Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses
Muktha S. Natrajan,
Nadine Rouphael,
Lilin Lai,
Dmitri Kazmin,
Travis L. Jensen,
David S. Weiss,
Chris Ibegbu,
Marcelo B. Sztein,
William F. Hooper,
Heather Hill,
Evan J. Anderson,
Robert Johnson,
Patrick Sanz,
Bali Pulendran,
Johannes B. Goll,
Mark J. Mulligan
Affiliations
Muktha S. Natrajan
Hope Clinic, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Decatur, GA 30030, USA
Nadine Rouphael
Hope Clinic, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Decatur, GA 30030, USA
Lilin Lai
Hope Clinic, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Decatur, GA 30030, USA
Dmitri Kazmin
Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Travis L. Jensen
The EMMES Corporation, Rockville, MD 20850, USA
David S. Weiss
Hope Clinic, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Decatur, GA 30030, USA
Chris Ibegbu
Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Marcelo B. Sztein
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA
William F. Hooper
The EMMES Corporation, Rockville, MD 20850, USA
Heather Hill
The EMMES Corporation, Rockville, MD 20850, USA
Evan J. Anderson
Departments of Medicine and Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
Robert Johnson
Biomedical Advanced Research and Development Authority, ASPR, Department of Health and Human Services, Washington, DC 20201, USA
Patrick Sanz
Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20892, USA
Bali Pulendran
Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Johannes B. Goll
The EMMES Corporation, Rockville, MD 20850, USA
Mark J. Mulligan
Hope Clinic, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Decatur, GA 30030, USA
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.
