Abstract Severe burn injury rapidly activates a systemic inflammatory response and cardiovascular dysfunction, causing distributive shock associated with increased endothelial permeability and organ injury. Sepsis is a leading cause of death in patients with severe burn injury, accounting for nearly 75% of mortality among burn patients. Preventing or recognizing sepsis early is key to preventing poor outcomes in burn patients. However, it is difficult to (1) detect burn patients at higher risk of sepsis at the time of intensive care unit presentation and (2) distinguish between sepsis and the non-infective inflammatory response to severe burn injury. To date, most data for detecting infection and sepsis in non-burn patients do not necessarily inform diagnosis in the burn patient population given the specificities of burn injury. Though some studies have identified potential biomarkers as candidate septic markers in burn patients, these markers are derived from a very small number of patients or were not combined and showed limited predictive value. Thus, due to the unique pathophysiology of severe burns, there is an unmet clinical need to identify early biomarker signatures of patients at risk of sepsis and septic shock in the burn patient population. Our central hypothesis is that the initial host response to burn injury could predispose to secondary sepsis. That is, a dysregulated cardiovascular injury and inflammatory profile in adult patients with severe burn injury exposes burn patients to a higher risk of developing sepsis. In this proposal, we will longitudinally analyze plasma samples and clinical outcomes in a large cohort of burn patients (n=400) with severe burn injury. Biomarker analysis of immune dysregulation and cardiovascular injury will be used to define sub-phenotypes of patients and linked to the primary endpoint (sepsis) and secondary outcomes (mortality, ICU length of stay, organ failure). Proof of principle results from this large prospective cohort study will then be used to guide and inform future prospective trials and emulated trials of therapeutic interventions to identify (1) populations at higher risk of sepsis and (2) therapeutic pathways that could be targeted to prevent secondary sepsis in this high-risk population. Finally, we will compare proteomic signatures between burn patients without sepsis (i.e., non-septic systemic inflammatory response) and burn patients with sepsis and control non-burn critically ill patients with sepsis or septic shock. The results of these studies will provide key insights into the identification of biomarkers and proteomic signatures specific to sepsis and improve our ability to recognize sepsis.