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 epitope-binding antibodies associated with immunopathology, including a non-isotype switching IgM response to a membrane protein epitope which is the strongest single immunological feature associated with severe COVID-19 to date (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 highlight a previously unrecognized coronavirus host:pathogen interaction which is potentially an upstream event in severe immunopathology and this may have implications for the ongoing medical and public health response to the pandemic. The membrane protein epitope is a promising vaccine and monoclonal antibody target which may complement anti-spike vaccination or monoclonal antibody therapies broadening immunological protection. One-Sentence SummaryUsing a novel B cell epitope discovery method we have identified antibody signatures strongly associated with SARS-CoV-2 immunopathology and suggest the membrane protein is a pathological T independent antigen.
