Abstract
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. Sequence-based repertoire analysis has so far offered little evidence for this phenomenon. 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. 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. Here, we search for evidence of geometric similarity/convergence across human antibody repertoires. We first structurally profile naïve ('baseline') antibody diversity using snapshots from 41 unrelated individuals, predicting all modellable distinct structures within each repertoire. This analysis uncovers a high (much greater than random) degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples ('Public Baseline' 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. 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). 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.
Highlights
A key component of the human immune system is the antibody/B-cell receptor (BCR) repertoire, a diverse array of immunoglobulins tasked with identifying pathogens and initiating the adaptive immune response
Sequencing antibody repertoires before and during an immune response can reveal how different people respond to the same antigenic challenge, and can both improve our understanding of immunology and inform future vaccine or therapeutic design [3,4,5]
We use data from a longitudinal immunoglobulin gene sequencing (Ig-seq) flu vaccination study by Gupta et al [5] to measure three individuals’ structural responses to exposure to a common antigen. Both translated Ig-seq datasets were downloaded from the Observed Antibody Space (OAS) database [9]
Summary
A key component of the human immune system is the antibody/B-cell receptor (BCR) repertoire, a diverse array of immunoglobulins tasked with identifying pathogens and initiating the adaptive immune response. Broad pathogenic recognition is achieved through enormous variable domain sequence diversity, with an estimated 1010 unique heavy variable domains (VH) circulating at any one time from a theoretical set of 1012 (or 1016-1018 full antibodies if light variable domain (VL) combinations are considered [1]). Sequencing antibody repertoires before and during an immune response (e.g. vaccination) can reveal how different people respond to the same antigenic challenge, and can both improve our understanding of immunology and inform future vaccine or therapeutic design [3,4,5]. Comparing the repertoires of healthy individuals against immunosuppressed (e.g. HIV) patients may make known the origins of increased disease susceptibility [6,7,8]
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