A Coarse-Grained Model of Affinity Maturation Indicates the Importance of B-Cell Receptor Avidity in Epitope Subdominance

Abstract

The elicitation of broadly neutralizing antibodies (bnAbs) is a major goal in the design of vaccines against rapidly-mutating viruses. In the case of influenza, many bnAbs that target conserved epitopes on the stem of the hemagglutinin protein (HA) have been discovered. However, these antibodies are rare, are not boosted well upon reinfection, and often have low neutralization potency, compared to strain-specific antibodies directed to the HA head. Different hypotheses have been proposed to explain this phenomenon. We use a coarse-grained computational model of the germinal center reaction to investigate how B-cell receptor binding valency affects the growth and affinity maturation of competing B-cells. We find that receptors that are unable to bind antigen bivalently, and also those that do not bind antigen cooperatively, have significantly slower rates of growth, memory B-cell production, and, under certain conditions, rates of affinity maturation. The corresponding B-cells are predicted to be outcompeted by B-cells that bind bivalently and cooperatively. We use the model to explore strategies for a universal influenza vaccine, e.g., how to boost the concentrations of the slower growing cross-reactive antibodies directed to the stem. The results suggest that, upon natural reinfections subsequent to vaccination, the protectiveness of such vaccines would erode, possibly requiring regular boosts. Collectively, our results strongly support the importance of bivalent antibody binding in immunodominance, and suggest guidelines for developing a universal influenza vaccine.

Antibody accessibility determines location of spike surface mutations in SARS-CoV-2 variants

“…Our findings here and earlier [18] complement a recent computational study that identifies the stalk domain as immunosubdominant due to the steric inability to recruit bivalently binding B-cell receptors [17]. Hindered accessibility of the conserved stalk covered by the glycan shield interferes with the development of broadly immunizing stalk antibodies.…”

“…Recently, a structural investigation found that RBD-ACE2 binding affinity of the Omicron variant is similar to the Delta variant, and that Omicron spike displays significant antibody evasion [14], in line with earlier studies [1,2,15,16]. Ovchinnikov & Karplus used a kinetic model of B-cell affinity maturation to determine the importance of bivalent versus monovalent antibody-antigen interactions in vaccination and infection [17].…”

“…The kinetic model of antigen/B-cell binding affinities developed in ref. [17] could be combined with our surface accessibility quantification methods to rationalize why antibodies appear to target only relatively few SARS-CoV-2 epitopes after natural infection.…”

Moving the needle: Employing deep reinforcement learning to push the boundaries of coarse-grained vaccine models

“…Two schools of thought have since arisen to overcome the aforementioned challenges presented by hm-IDPs: universal vaccines and personalized medicine. Progress towards universal vaccines continues to advance every year, with increasingly informed design rules on how to elicit antibodies that target conserved aspects of viral machinery ( 7 – 14 ). Much of this newfound knowledge has come from studying crystal structures of broadly neutralizing antibodies (bnAbs)—which neutralize diverse viral strains by targeting conserved regions on hm-IDP surface proteins—and attempting to reconstruct the evolutionary pathways of these bnAbs ( 15 – 26 ).…”