High-dimensional gene expression profiling studies in high and low responders to primary smallpox vaccination

Background. The mechanisms underlying smallpox vaccine-induced variations in immune responses are not well understood, but are of considerable interest to a deeper understanding of poxvirus immunity and correlates of protection.Methods.We assessed transcriptional messenger RNA expression changes in 197 recipients of primary smallpox vaccination representing the extremes of humoral and cellular immune responses.Results.The 20 most significant differentially expressed genes include a tumor necrosis factor-receptor superfamily member, an interferon (IFN) gene, a chemokine gene, zinc finger protein genes, nuclear factors, and histones (P ≤ 1.06E^-20, q ≤ 2.64E^-17). A pathway analysis identified 4 enriched pathways with cytokine production by the T-helper 17 subset of CD4+ T cells being the most significant pathway (P = 3.42E^-05). Two pathways (antiviral actions of IFNs, P = 8.95E^-05; and IFN-/signaling pathway, P = 2.92E ^-04), integral to innate immunity, were enriched when comparing high with low antibody responders (false discovery rate, < 0.05). Genes related to immune function and transcription (TLR8, P =. 0002; DAPP1, P =. 0003; LAMP3, P = 9.96E^-05; NR4A2, P ≤. 0002; EGR3, P = 4.52E^-05), and other genes with a possible impact on immunity (LNPEP, P = 3.72E^-05; CAPRIN1, P =. 0001; XRN1, P =. 0001), were found to be expressed differentially in high versus low antibody responders.Conclusion.We identified novel and known immunity-related genes and pathways that may account for differences in immune response to smallpox vaccination.