TY - JOUR T1 - Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response JF - bioRxiv DO - 10.1101/2021.05.25.445649 SP - 2021.05.25.445649 AU - Saborni Chakraborty AU - Joseph C. Gonzalez AU - Benjamin L. Sievers AU - Vamsee Mallajosyula AU - Srijoni Chakraborty AU - Megha Dubey AU - Usama Ashraf AU - Bowie Yik-Ling Cheng AU - Nimish Kathale AU - Kim Quyen Thi Tran AU - Courtney Scallan AU - Aanika Sinnott AU - Arianna Cassidy AU - Steven T. Chen AU - Terri Gelbart AU - Fei Gao AU - Yarden Golan AU - Xuhuai Ji AU - Seunghee Kim-Schulze AU - Mary Prahl AU - Stephanie L. Gaw AU - Sacha Gnjatic AU - Thomas U. Marron AU - Miriam Merad AU - Prabhu S. Arunachalam AU - Scott D. Boyd AU - Mark M. Davis AU - Marisa Holubar AU - Chaitan Khosla AU - Holden T. Maecker AU - Yvonne Maldonado AU - Elizabeth D. Mellins AU - Kari C. Nadeau AU - Bali Pulendran AU - Upinder Singh AU - Aruna Subramanian AU - Paul J. Utz AU - Robert Sherwood AU - Sheng Zhang AU - Prasanna Jagannathan AU - Gene S. Tan AU - Taia T. Wang Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/12/27/2021.05.25.445649.abstract N2 - A damaging inflammatory response is strongly implicated in the pathogenesis of severe COVID-19 but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated, anti-SARS-CoV-2 IgG predicted progression from mild, to more severe COVID-19. In contrast to the antibody structures that predicted disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were low in Fc afucosylation and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model which revealed that human IgG-FcγR interactions can regulate inflammation in the lung. Afucosylated IgG immune complexes induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine elicited IgG did not promote an inflammatory lung response. Here, we show that IgG-FcγR interactions can regulate inflammation in the lung and define distinct lung activities associated with the IgG that predict severe COVID-19 and protection against SARS-CoV-2.One Sentence Summary Divergent early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response and are functionally distinct in vivo.Competing Interest StatementThe authors have declared no competing interest. ER -