Single-cell Transcriptomics Reveal Signatures of Altered B cell Response 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 naïve nursing home residents with varying humoral responses following BNT162b2 vaccination and validated via flow cytometry. Responders (>4500 AU/mL anti-spike titers) showed enrichment for naïve B cell (IGHD, BACH2, CD22) and naïve CD4 T cell and early Tfh-related genes (CCR7, TCF7, LEF1, IL6ST, TGFBR2). Non-responders (<20 AU/mL) displayed elevated markers of T cell senescence (KLRG1, CCL4, CCL5, 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 non-responders. Despite reduced B cell frequency, non-responders upregulated plasma B cell genes (PRDM1, XPB1, IRF4), suggesting dysregulated B cell differentiation. Our findings point to impaired lymphocyte responses and increased immunosenescence in non-responders, emphasizing the need for enhanced vaccine strategies in aging populations.