Early Patterns of Gene Expression Correlate With the Humoral Immune Response to Influenza Vaccination in Humans

Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030-2504, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 02/2011; 203(7):921-9. DOI: 10.1093/infdis/jiq156
Source: PubMed


Annual vaccination is the primary means for preventing influenza. However, great interindividual variability exists in vaccine responses, the cellular events that take place in vivo after vaccination are poorly understood, and appropriate biomarkers for vaccine responsiveness have not been developed.
We immunized a cohort of healthy male adults with a licensed trivalent influenza vaccine and performed a timed assessment of global gene expression before and after vaccination. We analyzed the relationship between gene expression patterns and the humoral immune response to vaccination.
Marked up regulation of expression of genes involved in interferon signaling, positive IL-6 regulation, and antigen processing and presentation, were detected within 24 hours of immunization. The late vaccine response showed a transcriptional pattern suggestive of increased protein biosynthesis and cellular proliferation. Integrative analyses revealed a 494-gene expression signature--including STAT1, CD74, and E2F2--which strongly correlates with the magnitude of the antibody response. High vaccine responder status correlates with increased early expression of interferon signaling and antigen processing and presentation genes.
The results highlight the role of a systems biology approach in understanding the molecular events that take place in vivo after influenza vaccination and in the development of better predictors of vaccine responsiveness.

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Available from: Molly Bray, Oct 09, 2015
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    • "In addition to whole transcriptome analysis of vaccinated animals, recent advances in genome research enabled the acquisition of whole transcriptional data from vaccinated individuals and identification of gene expression after immunization with vaccines to yellow fever, measles, tularemia and tuberculosis [22]. With a focus on the influenza vaccine, Bucasas et al. reported a 494 gene set, including biomarkers identified in our previous study (MX1, IRF7) that strongly correlated with antibody responses in humans [23]. Wei et al. reported gene expression differences between HAv and live attenuated influenza vaccine. "
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    ABSTRACT: Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, β2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and vaccine safety as an alternative to animal testing.
    PLoS ONE 07/2014; 9(7):e101835. DOI:10.1371/journal.pone.0101835 · 3.23 Impact Factor
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    • "Though models built using either gene expression or cell populations from day 1 were not predictive, interferon signaling correlated robustly with MFC (Figure 5C). Coherent changes in interferonassociated transcripts have been detected on days 1 and 7 in our and other related studies (Bucasas et al., 2011; Gaucher et al., 2008; Nakaya et al., 2011; Obermoser et al., 2013; Querec et al., 2009). In contrast, highly predictive models could be built using day 7 cell population or gene expression data for both adjMFC and MFC (Figures 5D and 5F). "
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    ABSTRACT: A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and were used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of postvaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time points. Most of the parameters contributing to prediction delineated temporally stable baseline differences across individuals, raising the prospect of immune monitoring before intervention.
    Cell 04/2014; 157(2):499-513. DOI:10.1016/j.cell.2014.03.031 · 32.24 Impact Factor
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    • "One of the main findings of our study is the presence of an IFN signature, predominantly in CVID patients with inflammatory complications. An IFN signature is characteristic of an immune responses to viral vaccinations [42], as well as chronic viral diseases including HTLV-1 [20], hepatitis C [43] and HIV [44]. Subjects with CVID studied here, being immune deficient, may be susceptible to viral infections, but none who had symptomatic infections were enrolled. "
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    ABSTRACT: About half of all subjects with common variable immune deficiency (CVID) are afflicted with inflammatory complications including hematologic autoimmunity, granulomatous infiltrations, interstitial lung disease, lymphoid hyperplasia and/or gastrointestinal inflammatory disease. The pathogenesis of these conditions is poorly understood but singly and in aggregate, these lead to significantly increased (11 fold) morbidity and mortality, not experienced by CVID subjects without these complications. To explore the dysregulated networks in these subjects, we applied whole blood transcriptional profiling to 91 CVID subjects, 47 with inflammatory conditions and 44 without, in comparison to subjects with XLA and healthy controls. As compared to other CVID subjects, males with XLA or healthy controls, the signature of CVID subjects with inflammatory complications was distinguished by a marked up-regulation of IFN responsive genes. Chronic up-regulation of IFN pathways is known to occur in autoimmune disease due to activation of TLRs and other still unclarified cytoplasmic sensors. As subjects with inflammatory complications were also more likely to be lymphopenic, have reduced B cell numbers, and a greater reduction of B, T and plasma cell networks, we suggest that more impaired adaptive immunity in these subjects may lead to chronic activation of innate IFN pathways in response to environmental antigens. The unbiased use of whole blood transcriptome analysis may provides a tool for distinguishing CVID subjects who are at risk for increased morbidity and earlier mortality. As more effective therapeutic options are developed, whole blood transcriptome analyses could also provide an efficient means of monitoring the effects of treatment of the inflammatory phenotype.
    PLoS ONE 09/2013; 8(9):e74893. DOI:10.1371/journal.pone.0074893 · 3.23 Impact Factor
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