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Identification of Compounds That Prolong Type I Interferon Signaling as Potential Vaccine Adjuvants.

  • Shukla, Nikunj M
  • Arimoto, Kei-Ichiro
  • Yao, Shiyin
  • Fan, Jun-Bao
  • Zhang, Yue
  • Sato-Kaneko, Fumi
  • Lao, Fitzgerald S
  • Hosoya, Tadashi
  • Messer, Karen
  • Pu, Minya
  • Cottam, Howard B
  • Carson, Dennis A
  • Hayashi, Tomoko
  • Zhang, Dong-Er
  • Corr, Maripat
Publication Date
Oct 01, 2018
eScholarship - University of California
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Vaccines are reliant on adjuvants to enhance the immune stimulus, and type I interferons (IFNs) have been shown to be beneficial in augmenting this response. We were interested in identifying compounds that would sustain activation of an endogenous type I IFN response as a co-adjuvant. We began with generation of a human monocytic THP-1 cell line with an IFN-stimulated response element (ISRE)-β-lactamase reporter construct for high-throughput screening. Pilot studies were performed to optimize the parameters and conditions for this cell-based Förster resonance energy transfer (FRET) reporter assay for sustaining an IFN-α-induced ISRE activation signal. These conditions were confirmed in an initial pilot screen, followed by the main screen for evaluating prolongation of an IFN-α-induced ISRE activation signal at 16 h. Hit compounds were identified using a structure enrichment strategy based on chemoinformatic clustering and a naïve "Top X" approach. A select list of confirmed hits was then evaluated for toxicity and the ability to sustain IFN activity by gene and protein expression. Finally, for proof of concept, a panel of compounds was used to immunize mice as co-adjuvant with a model antigen and an IFN-inducing Toll-like receptor 4 agonist, lipopolysaccharide, as an adjuvant. Selected compounds significantly augmented antigen-specific immunoglobulin responses.

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