Multiomic analysis identifies glutaminolysis-dependent metabolic enhancement of immune memory utilised for vaccine development
Vaccines work by inducing an immunological memory response to protect against infection or disease. More effective vaccines are required to improve protection of high-risk groups such as the elderly. Here we screen transcriptional signatures of T cell memory against repurposable drug signatures, identifying a subclass of lysine deacetylase inhibitors (KDACi) capable of promoting a memory precursor phenotype in primary T cells. Leveraging combined acetylomic, metabolomic, transcriptomic and epigenomic analyses, we identify enhanced glutaminolysis as the mechanism responsible for the KDACi effect, with selective inhibition reversing the changes induced by KDACi treatment. We validate the ability of a repurposable KDACi (sodium valproate) to promote immune memory in four murine models of infection and immunisation, with the effect reversed by concurrently inhibiting glutaminolysis. Finally, we undertake a human challenge study, which demonstrates a 10-fold increase in correlates of protection following seasonal influenza vaccination. These results reveal immune-metabolic adjuvant properties of repurposable lysine deacetylase inhibitors and demonstrate that systematic screening can identify both efficacy and mechanism of repurposable drugs.
Authors
- Kenneth G. C. Smith (ORCID: https://orcid.org/0000-0003-3829-4326)
- I. Pshenichnaya
- Oliver Knight (ORCID: https://orcid.org/0000-0002-0424-2379)
- Alice E. Denton (ORCID: https://orcid.org/0000-0002-4580-3443)
- Prasanti Kotagiri (ORCID: https://orcid.org/0000-0002-9806-4349)
- Eoin McKinney (ORCID: https://orcid.org/0000-0003-3516-3072)
- Yorgo Modis (ORCID: https://orcid.org/0000-0002-6084-0429)
- Paul Lyons (ORCID: https://orcid.org/0000-0001-7035-8997)
- G. Dougan
- T. Birkle
- John Sowerby (ORCID: https://orcid.org/0000-0002-0224-3087)
- Ian Barr (ORCID: https://orcid.org/0000-0002-7351-418X)
- C. Matara
- C. Keel
- Iona Cuthbertson (ORCID: https://orcid.org/0000-0002-0245-4466)
- Nicholas J. Matheson (ORCID: https://orcid.org/0000-0002-3318-1851)
- Guido A. Stoll (ORCID: https://orcid.org/0000-0003-2531-9168)
- Daniel D Griffiths (ORCID: https://orcid.org/0009-0001-5312-511X)
- K. Harcourt
- P. Pereyra Gerber
- C. Connor
- H. Peck
- P. Naydenova
- S. Clare
- G. Manferrari
Institutions
- NHS Blood and Transplant (GB)
- MRC Laboratory of Molecular Biology (GB)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- National Institute for Health and Care Research (GB)
- Cambridge School (PT)
- Peter Doherty Institute (AU)
- MRC Epidemiology Unit (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-26
- DOI
- https://doi.org/10.1038/s41467-026-74866-4
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Versus Arthritis
- Addenbrooke's Charitable Trust, Cambridge University Hospitals