Structural epitope profiling identifies antibodies associated with critical COVID-19 and long COVID

Abstract

Antibodies can have beneficial, neutral, or harmful effects so resolving an antibody repertoire to its target epitopes may explain heterogeneity in susceptibility to infectious disease. However, the three-dimensional nature of antibody-epitope interactions limits discovery of important targets. We describe and experimentally validated a computational method and synthetic biology pipeline for identifying structurally stable and functionally important epitopes from the SARS-CoV-2 proteome. We identify patterns of antibodies associated with immunopathology, including a non-isotype switching IgM response to a membrane protein epitope strongly associated with severe COVID-19 (adjusted OR 72.14, 95% CI: 9.71 - 1300.15). We suggest the mechanism is T independent B cell activation and identify persistence (> 1 year) of this response in individuals with long COVID particularly affected by fatigue and depression. These findings may have implications for the ongoing medical and public health response to the pandemic.