The Role Of Antibody Feedback In Anti-Viral Humoral Immunity (360G-Wellcome-331728_Z_25_Z)

Everyone experiences multiple infections and vaccine exposures throughout life, despite this, viral disease remains a huge global health problem. Here we will take our understanding of how prior exposure controls humoral responses to a completely new level. We hypothesise antibodies “feedback” by competing with pre-existing memory B cells for antigen and so limit immune imprinting. This feedback leads to increased epitope coverage and clonal diversity because only B cells targeting new epitopes can steal the antigen back and participate in germinal centres. This project will discover the rules of this system to hijack and programme superior vaccine responses. We plan three transformative immunological and computational aims: (1) Determine how antibody feedback modulates viral imprinting in humans (2) Define how antibody feedback works mechanistically in the germinal centre (3) Test whether antibody feedback can be manipulated to tailor the breadth and specificity of antibody responses after immunisation. We have a unique combination of computational and 3D organoid models, human pre- and post-vaccination samples and an established experimental immunisation model to facilitate these aims. This programme promises to redefine our understanding of how antibody responses are regulated and to provide the most complete understanding of how to tailor vaccine outcomes to date.