Project Summary In the midst of emerging threats from sporadic viral entities, the perennial influenza viral strains continue to impose a substantial burden of morbidity and mortality that compounds total annual risks to the population at large. Last season (2018-19), influenza affected 35.5 million and led to 490,600 hospitalizations and 34,200 deaths in the U.S. These vital statistics have been steadily rising each year. Individuals with cardiovascular disease are especially susceptible to the morbidity and mortality associated community-acquired viral infections such as influenza. Vaccination significantly reduces the incidence of cardiovascular events at the population level; However, administration of influenza vaccination at the individual level is extremely variable with respect to (i) the extent of humoral antibody response achieved, and (ii) the degree of cardioprotection conferred. Intriguingly, the degree of cardioprotection conferred does not depend entirely on the level of humoral immunity achieved, highlighting further opportunities to discover and derive clinical benefit from a preventive therapy with both complex and non- uniform effects. Accumulating evidence now indicates that upstream mediators of endogenous immune- inflammatory pathways are likely key determinants of the individual-level response to and benefit from an administered vaccination. These molecular mediators of systemic immune-inflammatory activity, termed eicosanoids, include a diverse family of small bioactive lipids that are enzymatically derived from polyunsaturated fatty acids. Based on results from preliminary studies, we hypothesize that specific eicosanoids not only predict the immunologic response to influenza vaccination but also predict its conferred protection from adverse cardiovascular events, irrespective of infection status. Therefore, we propose an ancillary study for the NHLBI-funded INfluenza Vaccine to Effectively Stop cardioThoracic Events and Decompensated heart failure (INVESTED) trial, that aims to: (1) identify eicosanoids that predict the classic humoral antibody response to influenza vaccination in patients with chronic cardiovascular disease, who represent the population subset most at-risk for adverse events; and, (2) identify eicosanoids generated in response to vaccination that correspond with reduced risk for cardiovascular events, irrespective of humoral immunity and infection status. The existing infrastructure of the INVESTED trial offers a cost-effective way to reach individuals who are at the highest risk for influenza- associated events and enable a rigorous study design for investigating heterogeneity in the response to and benefit from vaccination.