Harnessing Biomaterials to Amplify Immunity in Aged Mice through T Memory Stem Cells.

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Public Summary:
The effectiveness of vaccines in eliciting a long-lasting immune defense is closely linked to their capacity to foster enduring T cell immunity. However, this ability often diminishes with age. Research indicates that the most durable protection is provided by T memory stem cells (TMSCs), which offer high levels of expandability and rapid activation upon exposure to pathogens. To harness this potential, we have developed a novel artificial antigen presenting cell (aAPC) platform. This platform, optimized for size, stiffness, and activation signals, is designed to induce TMSCs in both human and mouse CD8+ T cells in vitro. Our innovative vaccine booster, Vax-T, incorporates a prolonged release mechanism for small molecules that inhibit glycogen synthase kinase-3β, alongside targeted antigens. Utilizing the SARS-CoV-2 antigen as a test model, our studies demonstrate that a single Vax-T injection can prompt strong, durable antigen-specific CD8+ TMSC responses in both young and older mice, with humoral responses that are comparable to, if not better than, those elicited by conventional soluble vaccines. This Vax-T strategy holds promise for enhancing long-term immunity against infectious diseases, cancer, and other chronic ailments.
Scientific Abstract:
The durability of a protective immune response generated by a vaccine depends on its ability to induce long-term T cell immunity, which tends to decline in aging populations. The longest protection appears to arise from T memory stem cells (TMSCs) that confer high expandability and effector functions when challenged. Here we engineered artificial antigen presenting cells (aAPC) with optimized size, stiffness and activation signals to induce human and mouse CD8(+) TMSCs in vitro. This platform was optimized as a vaccine booster of TMSCs (Vax-T) with prolonged release of small-molecule blockade of the glycogen synthase kinase-3beta together with target antigens. By using SARS-CoV-2 antigen as a model, we show that a single injection of Vax-T induces durable antigen-specific CD8(+) TMSCs in young and aged mice, and generates humoral responses at a level stronger than or similar to soluble vaccines. This Vax-T approach can boost long-term immunity to fight infectious diseases, cancer, and other diseases.