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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Microbial Immunology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1460344
This article is part of the Research Topic Immune Mechanisms of Protection Against Mycobacterium tuberculosis View all 8 articles

Functional genomic analysis of the 68-1 RhCMV-Mycobacteria tuberculosis vaccine reveals an IL-15 response signature that is conserved with vector attenuation

Provisionally accepted
Cheng-Jung Sung Cheng-Jung Sung 1Leanne S. Whitmore Leanne S. Whitmore 1Elise Smith Elise Smith 1Jean Chang Jean Chang 1Jennifer Tisoncik-Go Jennifer Tisoncik-Go 1Aaron Barber-Axthelm Aaron Barber-Axthelm 2Andrea Selseth Andrea Selseth 2Shana Feltham Shana Feltham 2Sohita Ojha Sohita Ojha 2Scott G. Hansen Scott G. Hansen 2Louis J. Picker Louis J. Picker 2Michael Gale Michael Gale 1,3*
  • 1 Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, United States
  • 2 Vaccine and Gene Therapy Institute and Oregon National Primate Research Center (ONPRC), Oregon Health and Science University (OHSU), Beaverton, Oregon, United States
  • 3 Washington National Primate Research Center, University of Washington, Seattle, Washington, United States

The final, formatted version of the article will be published soon.

    Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is a deadly infectious disease having a major impact on global health. Using the CMV vector for development of novel vaccines is a promising new strategy that elicits strong and durable, high frequency memory T cell responses against heterologous immunogens. We conducted functional transcriptomic analysis of whole blood samples collected from cohorts of rhesus (Rh) macaques that were administered RhCMV/TB vector using a prime-boost strategy. Two modified CMV vectors were used in this study, including 68-1 RhCMV/TB-6Ag (encoding 6 Mtb protein immunogens, including Ag85A, ESAT-6, Rv3407, Rv2626, Rpf A, and Rpf D) and its attenuated variant, 68-1 RhCMV/Δpp71-TB-6Ag (a cell-to-cell spread-deficient vaccine vector lacking the Rh110 gene encoding the pp71 tegument protein). Bulk mRNA sequencing, differential gene expression, and functional enrichment analyses showed that these RhCMV/TB vaccines induce the innate and adaptive immune responses with specific transcriptomic signatures, including the IL-15-induced protective gene signature previously defined to be linked with protection against simian immunodeficiency virus (SIV) by the 68-1 RhCMV/SIV vaccine. While both vectors exhibited a transcriptomic response of the IL-15 protective signature in whole blood, we show that lack of pp71 does not maintain induction of the protective signature for the full duration of the study compared to the parental non-attenuated vector. Our observations indicate that RhCMV vector vaccines induce a transcriptomic response in whole blood that include a conserved IL-15 signature of which vector-encoded pp71 is an important component of response durability that upon future Mtb challenge may define specific vaccine protection outcomes against MTb infection.

    Keywords: Tuberculosis, Cytomegalovirus, rhesus macaque, Vaccine, Spread-deficient, IL-15, innate immunity, Transcriptomic Analysis

    Received: 05 Jul 2024; Accepted: 26 Sep 2024.

    Copyright: © 2024 Sung, Whitmore, Smith, Chang, Tisoncik-Go, Barber-Axthelm, Selseth, Feltham, Ojha, Hansen, Picker and Gale. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Michael Gale, Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.