(A) Intramuscular (IM) administration of AS03-adjuvanted H5N1 vaccine results in interferon (IFN) signaling. (B) Activation of IFN-inducible genes, in particular for monocytes (Mo), dendritic cells (DC), and neutrophils (Neut). (C) Significant up-regulation of CXCL10, the gene encoding IP-10, in peripheral blood Mo and DC implies that these cells contribute to increased serum IP-10 levels (in addition to local immune cells). (D) MHC class I- related antigen presentation genes are upregulated in monocytes Mo, Neut, and DC. (E) MHC class II- related antigen presentation genes are upregulated in Neut and, to a lesser extent, in Mo. At day 3, (F) IP-10 stimulates expansion of NK cells. (G) IFN-stimulated genes remain upregulated in Neut. (H) Upregulation of MHC class I and class II molecules stimulate cytotoxic T cells (CD8+) and T helper cells (CD4+), respectively, to initiate transition to the adaptive immune response. (I) Generation of protective H5-specific antibodies after a 2-dose vaccine regimen. Solid lines indicate that direct evidence for these events was seen in our serologic or transcriptomic data, while dashed lines indicate no direct evidence was observed.