NIH Institutes, Centers, and Offices participating in the Social, Behavioral, and Economic Impacts of COVID-19 in Vulnerable and Health Disparity Populations initiative are issuing this Notice of Special Interest (NOSI) to highlight interest in research to strengthen the understanding and response to the Coronavirus Disease 2019 (COVID-19) pandemic and help us prepare more effectively for future public health emergencies. While research related to the direct clinical effects of COVID-19 are supported by other funding opportunities, there are additional urgent public health needs, particularly in populations who experience health disparities and in vulnerable populations. The purpose of this Notice is to 1) emphasize the roles and impacts of interventions, particularly those under the umbrella of digital health, as well as community-engaged and multi-level interventions in healthcare settings to address access, reach, delivery, engagement, effectiveness, scalability, and sustainability of services that are utilized during and following the pandemic, and 2) encourage the leveraging of existing large-scale data sources with broad population coverage to improve prediction of various mitigation efforts (including vaccinations, masking, and physical distancing to inform the public health response) on transmission reduction and on social and economic impacts, and assess the downstream health and healthcare access effects, with an emphasis on underserved and vulnerable populations. Additionally, the use of large-scale data sources to study the indirect health impacts of the pandemic and subsequent social and economic changes is needed to understand the costs and benefits of various COVID-19 mitigation strategies.