Widespread impact of immunoglobulin V-gene allelic polymorphisms on antibody reactivity

The ability of the human immune system to generate antibodies to any given antigen can be strongly influenced by immunoglobulin V-gene allelic polymorphisms. However, previous studies have provided only limited examples. Therefore, the prevalence of this phenomenon has been unclear. By analyzing >1,000 publicly available antibody-antigen structures, we show that many V-gene allelic polymorphisms in antibody paratopes are determinants for antibody binding activity. Biolayer interferometry experiments further demonstrate that paratope allelic polymorphisms on both heavy and light chains often abolish antibody binding. We also illustrate the importance of minor V-gene allelic polymorphisms with low frequency in several broadly neutralizing antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus. Overall, this study not only highlights the pervasive impact of V-gene allelic polymorphisms on antibody binding but also provides mechanistic insights into the variability of antibody repertoires across individuals, which in turn have important implications for vaccine development and antibody discovery. [Display omitted] •Analysis of V-gene allelic polymorphisms in 1,048 antibody-antigen complex structures•Many antibodies contain allelic polymorphisms predicted to disrupt binding•These include antibodies with different V genes and to different pathogens•Some broadly neutralizing antibodies depend on minor V-gene allelic polymorphisms By analyzing >1,000 publicly available antibody-antigen complex structures, Yuan et al. demonstrate that antibody binding activity is often influenced by V-gene allelic polymorphisms. This result provides mechanistic insights into the variability of antibody repertoires across individuals, which in turn have important implications for vaccine development and antibody discovery.