Abstract Sickle cell disease (sickle cell) is the most common genetic hematologic disorder in the United States and an increasing global health problem. Sickle cell patients have a range of acute and chronic multisystem clinical complications and considerably shortened life expectancy. Paradoxically, despite their hyperinflammatory state, sickle cell patients have reduced responses to vaccination, suggesting dysregulation or impairments in immune pathways reminiscent of our studies of the chronic inflammatory milieu in aging. A broad investigation of the systemic immune response in patients with sickle cell disease is necessary for the understanding of whether chronic hyperinflammatory immune status may contribute to increased susceptibility to infections and reduced responses to vaccines in this vulnerable population. We will employ recent advances in single-cell technologies to quantify and analyze sickle cell disease patient immune status and responses to vaccinations. Our study will provide in-depth multiparameter immune profiles and analysis to identify molecular signatures defining the hyperinflammatory state and reduced vaccine efficacy in sickle cell disease patient populations.