Antiviral antibody Fc dysfunction is linked to increased IgG1 fucosylation in Long COVID

• September 2026
• medRxiv

Publication Details

Caution: This preprint is a work in progress that has not been peer-reviewed. It should not be relied upon to guide clinical practice or health behaviors, and it should not be reported in news media as established information. We will update this web page if this preprint becomes a peer-reviewed publication. (Not all research reports move past the preprint stage.)

DOI: 10.64898/2026.09.28.26364044

Abstract

Background: Persistent SARS-CoV-2 antigen is a leading hypothesis for post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID. Impaired Fc-mediated antiviral antibody function could contribute to inefficient clearance of infected cells and viral antigen despite preserved antibody levels. Therefore, we tested whether PASC is associated with altered Fcγ receptor-mediated antibody function and differences in IgG1 Fc fucosylation, a major regulator of Fc effector function.

Methods: Serum samples from RECOVER-Adult participants with prior SARS-CoV-2 infection (99 PASC, 139 non-PASC) were analyzed for anti-SARS-CoV-2 spike receptor-binding domain (RBD) IgG and subclasses, FcγRIIIa- and FcγRIIa-mediated reporter activity as surrogate measures of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), anti-RBD IgG1 Fc glycosylation, and circulating fucose-modifying enzymes.

Results: Despite higher anti-RBD IgG and IgG1 abundance, PASC sera showed lower ADCC- and ADCP-associated FcγR reporter activity, including after normalization for antibody abundance. Anti-RBD IgG1 showed greater fucosylation in PASC samples (30 PASC, 34 non-PASC). Serum FUCA2 was lower in PASC samples (24 PASC, 34 non-PASC), whereas FUCA1 and soluble CD16a levels did not differ between the two groups.

Conclusion: PASC is associated with impaired antiviral IgG Fc function, increased IgG1 Fc fucosylation, and reduced circulating FUCA2, identifying a glycoimmune axis that may contribute to impaired Fc-dependent antigen clearance and represents a potentially targetable pathway in Long COVID.

Authors

Rahul Ukey, Ioannis E Michailidis, Patricia Greenberg, Tracy Andrews, Sung Yun Jung, Haiyan Zheng, William Honnen, Abraham Pinter, Lawrence C Kleinman, Natalie Bruiners, Maria Laura Gennaro

Keywords

FcγR; IgG1 Fc glycosylation; Post-acute sequelae of SARS-CoV-2 infection (PASC); antibody effector function