，泛β冠状病毒的开发 疫苗对于防止未来由于出现新的人畜共患病CoV而爆发疫情至关重要。 基于信使RNA/LNP的疫苗已被证明对癌症和传染性疾病非常有效。 最有效的平台之一包括核苷修饰的mRNA（mod mRNA） 包封在LNP中。Moderna的两种领先的COVID-19疫苗正在进行3期临床试验， 辉瑞/BioNTech使用我们的核苷修饰mRNA-LNP疫苗平台，在3期试验中具有95%的保护性 审判除了效力之外，mRNA/LNP还可以进行快速、可规模化的生产并诱导持久的免疫反应。 应答在项目3中，我们建议开发交叉保护和安全的mod mRNA-LNP疫苗， 动物和人β CoV，并在临床前研究中评估其免疫原性和保护效力。 我们假设编码CoV免疫原的mod mRNA-LNP疫苗能够广泛诱导 保护性和广泛的交叉保护性B和T细胞反应将有效地提供对未来的保护， 人畜共患冠状病毒的爆发我们提出以下具体目标： 目的1）利用mod mRNA-LNP开发中和抗体panbetaCoV疫苗。 目的2）利用mod mRNA-LNP构建T细胞疫苗。 总之，该提案旨在开发安全、易于生产且可 在动物攻击模型中诱导保护性免疫应答。产生的数据将能够移动 这种泛β冠状病毒疫苗的临床开发方法。

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.