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

Jeeda Ismail; Banumathi Tamilselvan; Michael Rubsamen; Jillian Petrosky; Brian Richardson; Leah Zagore; Oladayo A Oyebanji; Debbie Keresztesy; Michael Payne; Dennis Wilk; Lenore Carias; Htin Aung; Kerri St Denis; Maegan Sheehan; Brigid M Wilson; Alejandro B Balazs; Stefan Gravenstein; Christopher L King; David H Canaday; Cheryl M Cameron; Mark J Cameron

doi:10.1016/j.isci.2026.115730

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

iScience. 2026 Apr 16;29(5):115730. doi: 10.1016/j.isci.2026.115730. eCollection 2026 May 15.

Authors

Jeeda Ismail¹, Banumathi Tamilselvan¹, Michael Rubsamen¹, Jillian Petrosky¹, Brian Richardson¹, Leah Zagore¹, Oladayo A Oyebanji², Debbie Keresztesy², Michael Payne², Dennis Wilk², Lenore Carias², Htin Aung², Kerri St Denis³, Maegan Sheehan³, Brigid M Wilson⁴, Alejandro B Balazs³, Stefan Gravenstein^{5

6

7}, Christopher L King^{2

4}, David H Canaday^{2

4}, Cheryl M Cameron¹, Mark J Cameron¹

Affiliations

¹ Systems Biology and Bioinformatics Program, Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
² Case Western Reserve University School of Medicine, Cleveland, OH, USA.
³ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
⁴ Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA.
⁵ Warren Alpert Medical School, Brown University, Providence, RI, USA.
⁶ Department of Health Services, Policy and Practice, School of Public Health, Brown University, Providence, RI, USA.
⁷ Center of Innovation in Long-Term Services and Supports, Veterans Administration (VA) Medical Center, Providence, RI, USA.

Abstract

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.

Keywords: Immunology; Molecular physiology; Transcriptomics.