RT Journal Article SR Electronic T1 Divergent early antibody responses define COVID-19 disease trajectories JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.05.25.445649 DO 10.1101/2021.05.25.445649 A1 Saborni Chakraborty A1 Joseph C. Gonzalez A1 Benjamin L. Sievers A1 Vamsee Mallajosyula A1 Megha Dubey A1 Bowie Yik-Ling Cheng A1 Kim Quyen Thi Tran A1 Srijoni Chakraborty A1 Arianna Cassidy A1 Steven T. Chen A1 Aanika Sinnott A1 Terri Gelbart A1 Yarden Golan A1 Mary Prahl A1 Upinder Singh A1 Seunghee Kim-Schulze A1 Robert Sherwood A1 Sheng Zhang A1 Thomas U. Marron A1 Sacha Gnjatic A1 Stephanie L. Gaw A1 Kari C. Nadeau A1 Miriam Merad A1 Prasanna Jagannathan A1 Gene S. Tan A1 Taia T. Wang YR 2021 UL http://biorxiv.org/content/early/2021/05/25/2021.05.25.445649.abstract AB Serologic markers that predict severe COVID-19 disease trajectories could enable early medical interventions and reduce morbidity and mortality. We found that distinct features of IgG Fab and Fc domain structures were present within three days of a positive test that predicted two separate disease trajectories in a prospective cohort of patients with COVID-19. One trajectory was defined by early production of neutralizing antibodies and led to mild disease. A distinct trajectory, characterized by an initial period of mild symptoms followed by rapid progression to more severe outcomes, was predicted by the absence of early neutralizing antibody responses with concomitant production of afucosylated IgGs. Elevated frequencies of monocytes expressing the receptor for afucosylated IgGs, FcγRIIIa (CD16a), were an additional antecedent in patients with the more severe outcomes. In mechanistic studies, afucosylated immune complexes in the lung triggered an inflammatory infiltrate and cytokine production that was dependent on CD16a. Finally, in healthy subjects, mRNA SARS-CoV-2 vaccination elicited neutralizing antibodies that were enriched for Fc fucosylation and sialylation and distinct from both infection-induced trajectories. These data show the importance of combined Fab and Fc domain functions in the antiviral response, define an early antibody signature in people who progressed to more severe COVID-19 outcomes and have implications for novel therapeutic strategies targeting FcγRIIIa pathways.Competing Interest StatementThe authors have declared no competing interest.