Ghada Alsaleh, Mohammad Ali, Amir Hossein Kayvanjoo, Feng Liu, Tanaïs Moreau, Sagida Bibi, Lin Luo, Melissa Govender, Miles Carroll, Sebastian J. Hofer, Eisenberg Tobias, Christoph Magnes, Loren Kell, Christopher Chung, Yu Deng, Aneesha Bhandari, Lucy Garner, Thomas Conrad, Liye Chen, Barbara Kronsteiner, Susie Dunachie, O. Brad Spiller, Teresa Lambe, Paul Klenerman, Lucy C. Jones, A. Katharina Simon
Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders. Single-cell RNA-seq after treatment revealed increased expression of TFEB targets and autophagy-related genes in B cells, in line with elevated autophagic flux. These findings suggest that targeting immune cell senescence with Spermidine may improve vaccine responsiveness in older adults and highlight immune-senescence markers as potential predictors of vaccine failure in ageing populations.