Initiation of neutralizing antibody response probed using synthetic virus-like structures

Virus-like particles are known to induce long-term humoral immunity, but the mechanisms involved have been less understood. Model antigens (Ags) are indispensable for understanding B-cell responses to immunization but immunogens that facilitate the dissection of viral features on B-cell responses are limited. Here we describe a system of liposome-based virus-like structures that allowed us to independently vary the contributions of fundamental viral attributes to the initiation and durability of antibody (Ab) responses, and to do so without additional adjuvants. We show that Ag display on a virion-sized liposome can serve as a stand-alone danger signal to initiate class-switched Ab response in the absence of either T cell help or Toll-like receptors but requires CD19. Introduction of internal nucleic acids lowers the epitope density required to elicit a response and transforms these structures into highly potent immunogens that are independent of CD19 engagement and rival well-established bacteriophage virus-like particles in the resulting Ag-specific IgG titers. As early as day 5 after injection, structures decorated with even a few molecules of surface Ag at doses as low as 100 ng can induce all IgG subclasses of Ab characterized by an off rate of ~0.0005 s-1. A single injection of these structures at low Ag dose led to life-long neutralizing Ab production in BALB/c mice. Thus, Ag valency and intrinsic sensing of viral nucleic acids coordinate quantitatively to mediate long-lasting antiviral IgG in a primary immune response.