Broadly neutralizing antibodies
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 identified strategies to promote the generation of broadly neutralizing antibodies in natural germinal centre (GC) reactions. We identified a feedback loop of GC derived antibodies onto the GC reaction itself . The simulations predict that antibodies and memory B cells from previous GC reactions promote GCs to focus on new epitopes. Antibodies specific for immunodominant epitopes control their 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 result infers a natural selection mechanism for GC-B cells to concentrate on new epitopes rather than refine affinity to already covered epitopes. In addition, the simulations suggest that the same shift of GC reactions to new epitopes can be induced by injection of antibodies against immunodominant epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols.
The representation of antigen and antibodies in germinal centre simulations involves different degrees of abstraction, ranging from the phenomenological shape space concept that maps affinity to an arbitrary 4-dimensional space up to a full simulation of protein structure and folding. The latter cannot be used for computer simulations of GC reactions, while the former may neglect important details of antibody-antigen interactions. We thus developed a structural representation based on amino-acid sequences but projected onto a rigid lattice. The reduction of the degrees of freedom in space together with innovative algorithms of calculating protein interactions retains key properties of the interaction while making the millions of interactions occurring during a GC reaction computationally feasible.
Sebastian Binder, Philippe Robert (former member), Andrea Marschall (former member)
Carlos Guzmán, Thomas Pietschmann
Gabriel Victora (Rockefeller University), Carola Vinuesa (Australian National University), Kai Toellner (University of Birmingham)
Meyer-Hermann M. Injection of antibodies against immunodominant epitopes tunes germinal centres to generate broadly neutralizing antibodies. BioRxiv 2018.
Robert PA, Marschall A, Meyer-Hermann M. Induction of broadly neutralizing antibodies in germinal center simulations. Curr Opin Biotechnol 2018 Jun; 51: 137-145
Zhang* Y, Meyer-Hermann* M, George L, Khan M, Figge MT, Falciani F, Kosco-Vilbois M, Toellner K-M. Germinal centre B cells govern their own fate via antibody feedback. J Exp Med 210 (2013) 457-464. [*shared first author]
Human Frontier Science Program
- System-Immunologie- Prof. Dr. Michael Meyer-Hermann
Geldgeber / Förderer