Technology and Computational Core

PROJECT SUMMARY CORE B The goal of this Program Project is to bring together a multi-disciplinary team to produce information necessary for the design and testing of the next-generation of CoV vaccine strategies that will have the greatest possible breadth across other CoVs. Results from all three projects will inform design of Pan-Coronavirus vaccines against evolving SARS-CoV-2 variants and other coronaviruses to stem current and prevent future pandemics. This will be accomplished through three dynamic and integrative projects examining various key aspects of vaccine strategies. The Technology and Computational Core B will support, in close interaction with each of the other investigators, all three Projects to gain maximal insight from the proposed experimental work. Based on the need for centralized tissue and blood processing, single-cell genomics and TCR sequencing data generation, and integrative computational analyses, we hypothesized that having a central Technology and Computational Core, as opposed to having each project working independently, will be critical to the success of the work proposed in this Program application and will maximize comparisons and integration of data across projects. A centralized working group of immunologists, sequencing experts, and computational biologists is the best way to ensure that this research will be properly carried out with maximal identification and use of appropriate computational methods. Through Aim 1, Core B will support all three Research Projects by providing expert advice and assistance on executing single-cell genomics and TCR sequencing experimental and analytical strategies of blood and tissue specimens collected from human subjects and lung from immunized mice. The standardized frameworks provided by the Core staff will add rigor and reproducibility to all experiments by removing any variation that might otherwise arise. Core B will also provide collaborative efforts on multi-variate modeling of immune system response and antigen/antibody binding (Aim 2). Because of the complexity of immune responses to pathogens, our ability to gain insights and principles from the experimental datasets generated across all three Projects will be enhanced by integrative computational analysis and modeling embracing an integrative systems perspective. This complexity derives from diverse issues including: (a) concomitant contributions from multiple variables together govern observed responses, rather than any single variable being determinative by itself; (b) these multi-variate contributions are generally not independent, but instead are typically co- or anti-correlated; and (c) these contributions often are non-linear in nature. Most standard statistical techniques typically violate one or more of these issues, so the purpose of this Core is to apply computational approaches arising from engineering and computer science, including "machine learning" techniques, that can in fact accommodate any or all of them. Finally, Core B will provide additional assistance for any complicated experimental design or analysis if/as needed. To aid with transparency, all data and analysis frameworks supporting all findings will be made publicly available upon acceptance for publication.