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

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.

The Whole Body as the System in Systems Immunology

“…Vaccine responses and efficacy can be further evaluated at the population level, addressing the challenge of designing vaccines that are effective among a diverse population ( Koff et al., 2013 ; Li et al., 2017 ; Tsang et al., 2014 ). Combined data from serum analyte profiling, multiparameter cytometry, multiomics technologies, and adaptive immune receptor repertoire profiling identify shared molecular signatures and biomarkers to predict vaccine responsiveness and immunogenicity ( Kazmin et al., 2017 ; Nakaya et al., 2015 ; Natrajan et al., 2019 ; Ramos, 2020 ; Sullivan et al., 2019 ; Team and Consortium, 2017 ). By incorporating molecular signatures of tissue responses, systems vaccinology approaches can inform development and monitoring of vaccines that ensure effective establishment of tissue immunity.…”

Japanese Encephalitis Vaccines

“…Investigations aimed at unravelling the complete profile of cell-mediated immune responses elicited by the various JEV vaccines are in order, not to mention the awe-inspiring systems immunology of innate immune responses that have been investigated following vaccinations against influenza, malaria, tularemia, etc. [68][69][70][71]. The complex role of T-follicular helper cells recruited by various viral epitopes and their contribution to protection versus pathology as observed in dengue disease would add another deeper layer to our understanding [72][73][74][75].…”

Current Challenges in Vaccinology

“…In turn, this led to the development of vaccinomics and systems vaccinology (7,13,(171)(172)(173)(174)(175)(176)(177)(178). This emerging paradigm is an approach that utilizes the tools and insights derived from systems biology; high-dimensional, high-throughput "omics" technologies; and genomics (7,13,59,66,79,175,(179)(180)(181)(182)(183). Vaccinomics leverages high-resolution data, such as transcriptomics, proteomics, and metabolomics/lipidomics/glycomics, epigenetics, etc., to derive holistic (systems-level) and mechanistic models of both protective and aberrant immune system responses (i.e., "immune signatures").…”