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

Florian Wimmers; Michele Donato; Alex Kuo; Tal Ashuach; Shakti Gupta; Chunfeng Li; Mai Dvorak; Mariko Hinton Foecke; Sarah E Chang; Thomas Hagan; Sanne E De Jong; Holden T Maecker; Robbert van der Most; Peggie Cheung; Mario Cortese; Steven E Bosinger; Mark Davis; Nadine Rouphael; Shankar Subramaniam; Nir Yosef; Paul J Utz; Purvesh Khatri; Bali Pulendran

doi:10.1016/j.cell.2021.05.039

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.

Authors

Florian Wimmers¹, Michele Donato², Alex Kuo³, Tal Ashuach⁴, Shakti Gupta⁵, Chunfeng Li¹, Mai Dvorak³, Mariko Hinton Foecke³, Sarah E Chang³, Thomas Hagan¹, Sanne E De Jong¹, Holden T Maecker¹, Robbert van der Most⁶, Peggie Cheung⁷, Mario Cortese¹, Steven E Bosinger⁸, Mark Davis⁹, Nadine Rouphael¹⁰, Shankar Subramaniam⁵, Nir Yosef¹¹, Paul J Utz³, Purvesh Khatri², Bali Pulendran¹²

Affiliations

¹ Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Department of Electrical Engineering and Computer Sciences and Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive MC 0412, La Jolla, CA 92093, USA.
⁶ GSK, 1330 Rixensart, Belgium.
⁷ Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁹ Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
¹⁰ Hope Clinic of the Emory Vaccine Center, Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Decatur, GA 30030, USA.
¹¹ Department of Electrical Engineering and Computer Sciences and Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Chan-Zuckerberg Biohub, San Francisco, CA, USA.
¹² Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: bpulend@stanford.edu.

Abstract

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: ClinicalTrials.gov 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

Substances

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

ClinicalTrials.gov/NCT01910519
ClinicalTrials.gov/NCT02154061

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding