Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial

• Published in: PloS one Vol. 12; no. 1; p. e0167488
• Main Authors: Howard, Leigh M., Hoek, Kristen L., Goll, Johannes B., Samir, Parimal, Galassie, Allison, Allos, Tara M., Niu, Xinnan, Gordy, Laura E., Creech, C. Buddy, Prasad, Nripesh, Jensen, Travis L., Hill, Heather, Levy, Shawn E., Joyce, Sebastian, Link, Andrew J., Edwards, Kathryn M.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.01.2017; Public Library of Science (PLoS)
• Subjects: Adjuvants, Immunologic - therapeutic use; Adolescent; Adult; Adults; Aluminum; Analysis; Antibodies, Viral - blood; Antibody Formation - immunology; Antigen presentation; Antigen Presentation - genetics; Antigen Presentation - immunology; Antigen processing; Antigens; Avian flu; Avian influenza; B cells; Biology; Biology and Life Sciences; Cell adhesion & migration; Cell cycle; Chemokine CXCL10 - blood; Clinical trials; Cytokines; Dendritic cells; Dendritic Cells - immunology; Double-Blind Method; Female; Gene expression; Genes; Genetic aspects; Hemagglutination inhibition; Hemagglutination Inhibition Tests; Humans; Immune response; Immunogenicity; Immunology; Influenza; Influenza A; Influenza A Virus, H5N1 Subtype - immunology; Influenza vaccines; Influenza Vaccines - immunology; Influenza, Human - immunology; Influenza, Human - prevention & control; Information processing; Interferon; Interleukin 6; Interleukin-6 - blood; IP-10 protein; Killer Cells, Natural - immunology; Leukocytes (neutrophilic); Lymphatic system; Lymphocytes; Major histocompatibility complex; Male; Medicine; Medicine and Health Sciences; Middle Aged; Molecular modelling; Monocytes; Monocytes - immunology; Neutrophils; Neutrophils - immunology; Pandemics; Pathology; Pediatrics; Physicians; Product development; Proteins; Public health; R&D; Randomization; Research & development; Serum levels; Signaling; Systems Biology - methods; T cell receptors; Vaccination; Vaccine development; Vaccines; Viruses; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0167488

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.