Search

While there have been extensive analyses characterizing cellular and humoral responses across the severity spectrum in COVID-19, outcome predictors within severe COVID-19 remain less comprehensively elucidated. Furthermore, properties of antibodies (Abs) directed against viral antigens beyond spike and their associations with disease outcomes remain poorly defined. We perform deep molecular profiling of Abs directed against a wide range of antigenic specificities in severe COVID-19 patients. The profiles included canonical (spike [S], receptor-binding domain [RBD], and nucleocapsid [N]) and non-canonical (orf3a, orf8, nsp3, nsp13, and membrane [M]) antigenic specificities. Notably, multivariate Ab profiles directed against canonical or non-canonical antigens are equally discriminative of survival in severe COVID-19. Intriguingly, pre-pandemic healthy controls have cross-reactive Abs directed against nsp13, a protein conserved across coronaviruses. Consistent with these findings, a model built on Ab profiles for endemic coronavirus antigens also predicts COVID-19 outcome. Our results suggest the importance of studying Abs targeting non-canonical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and endemic coronavirus antigens in COVID-19. [Display omitted] • Deep Ab profiling against different antigenic specificities in severe COVID-19 • Abs against canonical and non-canonical SARS-CoV-2 and endemic CoV antigens predict outcome • SARS-CoV-2-specific IgA and IgG3 Abs, including nsp13-specific IgA, associated with survival • Show importance of studying Ab profiles against underexplored antigenic specificities Peddireddy et al. perform deep molecular profiling of antibodies in severe COVID-19 patients and identify multivariate humoral signatures of outcome bifurcation involving canonical and non-canonical SARS-CoV-2, as well as endemic CoV antigenic specificities. Our results suggest the importance of Abs targeting non-canonical SARS-CoV-2 antigens, as well as those directed against endemic coronaviruses in favorable outcomes of severe COVID-19. [ABSTRACT FROM AUTHOR]