Mapping the SARS-CoV-2 Epitope Landscape and Uncovering the Origins of Immunodominant Public Epitopes

Abstract

The adaptive immune system relies on an extremely diverse antibody repertoire to mount responses to pathogens encountered over the course of a lifetime. Understanding the precise targets, or epitopes, recognized by the antibody repertoire is critical for improving diagnostics, therapeutics, and vaccines, and understanding fundamental aspects of antigenicity. In this dissertation, we use high-throughput antibody profiling to map the epitope landscape of SARS-CoV- 2 and to study the mechanisms that lead to shared epitope recognition across individuals. In the first part of this dissertation, we performed deep serological profiling of 232 COVID-19 patients and 190 pre-COVID-19 era controls and revealed over 800 epitopes in the SARS-CoV-2 proteome, including 10 epitopes likely recognized by neutralizing antibodies. Pre-existing antibodies in controls recognized SARS-CoV-2 ORF1, while only COVID-19 patients primarily recognized spike and nucleoprotein. A machine learning model trained on our data predicted SARS-CoV-2 exposure history with 99% sensitivity and 98% specificity; a rapid Luminex-based diagnostic was developed from the most discriminatory SARS-CoV-2 peptides. Individuals with more severe COVID-19 exhibited stronger and broader SARS-CoV-2 responses, weaker antibody responses to prior infections, and higher incidence of CMV and HSV-1, possibly influenced by demographic covariates. In the second part of this dissertation, we studied the striking observation that despite the vast diversity of the antibody repertoire, infected individuals often mount antibody responses to precisely the same epitopes within antigens. The immunological mechanisms underpinning this phenomenon remained unknown. By mapping 376 immunodominant “public epitopes” at high resolution and characterizing several of their cognate antibodies, we conclude that germline-encoded sequences in antibodies drive recurrent recognition. Systematic analysis of antibody–antigen structures uncovered 18 human and 21 partially overlapping mouse germline-encoded amino acid-binding (GRAB) motifs within heavy and light V gene segments that, in case studies, are critical for public epitope recognition. GRAB motifs represent a fundamental component of the immune system’s architecture that ensures antibody recognition of pathogens and promotes species-specific reproducible responses that can exert selective pressure on pathogens.