Vaccination is a concept that can be broadly applied to the prevention and treatment of human diseases, including but not limited to infectious diseases, cancer and neurodegenerative diseases. The ideal vaccines should elicit potent, long-lasting and broadly neutralizing antibody (Ab) response. Long-term humoral immunity is established by long-lived plasma cells (LLPCs) and memory B cells (MBCs). Once B cells acquire antigen (Ag) and receive help from cognate helper T cells, they proliferate and differentiate into short-lived plasmablasts (PB), MBCs, or Germinal Center (GC) B cells [1, 2]. Entry into the GCs is the first critical step for B cell selection and differentiation into class-switched MBCs and LLPCs [1, 3-5]. However, recruitment of epitope-specific B cells that are capable of eliciting broadly neutralizing Abs into GCs is a low-probability event that is limited by multiple processes. The low frequency of the initial encounter between antigen and the epitope-specific B cells, the accessibility of the neutralizing epitope on the Ag, preexisting Abs and competition with other Ag-specific B cells without neutralizing potential all contribute to this low probability [6-9]. In fact, poor recruitment of the subdominant B cell clones with broadly neutralizing potential is believed to be one of the major limiting events for generating robust broadly neutralizing antibody responses against HIV or Influenza virus [10, 11]. The specific aim of this application is to test a novel idea that ex vivo guidance of germline B cells can efficiently yield clonal B cells that are capable of producing potent neutralizing antibodies, the precursor cells that are required for long-term protective immunity. If successful, such procedures can be useful for generation of highly targeted, specific and yet very long-lived Ab responses against pathogens or disease targets, which offer a therapy for diseases that have been challenging through conventional vaccination.
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