Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling
Kylie M. Quinn, … , Alan Aderem, Robert A. Seder
Kylie M. Quinn, … , Alan Aderem, Robert A. Seder
Published February 2, 2015
Citation Information: J Clin Invest. 2015;125(3):1129-1146. https://doi.org/10.1172/JCI78280.
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Research Article

Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling

Abstract

Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee-derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines.

Authors

Kylie M. Quinn, Daniel E. Zak, Andreia Costa, Ayako Yamamoto, Kathrin Kastenmuller, Brenna J. Hill, Geoffrey M. Lynn, Patricia A. Darrah, Ross W.B. Lindsay, Lingshu Wang, Cheng Cheng, Alfredo Nicosia, Antonella Folgori, Stefano Colloca, Riccardo Cortese, Emma Gostick, David A. Price, Jason G.D. Gall, Mario Roederer, Alan Aderem, Robert A. Seder

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Figure 1

Hierarchy of protective CD8 T cell responses and Ag expression after rAd vaccination.

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Hierarchy of protective CD8 T cell responses and Ag expression after rAd...
(A) Frequency of tetramer+ CD8+ T cells in spleens at peak (day 23) or once memory CD8+ T cell responses were established (day 70) after vaccination with human-derived rAds. (B) Bacterial load in spleens at day 108 after challenge with L. monocytogenes expressing Gag. (C) Ag transcript expression in dLNs after vaccination with human-derived rAds at 1 × 109 PU or 1 × 108 PU. (D) Tetramer+ CD8+ T cell responses at peak or memory, (E) bacterial load, and (F) Ag expression for chimpanzee-derived rAds. (G) Tetramer+ CD8+ T cell responses at peak or once memory CD8+ T cell responses were established, (H) bacterial load, and (I) Ag expression for simian-derived rAds. For CD8 T cell responses and bacterial load analysis, mice received all rAds at 1 × 108 PU; rAd35 was administered at both 1 × 109 PU (rAd35hi) and 1 × 108 PU (rAd35lo). For Ag expression, mice received rAds at 1 × 109 PU or 1 × 108 PU as indicated. Error bars indicate mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, Mann-Whitney test. Dashed lines indicate the limit of detection (LOD). Data represent at least 2 independent experiments (n = 3–6).