Systems biological approaches to measure and understand vaccine immunity in humans.

Recent studies have demonstrated the utility of using systems approaches to identify molecular signatures that can be used to predict vaccine immunity in humans. Such approaches are now being used extensively in vaccinology, and are beginning to yield novel insights about the molecular networks driving vaccine immunity. In this review, we present a broad review of the methodologies involved in these studies, and discuss the promise and challenges involved in this emerging field of "systems vaccinology."

[1]  Eva K. Lee,et al.  Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans , 2009, Nature Immunology.

[2]  Kellen L. Olszewski,et al.  Reconstruction and flux-balance analysis of the Plasmodium falciparum metabolic network , 2010, Molecular systems biology.

[3]  S. Massart,et al.  Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa , 2010, Proceedings of the National Academy of Sciences.

[4]  Alistair G. Rust,et al.  Role of the transcription factor C/EBPδ in a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals , 2009, Nature Immunology.

[5]  David Artis,et al.  Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis , 2009, Mucosal Immunology.

[6]  Shannon McWeeney,et al.  MIFlowCyt: The minimum information about a flow cytometry experiment , 2008, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[7]  A. Iwasaki,et al.  Microbiota regulates immune defense against respiratory tract influenza A virus infection , 2011, Proceedings of the National Academy of Sciences.

[8]  B. Pulendran,et al.  Identifying gnostic predictors of the vaccine response. , 2012, Current opinion in immunology.

[9]  Xiao-Jiang Feng,et al.  Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy , 2008, Nature Biotechnology.

[10]  Peer Bork,et al.  Enterotypes of the human gut microbiome , 2011, Nature.

[11]  K. Honda,et al.  Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species , 2011, Science.

[12]  A. Perelson,et al.  Simulation and Prediction of the Adaptive Immune Response to Influenza A Virus Infection , 2009, Journal of Virology.

[13]  W. R. Wikoff,et al.  Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites , 2009, Proceedings of the National Academy of Sciences.

[14]  Masahiro Yamamoto,et al.  ATP drives lamina propria TH17 cell differentiation , 2008, Nature.

[15]  Mark M. Davis,et al.  Cell type–specific gene expression differences in complex tissues , 2010, Nature Methods.

[16]  Vipin Kumar,et al.  An Integrative Multi-Network and Multi-Classifier Approach to Predict Genetic Interactions , 2010, PLoS Comput. Biol..

[17]  F. Vannberg,et al.  GENETICS OF GENE EXPRESSION IN PRIMARY IMMUNE CELLS IDENTIFIES CELL-SPECIFIC MASTER REGULATORS AND ROLES OF HLA ALLELES , 2012, Nature Genetics.

[18]  V. Pascual,et al.  A genomic approach to human autoimmune diseases. , 2010, Annual review of immunology.

[19]  L. Carin,et al.  Temporal Dynamics of Host Molecular Responses Differentiate Symptomatic and Asymptomatic Influenza A Infection , 2011, PLoS genetics.

[20]  Alexander R. Abbas,et al.  Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data , 2005, Genes and Immunity.

[21]  Ronald N Germain,et al.  Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital ERK Responses , 2005, PLoS biology.

[22]  Paul Landais,et al.  Extended Report , 2022 .

[23]  D. Zak,et al.  Systems biology of innate immunity , 2009, Immunological reviews.

[24]  Charles R. M. Bangham,et al.  Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy , 2012, PLoS pathogens.

[25]  L. Carin,et al.  Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. , 2009, Cell host & microbe.

[26]  Nicolas Perry,et al.  Toward a multiscale model of antigen presentation in immunity , 2007, Immunological reviews.

[27]  Ramón Díaz-Uriarte,et al.  Gene selection and classification of microarray data using random forest , 2006, BMC Bioinformatics.

[28]  V. Bronte,et al.  Regulation of immune responses by L-arginine metabolism , 2005, Nature Reviews Immunology.

[29]  J. Lamb,et al.  Elucidating the murine brain transcriptional network in a segregating mouse population to identify core functional modules for obesity and diabetes , 2006, Journal of neurochemistry.

[30]  S. Mazmanian,et al.  The gut microbiota shapes intestinal immune responses during health and disease , 2009, Nature Reviews Immunology.

[31]  S. Mazmanian,et al.  An Immunomodulatory Molecule of Symbiotic Bacteria Directs Maturation of the Host Immune System , 2005, Cell.

[32]  Sean C. Bendall,et al.  Single-Cell Mass Cytometry of Differential Immune and Drug Responses Across a Human Hematopoietic Continuum , 2011, Science.

[33]  N. Sonenberg,et al.  Regulation of cap-dependent translation by eIF4E inhibitory proteins , 2005, Nature.

[34]  Pál Pacher,et al.  Adenosine receptors: therapeutic aspects for inflammatory and immune diseases , 2006, Nature Reviews Drug Discovery.

[35]  F. Bushman,et al.  Commensal bacterial–derived signals regulate basophil hematopoiesis and allergic inflammation , 2012, Nature Medicine.

[36]  Tanya Cashorali,et al.  Causal Modeling Using Network Ensemble Simulations of Genetic and Gene Expression Data Predicts Genes Involved in Rheumatoid Arthritis , 2011, PLoS Comput. Biol..

[37]  S. Batzoglou,et al.  Application of independent component analysis to microarrays , 2003, Genome Biology.

[38]  M. Newport,et al.  Influence of genetic and environmental factors on the immunogenicity of Hib vaccine in Gambian twins. , 2006, Vaccine.

[39]  S. Mazmanian,et al.  A microbial symbiosis factor prevents intestinal inflammatory disease , 2008, Nature.

[40]  Ying Wang,et al.  Genomewide association study of leprosy. , 2009, The New England journal of medicine.

[41]  J. Moffett,et al.  Tryptophan and the immune response , 2003, Immunology and cell biology.

[42]  B. Vickery,et al.  An Interferon-Inducible Neutrophil-Driven Blood Transcriptional Signature in Human Tuberculosis , 2011, Pediatrics.

[43]  K. Sachs,et al.  Causal Protein-Signaling Networks Derived from Multiparameter Single-Cell Data , 2005, Science.

[44]  Bali Pulendran,et al.  Translating Innate Immunity into Immunological Memory: Implications for Vaccine Development , 2006, Cell.

[45]  H. Stefánsson,et al.  Genetics of gene expression and its effect on disease , 2008, Nature.

[46]  D. Koller,et al.  The Immunological Genome Project: networks of gene expression in immune cells , 2008, Nature Immunology.

[47]  M. Katze,et al.  Systems biology and the host response to viral infection , 2007, Nature Biotechnology.

[48]  L. Hood,et al.  Systems medicine: the future of medical genomics and healthcare , 2009, Genome Medicine.

[49]  T. Bouchard,et al.  Genetic regulation of immunoglobulin and specific antibody levels in twins reared apart. , 1985, The Journal of clinical investigation.

[50]  Timothy D Veenstra,et al.  Metabolomics: the final frontier? , 2012, Genome Medicine.

[51]  Todd H. Stokes,et al.  k-Nearest neighbor models for microarray gene expression analysis and clinical outcome prediction , 2010, The Pharmacogenomics Journal.

[52]  W. Huber,et al.  Differential expression analysis for sequence count data , 2010 .

[53]  Rustom Antia,et al.  The role of models in understanding CD8+ T-cell memory , 2005, Nature Reviews Immunology.

[54]  N. Friedman,et al.  Densely Interconnected Transcriptional Circuits Control Cell States in Human Hematopoiesis , 2011, Cell.

[55]  V. Pavlov,et al.  Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity , 2011, Proceedings of the National Academy of Sciences.

[56]  R. Jacobson,et al.  Application of pharmacogenomics to vaccines. , 2009, Pharmacogenomics.

[57]  Cole Trapnell,et al.  Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. , 2010, Nature biotechnology.

[58]  Min Wang,et al.  Computational expression deconvolution in a complex mammalian organ , 2006, BMC Bioinformatics.

[59]  R. Knight,et al.  Error-correcting barcoded primers for pyrosequencing hundreds of samples in multiplex , 2008, Nature Methods.

[60]  Shuzhao Li,et al.  Predicting Network Activity from High Throughput Metabolomics , 2013, PLoS Comput. Biol..

[61]  V. Pankratz,et al.  Genome-wide association study of antibody response to smallpox vaccine. , 2012, Vaccine.

[62]  Eva K. Lee,et al.  Systems Biology of Seasonal Influenza Vaccination in Humans , 2011, Nature Immunology.

[63]  Matthew N Davies,et al.  Harnessing bioinformatics to discover new vaccines. , 2007, Drug discovery today.

[64]  A. Dupuy,et al.  Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting. , 2007, Journal of the National Cancer Institute.

[65]  J. Berzofsky,et al.  Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. , 2008, Immunity.

[66]  Jack T Stapleton,et al.  The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation , 2010, Science.

[67]  Doheon Lee,et al.  Inferring Pathway Activity toward Precise Disease Classification , 2008, PLoS Comput. Biol..

[68]  J. Cebra,et al.  Influences of microbiota on intestinal immune system development. , 1999, The American journal of clinical nutrition.

[69]  Patrick J. Brennan,et al.  Serum Metabolomics Reveals Higher Levels of Polyunsaturated Fatty Acids in Lepromatous Leprosy: Potential Markers for Susceptibility and Pathogenesis , 2011, PLoS neglected tropical diseases.

[70]  S. Plotkin,et al.  The development of vaccines: how the past led to the future , 2011, Nature Reviews Microbiology.

[71]  R. Caspi,et al.  Glutamate joins the ranks of immunomodulators , 2010, Nature Medicine.

[72]  T. Ideker,et al.  Network-based classification of breast cancer metastasis , 2007, Molecular systems biology.

[73]  A. Perelson.  Modelling viral and immune system dynamics , 2002, Nature Reviews Immunology.

[74]  Shuzhao Li,et al.  Systems vaccinology: Probing humanity’s diverse immune systems with vaccines , 2014, Proceedings of the National Academy of Sciences.

[75]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[76]  Elizabeth T. Cirulli,et al.  Common Genetic Variation and the Control of HIV-1 in Humans , 2009, PLoS genetics.

[77]  L. Trautmann,et al.  Solving vaccine mysteries: a systems biology perspective , 2011, Nature Immunology.

[78]  Dan R. Littman,et al.  Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria , 2009, Cell.

[79]  Maqc Consortium.  The MicroArray Quality Control ( MAQC )-II study of common practices for the development and validation of microarray-based predictive models , 2012 .

[80]  K. Wellen,et al.  A two-way street: reciprocal regulation of metabolism and signalling , 2012, Nature Reviews Molecular Cell Biology.

[81]  R. Murphy,et al.  New families of bioactive oxidized phospholipids generated by immune cells: identification and signaling actions. , 2012, Blood.

[82]  G. Nolan,et al.  Computational solutions to large-scale data management and analysis , 2010, Nature Reviews Genetics.

[83]  Martin Meier-Schellersheim,et al.  Multiscale modeling for biologists , 2009, Wiley interdisciplinary reviews. Systems biology and medicine.

[84]  Ash A. Alizadeh,et al.  Cell-type specific gene expression profiles of leukocytes in human peripheral blood , 2006, BMC Genomics.

[85]  Olga G. Troyanskaya,et al.  Global Prediction of Tissue-Specific Gene Expression and Context-Dependent Gene Networks in Caenorhabditis elegans , 2009, PLoS Comput. Biol..

[86]  Aleksey A. Nakorchevskiy,et al.  Expression deconvolution: A reinterpretation of DNA microarray data reveals dynamic changes in cell populations , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[87]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[88]  Kiyoko F. Aoki-Kinoshita,et al.  From genomics to chemical genomics: new developments in KEGG , 2005, Nucleic Acids Res..

[89]  Jason A. Papin,et al.  Applications of genome-scale metabolic reconstructions , 2009, Molecular systems biology.

[90]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[91]  Josef Spidlen,et al.  Flow cytometry data standards , 2011, BMC Research Notes.

[92]  P. Walter,et al.  Signal integration in the endoplasmic reticulum unfolded protein response , 2007, Nature Reviews Molecular Cell Biology.

[93]  E. Schadt.  Molecular networks as sensors and drivers of common human diseases , 2009, Nature.

[94]  B. Pulendran,et al.  Systems vaccinology: its promise and challenge for HIV vaccine development. , 2012, Current opinion in HIV and AIDS.

[95]  Atul J. Butte,et al.  Ten Years of Pathway Analysis: Current Approaches and Outstanding Challenges , 2012, PLoS Comput. Biol..

[96]  B A McKinney,et al.  Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine , 2010, Genes and Immunity.

[97]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[98]  B. Finlay,et al.  Impact of Salmonella Infection on Host Hormone Metabolism Revealed by Metabolomics , 2011, Infection and Immunity.

[99]  Hugo Y. K. Lam,et al.  Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes , 2012, Cell.

[100]  W. R. Wikoff,et al.  Response and recovery in the plasma metabolome tracks the acute LCMV-induced immune response. , 2009, Journal of proteome research.

[101]  Michal Linial,et al.  Using Bayesian Networks to Analyze Expression Data , 2000, J. Comput. Biol..

[102]  Rob Knight,et al.  PyNAST: a flexible tool for aligning sequences to a template alignment , 2009, Bioinform..

[103]  D. Zak,et al.  Merck Ad5/HIV induces broad innate immune activation that predicts CD8+ T-cell responses but is attenuated by preexisting Ad5 immunity , 2012, Proceedings of the National Academy of Sciences.

[104]  G. Siuzdak,et al.  Innovation: Metabolomics: the apogee of the omics trilogy , 2012, Nature Reviews Molecular Cell Biology.

[105]  Jason E. Stewart,et al.  Minimum information about a microarray experiment (MIAME)—toward standards for microarray data , 2001, Nature Genetics.

[106]  Qi Liu,et al.  Gene-set analysis and reduction , 2008, Briefings Bioinform..

[107]  E. Wherry,et al.  Commensal bacteria calibrate the activation threshold of innate antiviral immunity. , 2012, Immunity.

[108]  R. Tibshirani,et al.  Diagnosis of multiple cancer types by shrunken centroids of gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[109]  Mario Roederer,et al.  Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing , 2011, Science.

[110]  Bali Pulendran,et al.  Learning immunology from the yellow fever vaccine: innate immunity to systems vaccinology , 2009, Nature Reviews Immunology.

[111]  Kenneth H. Buetow,et al.  PID: the Pathway Interaction Database , 2008, Nucleic Acids Res..

[112]  John T. Wei,et al.  Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression , 2009, Nature.

[113]  J. Stark,et al.  Systems biology of persistent infection: tuberculosis as a case study , 2008, Nature Reviews Microbiology.

[114]  Joanne M. Morrisey,et al.  Branched Tricarboxylic Acid Metabolism in Plasmodium falciparum , 2010, Nature.

[115]  Kellen L. Olszewski,et al.  Host-parasite interactions revealed by Plasmodium falciparum metabolomics. , 2009, Cell host & microbe.

[116]  Gregory A. Poland,et al.  Genome-wide analysis of polymorphisms associated with cytokine responses in smallpox vaccine recipients , 2012, Human Genetics.

[117]  B. Palsson,et al.  The model organism as a system: integrating 'omics' data sets , 2006, Nature Reviews Molecular Cell Biology.

[118]  Advin K. Mathew.  METABOLOMICS: THE APOGEE OF THE OMICS TRILOGY , 2013 .

[119]  R. Deberardinis,et al.  Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? , 2012, Cell.

[120]  V. Pankratz,et al.  Twin studies of immunogenicity--determining the genetic contribution to vaccine failure. , 2001, Vaccine.

[121]  Z. Modrušan,et al.  Deconvolution of Blood Microarray Data Identifies Cellular Activation Patterns in Systemic Lupus Erythematosus , 2009, PloS one.

[122]  Rob Knight,et al.  Interleukin-1β (IL-1β) promotes susceptibility of Toll-like receptor 5 (TLR5) deficient mice to colitis , 2011, Gut.

[123]  Sylvia Janetzki,et al.  "MIATA"-minimal information about T cell assays. , 2009, Immunity.

[124]  Virginia Pascual,et al.  A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. , 2008, Immunity.

[125]  Bastian R. Angermann,et al.  Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses , 2008, The Journal of experimental medicine.

[126]  Steven H. Kleinstein,et al.  Cell subset prediction for blood genomic studies , 2012 .

[127]  D. Karger,et al.  Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity , 2009, Nature Genetics.

[128]  Y. Kamatani,et al.  A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians , 2009, Nature Genetics.

[129]  Martin Meier-Schellersheim,et al.  Systems biology in immunology: a computational modeling perspective. , 2011, Annual review of immunology.

[130]  F. Ciruela,et al.  Glutamate Released by Dendritic Cells as a Novel Modulator of T Cell Activation1 , 2006, The Journal of Immunology.

[131]  Bali Pulendran,et al.  Immunological mechanisms of vaccination , 2011, Nature Immunology.

[132]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[133]  S. Reed,et al.  Targeting TLRs Expands the Antibody Repertoire in Response to a Malaria Vaccine , 2011, Science Translational Medicine.

[134]  L. Liau,et al.  Cancer-associated IDH1 mutations produce 2-hydroxyglutarate , 2009, Nature.

[135]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[136]  Ronald N Germain,et al.  Vaccines and the future of human immunology. , 2010, Immunity.

[137]  William Stafford Noble,et al.  Support vector machine , 2013 .

[138]  Damien Chaussabel,et al.  Data management: it starts at the bench , 2009, Nature Immunology.

[139]  Matthew R. Laird,et al.  InnateDB: facilitating systems-level analyses of the mammalian innate immune response , 2008, Molecular systems biology.

[140]  A. Telenti,et al.  Infectious diseases not immune to genome-wide association , 2010, Nature Genetics.

[141]  Y. Li,et al.  An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling , 2011, Molecular systems biology.

[142]  S. Horvath,et al.  Variations in DNA elucidate molecular networks that cause disease , 2008, Nature.

[143]  Shuzhao Li,et al.  Constructing a fish metabolic network model , 2010, Genome Biology.

[144]  Sean C. Bendall,et al.  Cytometry by time-of-flight shows combinatorial cytokine expression and virus-specific cell niches within a continuum of CD8+ T cell phenotypes. , 2012, Immunity.

[145]  Eva K. Lee.  Machine Learning Framework for Classification in Medicine and Biology , 2009, CPAIOR.

[146]  K. Fritsche.  Fatty acids as modulators of the immune response. , 2006, Annual review of nutrition.

[147]  V. Pascual,et al.  Assessing the human immune system through blood transcriptomics , 2010, BMC Biology.

[148]  K. McCoy,et al.  Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. , 2007, Seminars in immunology.

[149]  V. Kuchroo,et al.  Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression , 2007, The Journal of experimental medicine.

[150]  A. Aderem,et al.  A 2020 vision for vaccines against HIV, tuberculosis and malaria , 2011, Nature.

[151]  Adrian E. Raftery,et al.  Bayesian model averaging: development of an improved multi-class, gene selection and classification tool for microarray data , 2005, Bioinform..

[152]  Sunia A Trauger,et al.  Metabolic oxidation regulates embryonic stem cell differentiation , 2010, Nature chemical biology.

[153]  Russell G. Jones,et al.  Enhancing CD8 T-cell memory by modulating fatty acid metabolism , 2009, Nature.

[154]  S. Plotkin.  Correlates of Protection Induced by Vaccination , 2010, Clinical and Vaccine Immunology.

[155]  Aviv Regev,et al.  Strategies to discover regulatory circuits of the mammalian immune system , 2011, Nature Reviews Immunology.

[156]  Bali Pulendran,et al.  Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity , 2006, The Journal of experimental medicine.

[157]  A. Mackensen,et al.  Tumor metabolism as modulator of immune response and tumor progression. , 2012, Seminars in cancer biology.

[158]  R Balfour Sartor,et al.  Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. , 2008, Cell host & microbe.

[159]  Ann L Oberg,et al.  Systems biology approaches to new vaccine development. , 2011, Current opinion in immunology.