Selection for immune evasion in SARS-CoV-2 revealed by high-resolution epitope mapping and sequence analysis

Here, we exploit a deep serological profiling strategy coupled with an integrated, computational framework for the analysis of SARS-CoV-2 humoral immune responses. Applying a high-density peptide array (HDPA) spanning the entire proteomes of SARS-CoV-2 and endemic human coronaviruses allowed identification of B cell epitopes and relate them to their evolutionary and structural properties. We identify hotspots of pre-existing immunity and identify cross-reactive epitopes that contribute to increasing the overall humoral immune response to SARS-CoV-2. Using a public dataset of over 38,000 viral genomes from the early phase of the pandemic, capturing both inter- and within-host genetic viral diversity, we determined the evolutionary profile of epitopes and the differences across proteins, waves, and SARS-CoV-2 variants. Lastly, we show that mutations in spike and nucleocapsid epitopes are under stronger selection between than within patients, suggesting that most of the selective pressure for immune evasion occurs upon transmission between hosts. [Display omitted] •High-density peptide arrays provide high resolution antibody epitope maps•Seasonal coronavirus cross-reactivity drives antibody responses to SARS-CoV-2 epitopes•Point mutations and natural selection in epitopes occur at higher rates upon transmission Immunology; Virology; Structural biology; Computational bioinformatics