HostSim: a virtual host framework to analyze the immune response to vaccination and Mycobacterium tuberculosis infection Louis R. Joslyn1, Jennifer J. Linderman2, Denise E. Kirschner3 1Department of Computational Medicine & Bioinformatics, University of Michigan Medical School, 100 Washtenaw Avenue, Ann Arbor, MI. 2Department of Chemical Engineering, University of Michigan, 2800 Plymouth Rd, NCRC B28, Ann Arbor, MI, 48109-2800; 3Department of Microbiology and Immunology, University of Michigan Medical School, 1150 W Medical Center Drive, 5641 Medical Science II, Ann Arbor, MI 48109-5620; To address outstanding questions related to M. tuberculosis (Mtb) infection, reinfection and vaccination, we developed a new computational tool, HostSim, that follows the immune response and infection at the host level. HostSim captures cells, cytokines, and bacterial dynamics tracking formation, dissemination and function of multiple granulomas, the hallmark of Mtb infection, across an entire virtual lung. HostSim also tracks immune cells within lung draining lymph nodes and blood to predict how T-cell priming, proliferation, and differentiation in response to Mtb antigens impacts whole-host outcomes, such as sterilization. HostSim is calibrated to experimental datasets across the cellular, granuloma, whole-lung, and whole-host scales of non-human primates. Altogether, this multi-scale and multi-compartment computational model allows us to represent a whole-body response to vaccination and infection. Through a series of parallel in silico experiments, we predict mechanisms that underlie protection, and why some individuals might exhibit greater protection than others. These results have implications for vaccination strategies against tuberculosis. Importantly, we use this new virtual host framework to develop a protocol for virtual pre-clinical trials. We predict dynamics and effects of vaccine-derived T cells throughout the course of Mtb infection. This study highlights the power of a systems biology approach to narrow and focus vaccine studies prior to experiments.