Project 3: Nucleoside-modified mRNA-LNP vaccine platform

摘要-项目3 冠状病毒有可能导致严重的发病率和死亡率，正如正在进行的 SARS-CoV-2大流行。这项计划项目的目的是发展安全和广泛保护的2b群 和2c贝塔冠状病毒(PanbetaCoV)疫苗能够诱导保护性免疫反应并评估 他们穿着动物挑战赛模型。已有3次重大冠状病毒暴发(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的想法 PanbetaCoV疫苗可为应对未来CoV的全球大流行准备做出重大贡献 流行病和流行病。冠状病毒(CoV)具有很大的大流行潜力，如 SARS-CoV-1、MERS和SARS-CoV-2在不到20年的时间里暴发。一种新型冠状病毒SARS的爆发-- CoV-2病毒已导致8500多万人感染和180万人死亡。因此，潘贝塔冠状病毒的发展 疫苗对于防止未来因出现新的人畜共患病冠状病毒而暴发至关重要。 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 其中最有效的平台之一就是核苷修饰的信使核糖核酸(Mod Mrna)。 封装在LNP中。两种领先的新冠肺炎疫苗正在进行第三阶段临床试验，由莫德纳公司和 辉瑞/BioNTech使用我们的核苷修饰的mRNA-LNP疫苗平台，在第三阶段具有95%的保护性 审判。除了效力外，mRNA/LNPs还可以进行快速、可扩展的生产和诱导持久免疫 回应。在项目3中，我们建议开发交叉保护和安全的mod mRNA-LNP疫苗 动物和人的BetaCov，并在临床前研究中评估其免疫原性和保护效果。 我们推测编码冠状病毒免疫原的mod mrna-lnp疫苗能够广泛诱导 保护性和广泛交叉保护的B和T细胞反应将有效地提供保护，防止未来 人畜共患冠状病毒的暴发。我们提出了以下具体目标： 目的1)应用mod m RNA-LNP构建中和抗体疫苗。 目的2)应用mod m RNA-LNP构建T细胞疫苗。 总而言之，这项提案旨在开发安全、易于生产和能够 在动物攻击模型中诱导保护性免疫反应。生成的数据将能够移动 这种潘贝塔冠状病毒疫苗的方法将用于临床开发。

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.