TopBMemory · Antigenic and Topographical Imprinting of Human B Cell Memory and Its Reprogramming Potential

The novel COVID-19 vaccines have effectively reduced morbidity and mortality but unexpectedly failed to provide long-lasting sterilizing immunity. While specific serum antibody (Ab) titers were durable, local upper respiratory tract (URT) mucosal Ab responses were surprisingly short-lived. This shows both our lack of and need for a deeper understanding of URT mucosal immunity and its distinctions from systemic immunity. My proposal is designed to answer two key questions arising from this: How does the initial exposure site—mucosal or systemic—shape and imprint immune memory? And how is this imprinting reprogrammed by subsequent exposures via different exposure routes?In the TopBMemory project, I will: (1) delineate how the antigen (ag) nature and primary exposure site shape human memory B cell (MBC) subset heterogeneity and their imprinting. I will generate the first single-cell (sc) multiomic profiles of ag-specific (ag+) MBCs with context-specific imprints by a project-specific pipeline integrating transcriptomic, epigenomic, and phenotypic data. (2) Determine how alternative re-exposure sites reprogram existing imprints—overwrite or complement them—which will be the first demonstration of the potential for natural imprint reprogramming in MBC. (3) Test targeted reprogramming of MBC subsets within tonsil and nasal mucosa-derived organoid co-culture systems. My findings will significantly advance understanding of MBC ontogeny and plasticity, both in host protection and also immunopathologies, and inform the development of a new generation of vaccines and therapies.The groundbreaking nature of TopBMemory lies in its first large-scale contextualization of human ag+ MBC subset origins and functions, exploring their responses and adaptions to varying routes of ag re-exposure. This is complemented by the development of innovative toolkits for sc multiomics and MBC (re-)programming within advanced organoid systems, to explore and guide precise manipulation strategies.