Dose-dependent interferon programs in myeloid cells after mRNA and adenovirus COVID-19 vaccination

The SARS-CoV-2 pandemic provided a rare opportunity to study how human immune responses develop to a novel viral antigen delivered through different vaccine platforms. However, to date, no study has directly compared immune responses to all three FDA-approved COVID-19 vaccines at single-cell multi-omic resolution. We longitudinally profiled SARS-CoV-2-naïve adults (n=31) vaccinated with BNT162b2, mRNA-1273, or Ad26.COV2.S, integrating plasma cytokines, antibody titers, and single-cell multi-omic data (DOGMA-seq). We discovered a distinct, transient interferon program (ISG-dim) that emerged specifically 1-2 days after the first mRNA dose in ~10% of myeloid cells. This state was characterized by ISGF3 complex activation and its target genes (e.g., MX1, MX2, DDX58), with transcriptional and epigenetic profiles distinct from the robust interferon program observed after mRNA boosting or a single Ad26.COV2.S dose (ISG-high). In vitro stimulation of human monocytes showed that IFN-α alone recapitulates ISG-dim, whereas both IFN-α and IFN-γ are required for ISG-high. These findings define dose-dependent interferon programming in human myeloid cells, highlight mechanistic differences between priming and boosting, with implications for optimizing vaccine platform choice, dose scheduling, and formulation.