Background <p>Severe respiratory infections have imposed an immense burden on healthcare worldwide, which could lead to fatal outcomes. The dysfunctional immune response impacts disease severity of respiratory infections, yet its underlying mechanisms remain largely obscure.</p> Methods <p>We explored the immunologic response underpinning severe respiratory viral infections by performing single-cell transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from 17 patients with coronavirus disease 2019 (COVID-19), including moderate, severe, critical, and convalescent cases. Furthermore, we analyzed the host responses following low- or high-dose vaccination with recombinant protein.</p> Results <p>We constructed an immunocyte landscape with 299,527 PBMCs. The significant dysregulation of immune homeostasis in severe respiratory viral infections was characterized by an increased ratio of CD14⁺ monocytes and exhausted CD8⁺ T cells, and reduced Tregs, memory T cells and cDC2 cells. Notably, highly inflamed CD14⁺ monocytes overexpressing interleukin (IL)-related genes emerged as central contributor of inflammatory storms in critical patients. Enhanced inflammatory response in exhausted CD8⁺ T cells, <i>FOS</i>/<i>JUN</i> overexpression in Tregs and Th17 cells, as well as suppressed antigen presentation activity in cDC2 cells were also remarkable features of severe and critical cases. Moreover, the high-dose vaccination with recombinant protein inhibited the inflammatory response of CD14⁺ monocytes, while enriched the memory T/NK cells to boost protective immunity. In mechanism, activated IL-6-JAK-STAT in CD14⁺ monocytes and T cells, coupled with impaired interferon (IFN)-α pathway, could drive excessive inflammatory response.</p> Conclusions <p>Our study creates a high-resolution transcriptomic atlas that uncovers distinct immune signatures across the disease severity of respiratory infections, which provides valuable resource for mechanistic exploration and therapeutic strategies development. Furthermore, we demonstrate that high-dose recombinant protein vaccines might mitigate the severity of illness.</p> Trial registration <p>This study was prospectively registered at ChiCTR (Registration number: ChiCTR2300067787).</p>