Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

Background: Tularemia is a potential biological weapon due to its high infectivity and ease of dissemination. This study aimed to characterize the innate and adaptive responses induced by two different lots of a live attenuated tularemia vaccine and compare them to other well-characterized viral vaccine immune responses. Methods: Microarray analyses were performed on human peripheral blood mononuclear cells (PBMCs) to determine changes in transcriptional activity that correlated with changes detected by cellular phenotyping, cytokine signaling, and serological assays. Transcriptional profiles after tularemia vaccination were compared with yellow fever [YF-17D], inactivated [TIV], and live attenuated [LAIV] influenza. Results: Tularemia vaccine lots produced strong innate immune responses by Day 2 after vaccination, with an increase in monocytes, NK cells, and cytokine signaling. T cell responses peaked at Day 14. Changes in gene expression, including upregulation of STAT1, GBP1, and IFIT2, predicted tularemia-specific antibody responses. Changes in CCL20 expression positively correlated with peak CD8+ T cell responses, but negatively correlated with peak CD4+ T cell activation. Tularemia vaccines elicited gene expression signatures similar to other replicating vaccines, inducing early upregulation of interferon-inducible genes. Conclusions: A systems vaccinology approach identified that tularemia vaccines induce a strong innate immune response early after vaccination, similar to the response seen after well-studied viral vaccines, and produce unique transcriptional signatures that are strongly correlated to the induction of T cell and antibody responses.

[1]  Shashank Tripathi,et al.  Moving from Empirical to Rational Vaccine Design in the ‘Omics’ Era , 2019, Vaccines.

[2]  Travis L. Jensen,et al.  AS03-Adjuvanted H5N1 Avian Influenza Vaccine Modulates Early Innate Immune Signatures in Human Peripheral Blood Mononuclear Cells , 2018, The Journal of infectious diseases.

[3]  K. Błaszczyk,et al.  A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses , 2018, Front. Immunol..

[4]  I. Golovliov,et al.  IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection , 2017, PLoS pathogens.

[5]  Johannes B. Goll,et al.  Tularemia vaccine: Safety, reactogenicity, "Take" skin reactions, and antibody responses following vaccination with a new lot of the Francisella tularensis live vaccine strain - A phase 2 randomized clinical Trial. , 2017, Vaccine.

[6]  M. Mulligan,et al.  Innate, T-, and B-Cell Responses in Acute Human Zika Patients , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[7]  Jinchun Pan,et al.  Positive Correlation between IP-10 and IFN-γ Levels in Rhesus Monkeys (Macaca mulatta) with Either Naturally Acquired or Experimental Infection of Mycobacterium tuberculosis , 2017, BioMed research international.

[8]  Travis L Jensen,et al.  Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial , 2017, PloS one.

[9]  Lydia M. Roberts,et al.  Inclusion of Epitopes That Expand High-Avidity CD4+ T Cells Transforms Subprotective Vaccines to Efficacious Immunogens against Virulent Francisella tularensis , 2016, The Journal of Immunology.

[10]  Jennifer A. Mitchell,et al.  Concordance between RNA-sequencing data and DNA microarray data in transcriptome analysis of proliferative and quiescent fibroblasts , 2015, Royal Society Open Science.

[11]  S. Thorne,et al.  CTL- vs Treg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma , 2015, British Journal of Cancer.

[12]  May D. Wang,et al.  Comparison of RNA-seq and microarray-based models for clinical endpoint prediction , 2015, Genome Biology.

[13]  K. Elkins,et al.  Francisella tularensis Vaccines Elicit Concurrent Protective T- and B-Cell Immune Responses in BALB/cByJ Mice , 2015, PloS one.

[14]  K. Davis,et al.  The Split Virus Influenza Vaccine rapidly activates immune cells through Fcγ receptors. , 2014, Vaccine.

[15]  L. Zárybnická,et al.  B cell subsets are activated and produce cytokines during early phases of Francisella tularensis LVS infection. , 2014, Microbial pathogenesis.

[16]  A. Bittner,et al.  Comparison of RNA-Seq and Microarray in Transcriptome Profiling of Activated T Cells , 2014, PloS one.

[17]  Sandra Romero-Steiner,et al.  Molecular signatures of antibody responses derived from a systems biological study of 5 human vaccines , 2013, Nature Immunology.

[18]  D. Dolfi,et al.  Vaccine-Induced Boosting of Influenza Virus-Specific CD4 T Cells in Younger and Aged Humans , 2013, PloS one.

[19]  R. Morita,et al.  Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis , 2013, Nature Immunology.

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

[21]  Helga Thorvaldsdóttir,et al.  Molecular signatures database (MSigDB) 3.0 , 2011, Bioinform..

[22]  Daniel Metzger,et al.  The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells , 2011, Nature communications.

[23]  D. Vestal,et al.  The guanylate-binding proteins: emerging insights into the biochemical properties and functions of this family of large interferon-induced guanosine triphosphatase. , 2011, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[24]  C. Rice,et al.  The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD8+ T Cell Response1 , 2009, The Journal of Immunology.

[25]  Wei Zhu,et al.  A whole genome transcriptional analysis of the early immune response induced by live attenuated and inactivated influenza vaccines in young children. , 2010, Vaccine.

[26]  T. Cate,et al.  Safety, reactogenicity and immunogenicity of Francisella tularensis live vaccine strain in humans. , 2009, Vaccine.

[27]  P. Khaitovich,et al.  BMC Genomics BioMed Central Methodology article Estimating accuracy of RNA-Seq and microarrays with proteomics , 2022 .

[28]  Chen Dong,et al.  CCR6 Regulates the Migration of Inflammatory and Regulatory T Cells1 , 2008, The Journal of Immunology.

[29]  D. Metzger,et al.  Humoral and cell‐mediated immunity to the intracellular pathogen Francisella tularensis , 2008, Immunological reviews.

[30]  M. Sztein,et al.  An improved Francisella tularensis live vaccine strain (LVS) is well tolerated and highly immunogenic when administered to rabbits in escalating doses using various immunization routes. , 2008, Vaccine.

[31]  A. Cross,et al.  From rabbits to humans: the contributions of Dr. Theodore E. Woodward to tularemia research. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[32]  K. Elkins,et al.  Innate and Adaptive Immunity to Francisella , 2007, Annals of the New York Academy of Sciences.

[33]  Mark W. Porter,et al.  Transcriptome analysis of human immune responses following live vaccine strain (LVS) Francisella tularensis vaccination. , 2007, Molecular immunology.

[34]  S. Bavari,et al.  Dominance of human innate immune responses in primary Francisella tularensis live vaccine strain vaccination. , 2006, The Journal of allergy and clinical immunology.

[35]  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.

[36]  J. Sirard,et al.  Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo. , 2006, Immunity.

[37]  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.

[38]  Wangxue Chen,et al.  Aerosol-, but not intradermal-immunization with the live vaccine strain of Francisella tularensis protects mice against subsequent aerosol challenge with a highly virulent type A strain of the pathogen by an alphabeta T cell- and interferon gamma- dependent mechanism. , 2005, Vaccine.

[39]  Lincoln Stein,et al.  Reactome: a knowledgebase of biological pathways , 2004, Nucleic Acids Res..

[40]  Lihan K. Yan,et al.  Induction of human T cell-mediated immune responses after primary and secondary smallpox vaccination. , 2004, The Journal of infectious diseases.

[41]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[42]  T. Matsui,et al.  Production of Macrophage Inflammatory Protein 3α (MIP-3α) (CCL20) and MIP-3β (CCL19) by Human Peripheral Blood Neutrophils in Response to Microbial Pathogens , 2003, Infection and Immunity.

[43]  K. Elkins,et al.  Susceptibility to Secondary Francisella tularensis Live Vaccine Strain Infection in B-Cell-Deficient Mice Is Associated with Neutrophilia but Not with Defects in Specific T-Cell-Mediated Immunity , 2001, Infection and Immunity.

[44]  A. Tärnvik,et al.  Various membrane proteins of Francisella tularensis induce interferon-gamma production in both CD4+ and CD8+ T cells of primed humans. , 1992, Immunology.

[45]  Theodore A. Mork,et al.  Young Children , 1949, Nature.

[46]  Richard W. Titball,et al.  Tularemia , 1927, Clinical Microbiology Reviews.

[47]  I. Golovliov,et al.  IFN-gamma extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida , 2017 .

[48]  R. Jacobs,et al.  Tularemia (Francisella tularensis) , 2011 .

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

[50]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[51]  T. Matsui,et al.  Production of macrophage inflammatory protein 3alpha (MIP-3alpha) (CCL20) and MIP-3beta (CCL19) by human peripheral blood neutrophils in response to microbial pathogens. , 2003, Infection and immunity.

[52]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..