Recent studies have revealed gene-expression signatures in response to vaccination; however, the epigenetic regulatory mechanisms that are underlying vaccine-induced immune responses remains to be elucidated. Here, we analyzed a multiomics single-nucleus data of 267,485 nuclei at 10 timepoints after SARS-CoV-2 inactivated vaccination, which showed critical time points on gene changes in each celltype. We identified some epigenetically distinct monocyte subtypes, which were characterized by persistent chromatin remodeling at AP-1-targeted binding sites after the second dose, which were only transiently activated after the first dose. This remolded chromatin correspond to changes in cytokine and interferon pathways overtime. We found a coordinated regulation of IL1B, CXCL8, CCL3 and CSF2RA by c-Fos, c-Jun, IRF family and RUNX in myeloid cells. Pseudotime analysis revealed that CD14+ monocytes tend to differentiate towards a highly inflammatory state, while high-inflammation state is characterized by prolonged open chromatin after transcriptional termination. These findings demonstrate that two-dose vaccination stimulates persistent epigenetic remodeling of the innate immune cells and highlight the potential of temporal and spatial specific regulatory elements to optimizing vaccines.