Injection of Antibodies against Immunodominant Epitopes Tunes Germinal Centers to Generate Broadly Neutralizing Antibodies

Abstract

Summary: Broadly neutralizing antibodies are crucial for the control of many life-threatening viral infections like HIV, influenza, or hepatitis. Their induction is a prime goal in vaccine research. Using computer simulations, we identify strategies to promote the generation of broadly neutralizing antibodies in natural germinal center (GC) reactions. The simulations predict a feedback loop based on antibodies and memory B cells from previous GC reactions that promotes GCs to focus on new epitopes. Memory-derived or injected antibodies specific for immunodominant epitopes control epitope availability, suppress the participation of memory B cells in the GC reaction, and allow for the evolution of other B cells to affinity mature for hidden or rare epitopes. This defines a natural selection mechanism for GC B cells to concentrate on new epitopes rather than refine affinity to already-covered epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols. : Antibodies specific for low-accessible pathogen epitopes are crucial for the control of life-threatening infections. Meyer-Hermann shows with computer simulations that memory-derived antibodies mask immunodominant epitopes, suppress participation of memory B cells in germinal centers, and promote affinity maturation to less-accessible epitopes. Vaccination with antibodies can induce the same effect. Keywords: germinal center, broadly neutralizing antibodies, simulation, mathematical modeling, targeting hidden epitopes, memory B cells, original antigenic sin, HIV, hepatitis, influenza