ABSTRACT We propose a deep interrogation and a systems approach that will identify molecular signatures to vaccination across three cohorts of vulnerable patient populations: autoimmune patients with B cell depletion, aged and frail individuals, and patients with sickle cell disease who are functionally asplenic. These distinct populations share a dysregulated inflammatory milieu that is linked to poor vaccination responsiveness. We have assembled an interdisciplinary team of investigators with a track record of longstanding and productive collaborations to use a systems approach that combines well-defined and understudied cohorts with unbiased large-scale profiling to elucidate signatures defining vaccine responsiveness. This goal will be accomplished by: 1) examining three vulnerable patient cohorts challenged with different vaccines, including novel mRNA vaccines and one shared vaccine; 2) using shared platforms that deeply interrogate immune responses from blood and limited-access compartments; and 3) refining new mathematical tools for multidimensional analysis of data to identify active pathways and modules and to determine specific connections among components in the immune network that contribute to differential vaccine effectiveness. This effort capitalizes on recent advances in single- cell and spatial immune profiling methods along with shared immunologic and proteomic platforms to create a novel public resource for vulnerable populations that characterizes diverse states of the human immune system. Integration across our cohorts will support the development of molecular signatures of vaccination responses and identify critical pathways relevant for potential therapeutic strategies.