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Our findings raise the prospect that modulating such immune baseline states may improve vaccine responsiveness and mitigate undesirable autoimmune disease activities. CITE-seq profiling of 82 surface proteins and transcriptomes of 53,201 single cells from healthy high and low influenza-vaccination responders revealed that our signatures reflect the extent of activation in a plasmacytoid dendritic cell-Type I IFN-T/B lymphocyte network. These same signatures evaluated at clinical quiescence are correlated with disease activity in systemic lupus erythematosus patients with plasmablast-associated flares. Here we uncover baseline blood transcriptional signatures predictive of antibody responses to both influenza and yellow fever vaccinations in healthy subjects. Identifying such baseline predictors and their biological basis are of broad interest given their potential importance for cancer immunotherapy, disease outcomes, vaccination and infection responses. Responses to vaccination and to diseases vary widely across individuals, which may be partly due to baseline immune variations.