RAPID: Collaborative Research: Enabling the Development of COVID-19 Vaccines, Therapeutics and Diagnostics through Innovations in Measurement Science

这项拟议的快速提案的更广泛影响是，通过美国国家科学基金会产学生物分析计量合作研究中心(CBM)的工作，为政府、行业和学术专业人士提供关键的支持测量科学的工具，这些专业人员致力于减轻新冠肺炎的影响。印第安纳大学的研究人员已经开发出独特的仪器来确定病毒等非常大的颗粒的组成，他们将表征病毒、候选疫苗和与病毒颗粒结合的抗体。让这一独特的仪器在整个国家政府、行业和学术研究人员网络中普遍提供给从事新冠肺炎疫苗工作的研究人员，将迅速解决在开发安全和可重复的疫苗的竞赛中不可避免地出现的测量科学问题。同时，CBM将解决快速抗体检测的挑战，这些检测既不是定量的，也不是高度敏感的，而且典型的基于实验室的确定抗体浓度的方法既冗长又繁琐。圣母大学和普渡大学的研究人员将开发出快速定量患者血清中新冠肺炎抗体数量的设备。随着时间的推移，这种分析对于低成本的抗体水平(从而免疫)检查是至关重要的。拟议的设备将利用巴黎圣母院开发的创新抗体捕获技术(提供增强的信号)和普渡大学在开发护理点诊断设备方面的专业知识。这些测量对于调查免疫力衰退的问题和确定特定患者的恢复期血浆是否适合进行治疗研究将是重要的。这项拟议的快速研究旨在提供新冠肺炎的结构及其引发的抗体反应的基础知识。疫苗和生物分子治疗研究的分析和测量科学支持是出了名的困难。所讨论的分子往往太大太复杂，无法用标准的表征方法进行表征，而且许多关于异质性、化学计量和结构的问题也不容易回答。研究人员将利用电荷检测质谱学和离子迁移率光谱分析的先进技术来研究病毒蛋白质组件的异质性、化学计量、结构和相互作用，并为鉴定新开发的新冠肺炎候选疫苗和治疗方案提供必要的测量数据。CBM的CDMS和IMS工具是独一无二的，研究人员将允许研究人员直接观察灭活病毒、没有核酸的“假”病毒颗粒、半抗原载体上含有免疫原的生物结合物、寡核苷酸、与目标蛋白复合的抗体以及与病毒颗粒结合的抗体。这些仪器正开始给生物结合分析、疫苗开发、基因疗法和蛋白质疗法带来革命性的变化。快速检测抗体效价的设备的开发将依赖于多孔膜中的抗体捕获，多孔膜具有用于灵敏光学检测的长路径和高表面积与体积比，从而能够有效地捕获抗体。设备设计将利用开发薄带微流控诊断方面的专业知识。基于捕获的二次抗体的荧光强度，这些设备将提供不同类别新冠肺炎抗体丰度的衡量标准。这一奖项反映了美国国家科学基金会的法定使命，并已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。

This broader impacts of this proposed RAPID proposal is to provide critically enabling measurement science tools to government, industry and academic professionals engaged in mitigating the effects of COVID-19 through work from the NSF Industry-University Cooperative Research Center for Bioanalytic Metrology (CBM). Researchers at Indiana University have developed unique instrumentation to determine the composition of very large particles such as viruses, and they will characterize viruses, vaccine candidates, and antibodies bound to viral particles. Making this unique instrumentation generally available to researchers working on COVID-19 vaccines across the national network of government, industry and academic researchers will quickly address the measurement science problems that will inevitably arise during the race to develop a safe and reproducible vaccine. In parallel, the CBM will address challenges of rapid antibody tests that are not quantitative nor highly sensitive, and typical lab-based methods for determining antibody concentrations are long and cumbersome. Researchers at the University of Notre Dame and Purdue University will develop devices to rapidly quantify the amount of COVID-19 antibodies in patient serum. Such analyses are vital for low-cost examination of antibody levels (and hence immunity) over time. The proposed devices will exploit a combination of innovative antibody capture technology developed at Notre Dame, which provides enhanced signals, and Purdue University’s expertise in the development of point-of-care diagnostic devices. These measurements will be important for investigating the problem of fading immunity and determining if convalescent plasma from a given patient is appropriate for therapeutic studies. The proposed RAPID research aims to provide fundamental knowledge of the structure of COVID-19 and its elicited antibody response. Analytical and measurement science support of vaccine and biomolecular therapeutic research is notoriously difficult. The molecules in question are often too big and complex for standard characterization methods, and many questions about heterogeneity, stoichiometry and structure cannot easily be answered. Researchers will use advancements in Charge Detection Mass Spectrometry (CDMS) and Ion Mobility Spectrometry (IMS) to study the heterogeneity, stoichiometry, structure and interactions of viral protein assemblies and to provide essential measurements for characterizing newly developed vaccine and therapeutic candidates for COVID-19. The CDMS and IMS tools at the CBM are unique and will allow researchers to directly observe inactivated viruses, 'dummy' viral particles without nucleic acids, bioconjugates containing immunogens on a hapten carrier, oligonucleotides, antibodies complexed to target proteins, and antibodies bound to viral particles. These instruments are starting to revolutionize the analysis of bioconjugations, vaccine development, gene therapies and protein therapeutics. Development of devices for rapidly examining antibody titer will rely on antibody capture in porous membranes that have a long pathlength for sensitive optical detection and a high surface area to volume ratio that enables efficient antibody capture. Device design will exploit expertise in the development of thin strip microfluidic diagnostics. Based on the fluorescence intensity of captured secondary antibodies, these devices will provide a measure of the abundance of different classes of COVID-19 antibodies.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.