Th10 and activated Tfh1 expansion correlate with strong, while Tfr expansion correlate with poor responses to Fluzone High Dose in older adults 2259592

Abstract

Abstract Introduction Seasonal influenza poses a significant health risk to older adults (>65 years), who exhibit reduced vaccine effectiveness compared to younger populations. Although enhanced influenza vaccines are commonly used, their efficacy remains suboptimal. Moreover, the cellular and molecular drivers of poor influenza vaccine responses remain unclear, limiting strategies to improve vaccine-induced immunity in aging. Methods To study this, we vaccinated older adults (n = 62) with Fluzone High-Dose during the 2022-2023 season and observed heterogenous antibody responses at day 35 post-vaccination. Based on antibody titers, we selected the top 10 responders and bottom 10 non-responders for in-depth T cell profiling. Results Using 5’ single-cell RNA-seq of longitudinal PBMCs, we identified a significant expansion of Th10 cells at day 7 in responders, a population shown to promote B cell help via the extrafollicular pathway. This expansion correlated positively with increased frequencies of total IgG+ and H1N1-specific plasmablasts. Notably, responders also exhibited an expansion of influenza-specific Th10 cells as inferred from paired single-cell TCR-seq data. Parallel CITE-seq analyses of sorted peripheral T follicular helper cells (Tfh) revealed that responders have higher pre-vaccination frequencies of Tfh1 cells and increased day 7 frequencies of activated Tfh1 (ICOS+, CD38+) cells, which showed higher expression of the CD38 protein. In contrast, non-responders showed an expansion of regulatory Tfr (FOXP3+ Tfh) cells at day 7, suggesting a potential suppression effect on humoral immunity. Conclusion Together, these data highlight Th10 and Tfh1 cells as positive immunological correlates of robust antibody responses to high-dose influenza vaccine in older adults, while Tfr expansion emerges as a negative correlate. These findings provide mechanistic insight into the T cell determinants of vaccine responsiveness in aging and may inform future strategies to enhance immunogenicity among older populations. Funding Source NIAID U01 AI165452 Topic Categories Computational and Systems Immunology (COMP)