Clonotype specificity distinguishes epitope-tailored and permissive somatic hypermutation

Authors

Rao, V. N., Bonnettaz, B., Civljak, A., Abbad, A., Krammer, F., Coelho, C. H., Bajic, G.

Abstract

Identifying antibody features that reliably encode epitope specificity poses a major barrier towards modeling antigen-antibody interactions. Affinity maturation offers a unique opportunity to probe the molecular basis of antigen-antibody interactions by revealing how individual somatic hypermutations (SHM) refine antibody binding. Using SARS-CoV-2 spike-specific germinal center B-cell repertoires, we show that antibodies harboring multiple SHMs that are restricted to their respective clonotypes (clonotype-restricted SHMs) preferentially recognize cryptic epitopes. We structurally characterized three such antibodies: two recognized a cryptic epitope on the receptor-binding domain whereas a third bound an N-terminal domain epitope that is almost entirely occluded in prefusion spike. In contrast, SHMs shared across multiple clonotypes using the same V gene recur across antibodies targeting diverse antigens but generally fail to enhance affinity when introduced into diverse antibody backgrounds. Together, these findings define a spectrum of SHM behavior, distinguishing epitope-tailored mutations from broadly recurrent but largely permissive substitutions.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 17 Oct 2026.

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