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

• Type of Material: Article
• Authors: Muktha S. Natrajan, Emory University; Nadine Rouphael, Emory University; Lilin Lai, Emory University; Dmitri Kazmin, Emory University; Travis L. Jensen, Emmes Corporation; David Weiss, Emory University; Chris Ibegbu, Emory University; Marcelo B. Sztein, University of Maryland; William F. Hooper, Emmes Corporation; Heather Hill, Emmes Corporation; Evan Anderson, Emory University; Robert Johnson, Biomedical Advanced Research and Development Authority, ASPR; Patrick Sanz, Biomedical Advanced Research and Development Authority, ASPR; Bali Pulendran, Emory University; Johannes B. Goll, Emmes Corporation; Mark Mulligan, Emory University
• Language: English
• Date: 2020-03-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/vaccines8010004
• Title of Journal or Parent Work: Vaccines
• Volume: 8
• Issue: 1
• Grant/Funding Information: University of Maryland, Baltimore, Maryland, contract HHSN27220800057C; Emmes, contracts HHSN272200800013C and HHSN272201500002C; Georgia Research Alliance support to The Hope Clinic; and the Immunology Core Center for AIDS Research Grant P30 A1050409.; This work was supported by awards from the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases at the National Institutes of Health to the Emory Vaccine and Treatment Evaluation Unit, contracts HHSN272200800005C and HHSN272201300018I
• Keywords: Immunogenicity; Influenza; Research & Experimental Medicine; Strain LVS; Subsets; comparative vaccines; immune signaling; transcriptomics; Medicine, Research & Experimental; Innate; Life Sciences & Biomedicine; T-cells; Pathogen; Immunization; Yellow fever vaccine; Immunology; tularemia; live attenuated vaccines; Reactogenicity; Science & Technology
• Research Categories: Biology, Cell; Health Sciences, Epidemiology; Health Sciences, Immunology; Health Sciences, Public Health

Abstract

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.