title: Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial.
abstract: Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.
  
  
  
  We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.
  
  
  
  Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.
  
  
  
  Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.
  
  
  
  ClinicalTrials.gov NCT01573312.
authors.affiliation: Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Leigh M
authors.identifier: 0000-0003-4301-7235
authors.initials: LM
authors.lastname: Howard
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Hoek
authors.affiliation: The Emmes Corporation, Rockville, MD, United States of America.
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Goll
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Parimal
authors.initials: P
authors.lastname: Samir
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN, United States of America.
authors.forename: Allison
authors.initials: A
authors.lastname: Galassie
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Allos
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Xinnan
authors.initials: X
authors.lastname: Niu
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Gordy
authors.affiliation: Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: C Buddy
authors.initials: CB
authors.lastname: Creech
authors.affiliation: HudsonAlpha Institute for Biotechnology; Huntsville, AL, United States of America.
authors.forename: Nripesh
authors.initials: N
authors.lastname: Prasad
authors.affiliation: The Emmes Corporation, Rockville, MD, United States of America.
authors.forename: Travis L
authors.initials: TL
authors.lastname: Jensen
authors.affiliation: The Emmes Corporation, Rockville, MD, United States of America.
authors.forename: Heather
authors.initials: H
authors.lastname: Hill
authors.affiliation: HudsonAlpha Institute for Biotechnology; Huntsville, AL, United States of America.
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Levy
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.|Veterans Administration Tennessee Valley Healthcare System, Nashville, TN, United States of America.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Link
authors.affiliation: Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Edwards
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation / Q000276:immunology; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D054357:Chemokine CXCL10 / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control*; D015850:Interleukin-6 / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D049490:Systems Biology / Q000379:methods*; D014611:Vaccination; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C508600:IL6 protein, human; D007252:Influenza Vaccines; D015850:Interleukin-6