Impaired B Cell and cTfh Immune Pathways Underlie Influenza Vaccine Hyporesponsiveness in Older, Frail, and Multimorbid Adults 2309992

Abstract Introduction Older adults face the highest rates of influenza-related hospitalization and death due to immunosenescence and diminished vaccine responsiveness. Despite the use of high-dose and adjuvanted flu vaccines, substantial variability persists. The biological features distinguishing robust (“Hyper”) from poor (“Hypo”) vaccine responders (HyperR and HypoR) remain unclear. By integrating B cell and circulating T follicular helper cell (cTfh) activation, and RNA-seq transcriptional analysis, we identified coordinated signatures underlying response heterogeneity between HyperR and HypoR cohorts. Methods Samples from 21 frail multimorbid nursing home residents receiving flu vaccine were analyzed across visits (D0, D28). Hemagglutinin inhibition assays (HAI) quantified ab response to define HypoR and HyperR cohorts. Differential expression and pathway analyses of RNAseq data were performed after mitogenic stimulation of purified cTfh and B-cells. Results Transcriptomic profiling showed enrichment of antigen presentation, germinal-center differentiation, and metabolic activation pathways in HyperR. A Custom Nakaya B-cell pathway showed markedly higher expression in HyperR and reduced expression in HypoR, with AICDA (somatic hypermutation enzyme) as the most highly differentially expressed gene. Additional B-cell genes associated with survival and differentiation (BCL2L10, TBX21, CD27) were increased in HyperR. cTfh cells from HyperR showed increased expression of helper and trafficking genes (IL21, CXCR5, CXCL13, CRTAM). In contrast, HypoR exhibited attenuated pathway activity, increased TIGIT (checkpoint receptor) expression, and weakened concordance between cellular and antibody responses. Conclusion HyperR to flu vaccination mount coordinated cellular and molecular responses, whereas HypoR show reduced activation and fragmented B-cell proliferation and plasmablast maturation signaling. Our findings highlight putative mechanisms to inform improvements in influenza protection in frail adults. Funding Source 1R01AI129709-01A1 Topic Categories Vaccines and Immunotherapy (VAC)