PROJECT SUMMARY AND ABSTRACT. The COVID-19 pandemic due to the SARS-CoV-2 infection poses new challenges to the ~3 million persons with multiple sclerosis (PwMS) worldwide. Major knowledge gaps include the extent to which common MS disease modifying therapies (DMTs) modulate the COVID-19 risk and severity, the efficacy of the COVID-19 vaccines and any impact on MS neurological outcomes given the exclusion of PwMS from COVID-19 vaccine trials, and the broader consequence of the pandemic on social connection and health outcomes in PwMS. These gaps create a critical need to rapidly generate rigorous information with which to guide clinical management. To address these challenges, we created the MSReCOV (MS Resilience to COVID-19) Collaborative in late March 2020 by assembling a network of MS Centers to leverage existing clinical research infrastructure and collect patient-reported data. Given the reduced interaction between PwMS and healthcare systems and the restriction on in-person research activities at the onset and during subsequent phases, we rapidly deployed online survey studies to gather real-time data directly from PwMS during the pandemic to complement the effort of physician-reported registries. To complement MSReCOV, we will interrogate the Optum data warehouse of integrated claims and electronic health records data from a virtual cohort of ~40,000 commercially insured PwMS (per year). Building on the MSReCOV and Optum infrastructure, we propose the following aims to address the knowledge gaps. Aim 1: Examine the association between MS DMTs and COVID-19. We will test the hypothesis that certain DMTs such as IFNb are associated with reduced COVID- 19 risk, while others such as B-cell depleting agents are associated with increased COVID-19 risk. Aim 2: Examine the COVID-19 vaccine efficacy and safety in MS and association with MS outcomes. We will first test the hypothesis that COVID-19 vaccines are effective and safe in PwMS and do not worsen clinically relevant patient-reported outcomes (PROs) of neurological function, and secondarily test the hypothesis that B- cell depleting treatments reduce vaccine efficacy whereas other DMTs do not. Aim 3: Examine the effect of the pandemic on personal social network and MS outcomes in PwMS. Building on our prior works, we will test the hypothesis that the pandemic (independent of the SARS-CoV-2 infection) negatively influences the neurological function in PwMS by altering personal social connection. Given the extent of the COVID-19 pandemic, real-world evidence emerging from the proposed study will critically inform the clinical management of PwMS during the rapidly changing landscape of neurological care. The project is highly relevant to the mission of the NIH/NINDS to reduce the burden of neurological diseases such as MS in the setting of the pandemic.