Rybniker, Jan | Theobald, Sebastian - B 10

Durable cell-mediated immune responses require efficient innate immune signaling and the release of pro-inflammatory cytokines. How precisely currently applied SARS-CoV-2 vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Data from our recent publications show that both SARS-CoV-2 infection and vaccination prime human macrophages for activation of the NLRP3 inflammasome. Furthermore, we identified spleen tyrosine kinase (SYK) as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein specific T cell responses. In addition, vaccination induced macrophage priming can be enhanced with repetitive antigen exposure, providing a rationale for prime-boost concepts to augment immune signaling and crosstalk. Our study aims to further improve our understanding of the exact role and impact of innate immune cell signaling in shaping the immune response following vaccination. In a comprehensive approach, we will exploit ex vivo and in vivo models to activate inflammasomes with different adjuvants and vaccine constructs targeting toll-like receptors (TLR) and C-type lectins. Using autologous co-culture experiments with cell subsets of the adaptive immune system, we will systematically determine the impact of innate immune signaling on the quantity and quality of long-lived anti-viral immunity. These data will be of high relevance for future vaccine constructs, choice of adjuvants and vaccination regimen targeting SARS-CoV-2 and other viral pathogens.