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Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity.

ABSTRACT: A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc-gamma receptor (FcγR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from patients with COVID-19 induced inflammatory cytokine production and robust infiltration of the lung by immune cells. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by messenger RNA SARS-CoV-2 vaccines were highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. Vaccine-elicited IgG did not promote an inflammatory lung response. These results show that human IgG-FcγR interactions regulate inflammation in the lung and define distinct lung activities mediated by the IgG that are associated with protection against, or progression to, severe COVID-19.

SUBMITTER: Chakraborty S

PROVIDER: S-EPMC8939764 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity.

Chakraborty Saborni S Gonzalez Joseph C JC Sievers Benjamin L BL Mallajosyula Vamsee V Chakraborty Srijoni S Dubey Megha M Ashraf Usama U Cheng Bowie Yik-Ling BY Kathale Nimish N Tran Kim Quyen Thi KQT Scallan Courtney C Sinnott Aanika A Cassidy Arianna A Chen Steven T ST Gelbart Terri T Gao Fei F Golan Yarden Y Ji Xuhuai X Kim-Schulze Seunghee S Prahl Mary M Gaw Stephanie L SL Gnjatic Sacha S Marron Thomas U TU Merad Miriam M Arunachalam Prabhu S PS Boyd Scott D SD Davis Mark M MM Holubar Marisa M Khosla Chaitan C Maecker Holden T HT Maldonado Yvonne Y Mellins Elizabeth D ED Nadeau Kari C KC Pulendran Bali B Singh Upinder U Subramanian Aruna A Utz Paul J PJ Sherwood Robert R Zhang Sheng S Jagannathan Prasanna P Tan Gene S GS Wang Taia T TT

Science translational medicine 20220309 635

A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model ...[more]

PMID: 35040666

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Project description:BackgroundInnate immunity, armed with pattern recognition receptors including Toll-like receptors (TLR), is critical for immune cell activation and the connection to anti-microbial adaptive immunity. However, information regarding the impact of age on the innate immunity in response to SARS-CoV2 adenovirus vector vaccines and its association with specific immune responses remains scarce.MethodsFifteen subjects between 25-35 years (the young group) and five subjects between 60-70 years (the older adult group) were enrolled before ChAdOx1 nCoV-19 (AZD1222) vaccination. We determined activation markers and cytokine production of monocyte, natural killer (NK) cells and B cells ex vivo stimulated with TLR agonist (poly (I:C) for TLR3; LPS for TLR4; imiquimod for TLR7; CpG for TLR9) before vaccination and 3-5 days after each jab with flow cytometry. Anti-SARS-CoV2 neutralization antibody titers (surrogate virus neutralization tests, sVNTs) were measured using serum collected 2 months after the first jab and one month after full vaccination.ResultsThe older adult vaccinees had weaker vaccine-induced sVNTs than young vaccinees after 1st jab (47.2±19.3% vs. 21.2±22.2%, p value<0.05), but this difference became insignificant after the 2nd jab. Imiquimod, LPS and CpG strongly induced CD86 expression in IgD+CD27- naïve and IgD-CD27+ memory B cells in the young group. In contrast, only the IgD+ CD27- naïve B cells responded to these TLR agonists in the older adult group. Imiquimode strongly induced the CD86 expression in CD14+ monocytes in the young group but not in the older adult group. After vaccination, the young group had significantly higher IFN-γ expression in CD3- CD56dim NK cells after the 1st jab, whilst the older adult group had significantly higher IFN-γ and granzyme B expression in CD56bright NK cells after the 2nd jab (all p value <0.05). The IFN-γ expression in CD56dim and CD56bright NK cells after the first vaccination and CD86 expression in CD14+ monocyte and IgD-CD27-double-negative B cells after LPS and imiquimod stimulation correlated with vaccine-induced antibody responses.ConclusionsThe innate immune responses after the first vaccination correlated with the neutralizing antibody production. Older people may have defective innate immune responses by TLR stimulation and weak or delayed innate immune activation profile after vaccination compared with young people.

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Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity.

Publications

Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity.

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