TEaR-flu · Tfh determinants for effective responses to influenza vaccination in older individuals

Seasonal influenza causes significant morbidity and mortality each year, especially among older adults. This is due to reduced vaccine efficacy in this group. Indeed, despite vaccination efforts, many individuals in this age range remain unprotected, highlighting the urgent need to identify factors that influence effective immune responses. This project, TEaR-flu, focuses on antigen-specific T follicular helper (Tfh) cells, the specialised T cell subset that provides help to B cells, to uncover molecular and cellular features that differentiate older individuals who mount strong (high responders, HR) from those who mount weak (low responders, LR) responses to influenza vaccination.Leveraging a large clinical cohort (~300 older individuals) that will be collected before the start of this proposal, I will stratify participants based on serological responses and perform single-cell transcriptomics and TCR repertoire sequencing on influenza-specific T cells from 40 selected HR and LR individuals. Using computational analyses, I will then identify transcriptional programs and TCR motifs that differ between HR and LR and, consequently, are linked to vaccine immunogenicity. Findings will be validated in silico, using publicly available datasets, and functionally tested in human tonsil organoids, providing mechanistic insights into the drivers of vaccine responsiveness. Finally, a model for vaccine immunogenicity will be developed, considering not only the transcriptional differences but also clinical data from the cohort volunteers.All together, TEaR-flu is a highly interdisciplinary proposal that combines immunology, single-cell genomics, computational biology, and organoid models to generate predictive models of vaccine immunogenicity and identify potential targets for improved vaccine efficacy and new vaccine strategies.