Rapid boosting increases germinal center responses to sequential vaccines

Germinal centers (GCs) are a complex and important aspect of humoral immunity. How germinal centers deal with changing antigens remains unclear, yet this biology could be central to next-generation vaccine strategies such as germline-targeting. Here we demonstrate, in a mouse model with protein immunogens, that rapid delivery of homologous or heterologous boosts results in highly positive outcomes. Rapid reimmunization expands on-target GC B cell (BGC) populations, which emerge almost exclusively from existing BGC cells. Early homologous boosting avoids prohibitive antibody titers and utilizes off-target antibodies to maximize the BGC response, with 24-fold increases in on-target VRC01gHL cell numbers. Heterologous rapid boosting shifts affinity maturation towards the new antigen. The ‘refueled’ GCs are sustained, developing large affinity gains, and rapidly evolving to bind wild-type HIV trimer within 56 days, even when using as few as two distinct antigens. These findings provide new insights into GC biology and translatable paths to leveraging accelerated GC functions.