Specific antibody deficiency (SAD) and common variable immunodeficiency (CVID) are two heterogeneous groups of inborn immunodeficiencies characterised by recurrent infections and reduced antibody responses to vaccination[1,2]. While immune profiling of CVID revealed substantial defects in the frequency of different B cell subsets[3], potentially explaining their increased susceptibility to infections, SAD is a poorly characterised disorder. To identify shared and/or unique immune differences between SAD and CVID and to test whether these differences might be associated with responses to vaccination, we have generated a single-cell multi-omic atlas of peripheral blood-derived mononuclear cells (PBMCs) from a cohort of healthy controls (n=10), individuals with CVID (n=10) and individuals with SAD (n=10) before and after vaccination with a typhoid polysaccharide antigen. We have detected widespread significant differences in cell type abundance at baseline in both CVID and SAD compared to healthy controls. For example, we identified a unique enrichment of cytotoxic T cells in SAD and, similarly to CVID, a depletion of a population of CD14⁺ monocytes associated with responses to lipopolysaccharide. We then compared the molecular and cellular differences upon vaccination across cohorts and identified signatures of successful vaccination responses within the B cell compartment only of healthy individuals. In particular, we found a significantly higher expression post-vaccination of NF-kB related genes in healthy naïve B cells as well as a significant enrichment of a population of CD95⁺ switched memory B cells carrying a gene expression signature associated with active proliferation in the blood. In summary, we show that while SAD might represent a distinct disorder, individuals share similar defects as those with CVID for CD14⁺ monocyte and memory B cells which would explain their impaired responses to polysaccharide antigens.