However, existing methods of antibody repertoire comparison (which focus on genetic relatedness) only predict a tiny number of functionally equivalent antibodies in the resting state repertoires of different individuals. It is commonly thought that most people’s adaptive immune systems can recognise the same endemic pathogens, many of which invade our bodies daily. We show that Antibody Model Libraries derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes (‘Public Response’ structures). Our approach is the first computational method to find levels of BCR commonality commensurate with epitope immunodominance and could therefore be harnessed to find more genetically distant antibodies with same-epitope complementarity. For instance, around 3% of distinct structures are common to the ten most diverse individual samples (‘Public Baseline’ structures). This analysis uncovers a high (much greater than random) degree of structural commonality. We first structurally profile naïve (‘baseline’) antibody diversity using snapshots from 41 unrelated individuals, predicting all modellable distinct structures within each repertoire. Here, we search for evidence of geometric similarity/convergence across human antibody repertoires. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. For example, a recent study estimated the number of shared (‘public’) antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. Sequence-based repertoire analysis has so far offered little evidence for this phenomenon. The naïve antibody/B-cell receptor (BCR) repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger an effective antibody response to immunodominant epitopes.
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