The single-cell epigenomic and transcriptional landscape of immunity to influenza vaccination

Cell. 2021 Jul 22;184(15):3915-3935.e21. doi: 10.1016/j.cell.2021.05.039. Epub 2021 Jun 25.


Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.

Trial registration: NCT01910519 NCT02154061.

Keywords: adjuvant; antiviral immunity; epigenome; influenza; innate memory; monocyte; single cell; systems biology; trained immunity; vaccines.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anti-Bacterial Agents / pharmacology
  • Antigens, CD34 / metabolism
  • Antiviral Agents / pharmacology
  • Cellular Reprogramming
  • Chromatin / metabolism
  • Cytokines / biosynthesis
  • Drug Combinations
  • Epigenomics*
  • Female
  • Gene Expression Regulation
  • Histones / metabolism
  • Humans
  • Immunity / genetics*
  • Immunity, Innate / genetics
  • Influenza A Virus, H5N1 Subtype / drug effects
  • Influenza A Virus, H5N1 Subtype / immunology
  • Influenza Vaccines / genetics*
  • Influenza Vaccines / immunology*
  • Interferon Type I / metabolism
  • Male
  • Myeloid Cells / metabolism
  • Polysorbates / pharmacology
  • Single-Cell Analysis*
  • Squalene / pharmacology
  • Toll-Like Receptors / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic*
  • Transcriptome / genetics
  • Vaccination*
  • Young Adult
  • alpha-Tocopherol / pharmacology


  • Anti-Bacterial Agents
  • Antigens, CD34
  • Antiviral Agents
  • Chromatin
  • Cytokines
  • Drug Combinations
  • Histones
  • Influenza Vaccines
  • Interferon Type I
  • Polysorbates
  • Toll-Like Receptors
  • Transcription Factor AP-1
  • Squalene
  • AS03 adjuvant
  • alpha-Tocopherol

Associated data