Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling
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
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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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 10

Effect of enhancing type I IFN signaling on Ag expression and CD8 T cell immunity.

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Effect of enhancing type I IFN signaling on Ag expression and CD8 T cell...
(A) Radar plots of modules and individual genes within modules C2 and C3 at 24 hours after vaccination with rAd5, chAd63, or poly I:C. Axes represent (left) maximum = +4, minimum = –4, circles = +4 (outside), +3, +2, +1, 0 (gray circle), –1, –2, –3, and –4 or (right) maximum = +8, minimum = –1, circles = +8 (outside), +7, +6, +5, +4, +3, +2, +1, 0 (gray circle), and –1 log2 fold change relative to PBS. (B) Ag expression at 40 hours after vaccination with 1 × 107 PU rAd5 with or without 1 × 108 PU chAd63 or 50 μg poly I:C. (C) The number of total CD11c+ DCs, (D) the MFI of EGFP in EGFP+ DCs, (E) the frequency of nonviable CD11c+ DCs, and (F) the number of live EGFP+ CD11c+ DCs per dLN at 24 hours after vaccination with 5 × 108 PU rAd5-EGFP with or without 50 μg poly I:C. (G) Tetramer+ CD8+ T cell responses at day 28 after vaccination with 1 × 107 PU rAd5 with or without 50 μg poly I:C. Error bars represent mean ± SEM. **P ≤ 0.01, Mann-Whitney test. The dashed line indicates the LOD. Data represent (B and G) 3 independent experiments with n = 3–6 or (C–F) 5 to 10 pooled dLNs per group.