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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 Vaccines

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

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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 5

Ingenuity pathway analysis of innate gene activation in vivo after rAd vaccination.

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Ingenuity pathway analysis of innate gene activation in vivo after rAd v...
(A) Analysis of canonical pathway enrichment in genes differentially expressed 8 hours after rAd vaccination. The left axis (bar plots) shows percentage of genes annotated to a given canonical pathway that were upregulated (magenta) or downregulated (cyan) in dLNs at 8 hours after rAd vaccination. The right axis (line graph) shows log10 probability (P value) that an equivalent number of genes in the indicated pathways could be obtained by randomly selecting gene groups of the same size. Results are shown for the top 15 pathways with P < 1 × 10–4. Numbers above bars indicate the number of genes included each pathway. (B) Fold change (log2) in expression of type I and type II IFN signaling transcripts Ifng, Ifnb, Ifngr1, and Irf9 over time after vaccination with each rAd compared with the PBS control. Error bars represent mean ± SEM (n = 4–8).
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