Project Summary/Abstract In 2019, our competitive renewal for our NIDA-funded work on opioids, HIV, and HCV was funded with a MERIT award. In this supplement to our MERIT grant, we will address pressing issues in vulnerable populations at risk from SARS-CoV-2. We will adapt the modeling frameworks we have developed to address how best to protect vulnerable populations from COVID-19, including people who inject drugs (PWID), people who are incarcerated, and people in other vulnerable settings, including long-term care facilities, and schools. We will address strategies to protect vulnerable populations, including physical distancing measures, scaled-up and targeted testing and tracing, and strategic deployment of new technological innovations in diagnostics, therapeutics and vaccines as they arise. Our aims are to: 1. Model the intersecting epidemics of SARS-CoV-2, HIV and HCV in opioid-using and related vulnerable populations. We will extend our foundational epidemic models of HIV and HCV to include SARS- CoV-2. Doing so enables us to analyze the impacts of strategies in Aims 2 and 3. 2. Model the epidemiologic and population health impacts of currently available strategies to prevent and mitigate the harms from transmission of SARS-CoV-2 in vulnerable populations. We will evaluate prevention strategies involving physical distancing and intensive testing programs for vulnerable populations. We will assess the impact of strategies on epidemiologic outcomes including incidence, prevalence, mortality, life expectancy, quality of life, and quality-adjusted life years (QALYs). 3. Model the epidemiologic and population health impacts of future strategies, including improved therapeutics and vaccines, to prevent and mitigate the harms from transmission of SARS-CoV-2 in populations of interest. Because no single and sustainable strategy based on currently available technologies will likely have sufficient impact on reducing risks of continuing SARS-CoV-2 transmission, we will examine selected key strategies based on technologies that may become available in the next 18 months, particularly the use of a partially effective vaccine. The proposed work will synergistically expand on our current project and provide clinicians and policymakers with critically needed guidance about which strategies can most efficiently mitigate the national public health crisis from COVID-19 in vulnerable populations and settings.