Germinal centers (GCs) are a complex and important aspect of humoral immunity. How GCs 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 human immunodeficiency virus envelope surface 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 BGCcells. Early homologous boosting avoids prohibitive antibody titers and utilizes off-target antibodies to maximize the BGCresponse. Heterologous rapid boosting shifts affinity maturation towards the new antigen. The 'refueled' GCs are sustained, developing large affinity gains and evolving rapidly to bind wildtype HIV Env trimer within 56 days, even when using as few as two distinct antigens. These findings provide insights into GC biology and translatable paths to leveraging accelerated GC function.
