Private Antibody Repertoires Are Public

Arora, Rohit; Arnaout, Ramy

When faced with a given pathogen, the antibody response generally functions similarly across different people,1–4 but the source of this similarity has been unclear. One hypothesis was that people share a high proportion of the same VDJ-recombined antibody genes, but this has been disproven.5,6 An alternative is that people share a high proportion of functionally similar antibodies,7,8 but testing this hypothesis requires a method for measuring functional similarity that scales to the millions of antibodies per repertoire and across multiple repertoires, which is impossible experimentally. We recently described a framework for doing so computationally,9 which revealed that repertoires consist of loose overlapping functional classes of antibodies with similar antigen-binding capacities;10–12 this framework allowed us to estimate a repertoire’s antigen-binding capacity, τ, for the ideal target of any given antibody. Here, we show that this framework supports the second hypothesis, and provide the first comprehensive demonstration of overwhelming functional overlap between repertoires from 20 different individuals directly from sequence, without need of binding studies. Overlap is highest among the young and falls with age, due to the selective loss of antibodies that represent a core set of shared or “public” antigen-binding capacities. We reveal considerable heterogeneity in antigen-binding capacities for antibodies against influenza, HIV, and SARS-CoV-2, and show that while some of these classes shrink with age, others persist across individuals. These discoveries change our understanding of repertoire diversity and have implications for vaccine and therapeutic-antibody development, especially for the aged.