@article{5cd7370ff60c437f89bcff184b985757,
title = "Cell-based systems biology analysis of human AS03-adjuvanted H5N1 avian influenza vaccine responses: A phase i randomized controlled trial",
abstract = "Background: 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. Objective and Methods: 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. Results: 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 presentationrelated 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. Conclusions: Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.",
author = "Howard, {Leigh M.} and Hoek, {Kristen L.} and Goll, {Johannes B.} and Parimal Samir and Allison Galassie and Allos, {Tara M.} and Xinnan Niu and Gordy, {Laura E.} and Creech, {C. Buddy} and Nripesh Prasad and Jensen, {Travis L.} and Heather Hill and Levy, {Shawn E.} and Sebastian Joyce and Link, {Andrew J.} and Edwards, {Kathryn M.}",
note = "Funding Information: KME has received grant funding for group B streptococcal vaccine research from Novartis and has participated as a member on a Novartis Data Safety Monitoring Board on influenza vaccines. CBC has received institutional grant support for staphylococcal vaccine research from Pfizer and Novartis Vaccines. JBG, TJL, and HH are employed by The Emmes Corporation. The Emmes Corporation is an independent contract research organization NIH-NIAID-DMID contracted with for collecting and analyzing data for clinical trials and studies to evaluate the safety and efficacy of vaccines, devices, and therapeutics for infectious diseases. The Emmes Corporation does not have any patents, products in development or marketed products to declare. These affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials; however, we have not released raw sequencing data to maintain accordance with subject confidentiality requirements as outlined in the study{\textquoteright}s Informed Consent Document, as approved by the Vanderbilt University Medical Center Institutional Review Board. The other authors declare that they have no conflicts of interest. Funding Information: We would like to acknowledge and thank our study volunteers for their participation in this study. In addition, we would like to acknowledge the contributions of Vanderbilt Vaccine Research Center staff: Gayle Johnson, RN, CCRP; Shanda Phillips, RN, BSN, CCRP, Wendi McDonald, RN, BSN, CCRP; Deborah Hunter, RN, BSN, CCRC; Deborah Myers, CCRP; Roberta Winfrey, Kevin Booth, MBA, Jennifer Nixon, MBA, John Oleis, DPh, and the Vanderbilt Clinical Research Center. The authors also thank John Mote, Angela Jones and the Sequencing and Analysis teams of the Genomic Services Laboratory at HudsonAlpha for their support of the genomic studies, and Megan McDonough, MPH; Bernadette Jolles and Brenda Leung of Emmes for their support of clinical data management. This project was funded in part with federal funds from the National Institutes of Allergy and Infectious Disease, National Institutes of Health, Department of Health and Human Services, under Contract Nos. 272200800007C and 2722001300023I and Grant No. GM64779; the Vanderbilt Clinical and Translational Science Award grant NIH RR024975 (UL1TR000445); the Childhood Infections Research Program grant T32-AI095202-01; the Vanderbilt Department of Pediatrics Turner-Hazinski Award, and a VA Merit Award BX001444. This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, Tennessee. Flow Cytometry experiments were performed in the VMC Flow Cytometry Shared Resource. The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). Publisher Copyright: {\textcopyright} 2017 Howard et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2017",
month = jan,
doi = "10.1371/journal.pone.0167488",
language = "English (US)",
volume = "12",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "1",
}