Modeling SARS-CoV-2 variant emergence from immunocompromised hosts

Project Summary/Abstract This proposal describes a five-year research training program that will facilitate my ongoing transition from an applied mathematician to an independent, quantitative, multidisciplinary biomedical researcher. I will work closely with clinicians, mathematical modelers, bioinformaticians, evolutionary biologists, virologists and immunologists to develop a suite of mathematical models which will be validated against viral, immune, phylogenetic and epidemiolocal datasets. The goals of my proposal will be to: 1) understand the mechanisms facilitating generation of SARS-CoV-2 variants of concern (VOC) during prolonged infections in immunocompromised (IC) individuals, and 2) identify key bottle necks that limit the number of VOCs that predominate in the general population. SARS-CoV-2 is the appropriate virus for which to develop this modeling framework due to the availability of data, and ongoing incidence, but the approach will be widely applicable to other pathogens. The training program includes an outstanding group of mentors and collaborators. My scientific advisory committee consists of experts in modeling infectious diseases (Dr Josh Schiffer and Dr Dan Reeves), clinical care for IC individuals (Dr Josh Schiffer and Dr. Alpana Wahgmare), epidemiology (Dr Cheryl Cohen and Dr Dobromir Dimitrov), viral evolution (Dr JT McCrone and Dr Mahan Ghafari), and biostatistics and machine learning (Dr Ollivier Hyrien). This group is dedicated to ensuring the success of my project, and my career development as an independent researcher. The specific learning goals required for my successful transition to biomedical research will be accomplished through didactic coursework in virology, immunology, epidemiology and phylogenetics as well as conferences and professional training in the skills of a successful mentor and group leader. The research plan addresses a critically important clinical and public health issue. Prolonged SARS-CoV- 2 infections in IC individuals are the most likely source of most novel VOC, which have extended and strongly exacerbated the impact of the pandemic. Though these infections have had an outsized public health impact, clear guidance regarding clinical management and safety measures is lacking. Understanding the within-host evolution of SARS-CoV-2 is paramount to addressing these issues. Through accomplishing the aims of this proposal, Dr Owens will address critical gaps in our knowledge of SARS-CoV-2 evolution and create an in silico framework to study SARS-CoV-2 interventions at both individual and population level. Ultimately, this proposal will allow Dr Owens to influence the future of pandemic response research as well as build a self-sustaining program at the interface of mathematical modeling, immunology, viral dynamics, and viral evolution.