VaccinNate · From adjuvants-based vaccines for inflammatory diseases to refined vaccine adjuvants

T cell–driven inflammatory diseases like multiple sclerosis (MS), are a leading cause of global mortality. This project seeks to harness recent advances in the anti-inflammatory mechanisms of innate immune memory (IIM) and my expertise in vaccinology to develop innovative strategies against these conditions. Innate immune cells can be reprogrammed through trained immunity (TI), enabling them to mount stronger and sustained responses upon re-stimulation. In vaccinology, adjuvants or adjuvant components (ACs) like β-glucan can trigger such effects. Importantly, myeloid cells such as macrophages can also adopt tolerogenic forms of IIM, known as Trained Tolerogenic Immunity (TTI). These observations suggest that strongest immunosuppressive myeloid-derived suppressor cells (MDSCs) could likewise be reprogrammed to develop TTI. Harnessing this phenotype through ACs presents a novel approach to adjuvant-based vaccine design. Therefore, building on the premise that ACs such as β-glucan induce robust TI in different innate cells, I hypothesize that selected ACs, or TLR agonists known to promote anti-inflammatory responses, can also elicit specific TTI in MDSCs, which could be leveraged for vaccine development against T cell–driven inflammatory diseases such as MS. To test this, I will characterise the functional, epigenetic and metabolic mechanisms of TTI induced by ACs in MDSCs, building on initial macrophage studies, for subsequently assessing their durability and immunosuppressive capacity using antigen-specific assays to, finally, evaluate their protective potential in a mouse model of MS. By identifying ACs capable of inducing TTI, this project aims to establish proof-of-concept for novel vaccines that optimise immune responses through precise balance of TI and TTI. These advances will not only contribute to improved vaccine strategies against inflammatory and infectious diseases but also serve as the foundation for my long-term career development in vaccinology.