Single-cell transcriptomics reveal altered B cell responses and T cell senescence in geriatric non-responders to COVID-19 mRNA vaccination.

The immune response to COVID-19 vaccines is diminished in older individuals. To understand the underlying immunobiology, we analyzed single-cell RNA-seq data from PBMCs of SARS-CoV-2 naive nursing home residents with varying humoral responses following BNT162b2 vaccination and validated via flow cytometry. Responders (R) (>4500 AU/mL anti-spike titers) showed enrichment for naive B cell (IGHD, BACH2, CD22) and naive CD4 T cell and early T follicular helper (Tfh)-related genes (CCR7, TCF7, LEF1, IL6ST, and TGFBR2). Non-responders (NR) (<20 AU/mL) displayed elevated markers of T cell senescence (KLRG1, CCL4, CCL5, and IL32), immune exhaustion (PD-1), and inflammation (TNF-α, IFN-γ). Flow cytometry revealed reduced CD4 T and B cell frequencies but higher CD8 T and NK cells in NR. Despite reduced B cell frequency, NR upregulated plasma B cell genes (PRDM1, XPB1, IRF4), suggesting dysregulated B cell differentiation. Our findings point to impaired lymphocyte responses and increased immunosenescence in NR, emphasizing the need for enhanced vaccine strategies in aging populations.