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

这项拟议的RAPID提案的更广泛影响是，通过NSF生物分析计量学产学研合作研究中心（CBM）的工作，为从事减轻COVID-19影响的政府、行业和学术专业人员提供关键的支持测量科学工具。印第安纳大学的研究人员开发了一种独特的仪器来确定病毒等超大颗粒的组成，他们将表征病毒、候选疫苗和与病毒颗粒结合的抗体。将这种独特的仪器普遍提供给全国政府、行业和学术研究人员网络上从事COVID-19疫苗研究的研究人员，将迅速解决在开发安全和可重复疫苗的竞赛中不可避免地出现的测量科学问题。与此同时，CBM将解决快速抗体测试的挑战，这些测试既非定量也非高度敏感，而且用于确定抗体浓度的典型实验室方法耗时且繁琐。圣母大学（University of Notre Dame）和普渡大学（Purdue University）的研究人员将开发快速量化患者血清中COVID-19抗体数量的设备。这种分析对于长期低成本地检测抗体水平（从而检测免疫力）至关重要。拟议的设备将利用圣母大学开发的创新抗体捕获技术，该技术提供增强信号，以及普渡大学在开发即时诊断设备方面的专业知识。这些测量对于研究免疫消退问题和确定来自特定患者的恢复期血浆是否适合用于治疗性研究将是重要的。拟议的RAPID研究旨在提供COVID-19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。对于标准的表征方法来说，所讨论的分子往往太大太复杂，而且许多关于非均质性、化学计量和结构的问题都不容易回答。研究人员将利用电荷检测质谱法（CDMS）和离子迁移谱法（IMS）的进展来研究病毒蛋白组装的异质性、化学计量学、结构和相互作用，并为表征新开发的COVID-19疫苗和候选治疗方法提供必要的测量。CBM的CDMS和IMS工具是独一无二的，将使研究人员能够直接观察灭活病毒、没有核酸的“虚拟”病毒颗粒、半抗原载体上含有免疫原的生物偶联物、寡核苷酸、与靶蛋白络合的抗体以及与病毒颗粒结合的抗体。这些仪器正开始彻底改变生物偶联分析、疫苗开发、基因治疗和蛋白质治疗。用于快速检测抗体滴度的设备的开发将依赖于在多孔膜中捕获抗体，多孔膜具有灵敏光学检测的长路径和高表面积体积比，可实现有效的抗体捕获。设备设计将利用专业知识在薄带微流体诊断的发展。根据捕获的二抗的荧光强度，这些设备将提供不同类别COVID-19抗体丰度的测量。该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知识价值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.