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.