ABSTRACT Vaccination of adults is central to control of SARS-CoV-2/COVID-19 and multiple other infectious diseases. Failure to engage in vaccine uptake is a complex, multilevel systems problem--individual factors such as fatalism, lack of factual information, medical and government mistrust, and political affiliation are all known inhibitors to vaccine uptake, as are community factors such as lack of access, limited delivery mechanisms, and messages from untrusted communicators. Thus, addressing vaccine hesitancy requires a multilevel intervention that aligns and addresses individual, relational, and structural elements to incorporate all of the necessary and sufficient components to increase uptake. COVID-19 vaccine uptake among Appalachian residents has been unacceptably low, with rates plateauing months ago. Appalachian Kentucky encompasses a number of population characteristics that add up to a "perfect storm" for a vaccine hesitant population. Structurally, the region is rural, with many communities geographically isolated and lacking access to health care. This, in addition to poverty, low education and high levels of chronic disease, place this population at significant risk of complications and mortality due to COVID-19 infection. In a population that historically has distrusted institutions, vaccination interventions must leverage culturally appropriate community partnerships and strategies. The purpose of this community-engaged study is to optimize SARS-CoV-2 vaccine uptake by this highly vulnerable Appalachian Kentucky population. We will achieve three specific aims: Aim 1: Using a community-engaged approach, elucidate: a) key themes for message content and framing that address individual-level factors, b) trusted communicators to deliver culturally-sensitive messages, and c) structural barriers to effective vaccine delivery, as well determining to what degree such factors are community-specific versus more generalizable. Aim 2: Using a cluster randomized trial design, assess the efficacy of a multilevel intervention that delivers individual-level target messaging tailored for theme and presentation by trusted local communicators AND that provides structural components to facilitate easy and acceptable access to vaccination delivery. Aim 3: Determine the process factors that affect reach, acceptance, and implementation fidelity for the intervention components, as well as necessary adaptation components for broader transferability, dissemination, and delivery of the intervention. Our long-term goal as a research team is to develop effective, multilevel intervention strategies that can be used to address vaccine hesitancy in Appalachian and similar rural populations for existing vaccination concerns.