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Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8<jats:sup>+<\/jats:sup> T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68\u20131 RhCMV\/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68\u20131 RhCMV\/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome\/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV\/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust <jats:italic>de novo<\/jats:italic> vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV\/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8<jats:sup>+<\/jats:sup> T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8<jats:sup>+<\/jats:sup> T cells to mediate protection against SIV challenge.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009278","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T17:43:37Z","timestamp":1625593417000},"page":"e1009278","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":33,"title":["Interleukin-15 response signature predicts RhCMV\/SIV vaccine efficacy"],"prefix":"10.1371","volume":"17","author":[{"given":"Fredrik","family":"Barren\u00e4s","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott 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