Determinants of B cell selection in germinal centers Implications for antibody responses and vaccine design

Viruses such as HIV-1, Hepatitis C virus (HCV), and SARS-CoV-2 pose major global health challenges due to their rapid evolution. To develop effective vaccines, it is essential to understand the principles that govern how the immune system selects and refines B cells capable of producing broadly neutralizing antibodies. This thesis explores the determinants of B cell selection within germinal centers, identifying the molecular and cellular factors required for successful antibody responses.
The first part of this thesis examines how antigen properties and the availability of B cell precursors shape the early immune response. We demonstrate that the abundance of specific B cells can significantly influence their initial recruitment and the resulting antibody response. In contrast, we show that rare B cell precursors, such as those capable of broad neutralization against HCV, require highly optimized vaccine designs for successful activation. We also investigate the role of binding dynamics, suggesting that the speed and stability of the interaction between B cells and antigens are critical factors during immune selection.
In the second part, we develop strategies to enhance and model these selection processes. We show that molecular engineering, through C3d fusion, lowers the activation threshold for B cells and prolongs the presence of vaccines in lymphoid tissues. Furthermore, we introduce a novel three-dimensional human tonsil organoid model to study these processes in a human context. Collectively, this thesis provides a framework for the rational design of next generation vaccines, highlighting how targeted engineering can guide the immune system toward durable protection.