Table4_Functional genomic analysis of the 68-1 RhCMV-Mycobacteria tuberculosis vaccine reveals an IL-15 response signature that is conserved with vector attenuation.xlsx

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.

结核病（TB），由结核分枝杆菌（Mycobacterium tuberculosis，Mtb）引起，是一种致命的传染性疾病，对全球公共卫生产生了重大影响。利用CMV载体开发新型疫苗是一种具有巨大潜力的新策略，该策略能够激发针对异源抗原的强烈且持久的、高频率记忆T细胞反应。本研究采用prime-boost策略，对接受RhCMV/TB载体治疗的猕猴（Rh）血液样本进行了功能转录组学分析。本研究使用了两种改良的CMV载体，包括编码6种Mtb蛋白免疫原（包括Ag85A、ESAT-6、Rv3407、Rv2626、Rpf A和Rpf D）的68-1 RhCMV/TB-6Ag及其减毒变体，68-1 RhCMV/Δpp71-TB-6Ag（一种缺乏编码pp71包膜蛋白的Rh110基因的细胞间传播缺陷型疫苗载体）。大量mRNA测序、差异基因表达和功能富集分析表明，这些RhCMV/TB疫苗能够诱导具有特定转录组特征的先天性和适应性免疫反应，包括先前由68-1 RhCMV/SIV疫苗定义的与对猴免疫缺陷病毒（SIV）的保护相关的IL-15诱导的保护基因特征。尽管两种载体在血液中均表现出IL-15保护特征的转录组反应，但我们发现，与亲本非减毒载体相比，缺乏pp71不能在整个研究期间维持保护特征的诱导。我们的观察结果表明，RhCMV载体疫苗在血液中诱导的转录组反应包括一个保守的IL-15特征，其中载体编码的pp71是反应持久性的重要组成部分，在未来的Mtb挑战中，它可能定义针对Mtb感染的特定疫苗保护结果。