STTR Phase I: Formulation of a COVID-19 mRNA Vaccine by Inverse Flash NanoPrecipitation

这个小企业技术转移第一阶段项目的更广泛的影响/商业潜力是为新冠肺炎开发一种新型的信使核糖核酸疫苗。新冠肺炎最快的临床疫苗是基于信使核糖核酸的疫苗，然而，目前市场上还没有基于信使核糖核酸的疫苗。这在一定程度上是因为这类疫苗很难优化和大规模生产。如果临床试验成功，仅在美国就需要数亿剂。该项目旨在开创一种新技术，最初为新冠肺炎生产基于信使核糖核酸的疫苗。这项技术高度模块化，可以更好地了解和优化这类疫苗。重要的是，这项新技术可以扩大规模，以生产当前新冠肺炎大流行和未来爆发所需的剂量。该平台技术的灵活性和可扩展性提供了持久的竞争优势。在展示临床前疗效后，该公司将与一家成熟的制药合作伙伴合作进行测试和制造。占领美国新冠肺炎疫苗市场5%的份额，估计将带来1.25亿美元的收入。这是一个滩头市场，一旦成功，该公司将扩展到其他基于信使核糖核酸的疫苗和治疗市场。这个小企业技术转移第一阶段项目旨在为新冠肺炎开发一种基于信使核糖核酸的纳米颗粒疫苗，而不使用阳离子材料。目前的制剂方法需要阳离子脂类或聚合物与阴离子信使核糖核酸形成基于电荷的络合物。基于电荷的组装限制了可获得的纳米颗粒表面化学成分，这一特征对于指导将被转基因的细胞类型和由此产生的免疫反应至关重要。此外，信使核糖核酸只是最终配方中的一小部分。所提出的制备方法在两步过程中将信使核糖核酸从纳米颗粒表面解偶联。该方法不需要阳离子材料，允许mRNA负载量比通过其他途径获得的高出5倍。然而，在没有使用阳离子材料的情况下，以前还没有证明过mRNA的转染。这将通过完成三个关键里程碑来实现：(1)优化信使核糖核酸的包裹，(2)改变表面涂层以增强树突状细胞的摄取，以及(3)证明有效的细胞转染。需要一种能够有效靶向和转染树突状细胞的高负载纳米颗粒制剂。在第一阶段工作完成后，这种配方可能会应用于SARS-CoV-2尖峰蛋白编码基因，以生产新冠肺炎疫苗。这一奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this this Small Business Technology Transfer (STTR) Phase I project is the development of a novel messenger ribonucleic acid (mRNA)-based vaccine for COVID-19. The fastest-to-clinic vaccine for COVID-19 was mRNA-based; however, there are no mRNA-based vaccines on the market currently. This is, in part, because this class of vaccines is difficult to optimize and manufacture at a large scale. If clinical trials are successful, hundreds of millions of doses will be needed in the U.S. alone. This STTR project aims to pioneer a novel technique to manufacture mRNA-based vaccines initially for COVID-19. This technology is highly modular, allowing for the better understanding and optimization of this class of vaccines. Importantly, this new technique can be scaled to manufacture the doses needed both for the current COVID-19 pandemic and in the case of future outbreaks. The flexibility and scalability of this platform technology provide a durable competitive advantage. Following demonstration of preclinical efficacy, the company will work with an established pharmaceutical partner for testing and manufacturing. Capturing 5% of the U.S. COVID-19 vaccine market would bring an estimated $125 million in revenue. This is a beachhead market, and, once successful, the company will expand into other mRNA-based vaccine and therapeutic markets.This Small Business Technology Transfer (STTR) Phase I project aims to develop an mRNA-based nanoparticle vaccine for COVID-19 without the use of cationic materials. Current formulation methods require cationic lipids or polymers to form charge-based complexes with the anionic mRNA. Charge-based assembly limits the accessible nanoparticle surface chemistries, a feature crucial to directing which cell types will be transfected and the resulting immune response. Additionally, mRNA is only a minor component of the resulting formulations. The proposed formulation method decouples the mRNA encapsulation from the nanoparticle surface in a two-step process. The method does not require cationic materials, allowing for mRNA loadings up to 5-times higher than those achievable through other routes. However, mRNA transfection has not previously been demonstrated without the use of cationic materials. This will be achieved by completing three key milestones: (1) optimize mRNA encapsulation, (2) vary surface coatings to enhance dendritic cell uptake, and (3) demonstrate efficient cell transfection. A highly loaded nanoparticle formulation that can efficiently target and transfect dendritic cells is desired. Following the completion of this Phase I work, this formulation may be applied to a SARS-CoV-2 spike protein-coding mRNA to produce a COVID-19 vaccine.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.