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

Abstract

AbstractAntibodies 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 novel computational method and synthetic biology pipeline for identifying epitopes that are structurally stable and functionally important and apply it to the SARS-CoV-2 proteome. We show patterns of epitope-binding antibodies associated with immunopathology, including a non-isotype switching IgM response to a Membrane protein epitope which is amongst the strongest immunological features associated with severe COVID-19 to date (adjusted OR 72.14, 95% CI: 9.71 – 1300.15). Consistent with a hypothesis that the mechanism driving the non-switching response was T independent B cell activation, we find that B cells secrete IgM and proliferate on exposure to virus-like particles lacking Spike. We also identified persistence (> 1 year) of this response in individuals with longCOVID particularly affected by fatigue and depression. These findings point to a previously unrecognized coronavirus host-pathogen interaction. We demonstrate that the Membrane epitope is a promising vaccine and monoclonal antibody target, which may complement spike-directed vaccination broadening immunological protection.One-Sentence SummaryUsing a protein-structure-based B cell epitope discovery method with a wide range of possible applications, we have identified a novel host-pathogen signature associated with SARS-CoV-2 immunopathology and suggest the viral Membrane protein contains a pathological T independent antigen.