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IL-21 is a multifunctional cytokine linked with the pathophysiology of several autoimmune diseases, including type 1 diabetes. In this study, our aim was to examine plasma IL-21 levels in individuals at different stages of type 1 diabetes progression. We measured plasma IL-21 levels, as well as levels of other key pro-inflammatory cytokines (IL-17A, TNF-α and IL-6), from 37 adults with established type 1 diabetes and 46 healthy age-matched adult controls, as well as from 53 children with newly diagnosed type 1 diabetes, 48 at-risk children positive for type 1 diabetes-associated autoantibodies and 123 healthy age-matched pediatric controls using the ultrasensitive Quanterix SiMoA technology. Adults with established type 1 diabetes had higher plasma IL-21 levels compared to healthy controls. However, the plasma IL-21 levels showed no statistically significant correlation with clinical variables, such as BMI, C-peptide, HbA1c, or hsCRP levels, evaluated in parallel. In children, plasma IL-21 levels were almost ten times higher than in adults. However, no significant differences in plasma IL-21 levels were detected between healthy children, autoantibody-positive at-risk children, and children with newly diagnosed type 1 diabetes. In conclusion, plasma IL-21 levels in adults with established type 1 diabetes were increased, which may be associated with autoimmunity. The physiologically high plasma IL-21 levels in children may, however, reduce the potential of IL-21 as a biomarker for autoimmunity in pediatric subjects., Competing Interests: JPo, SM, SB, LZ, and RB are employees of Eli Lilly & Company and may own stock. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Schroderus, Poorbaugh, McElyea, Beasley, Zhang, Näntö-Salonen, Rintamäki, Pihlajamäki, Knip, Veijola, Toppari, Ilonen, Benschop and Kinnunen.)

Background: Neutralizing monoclonal antibodies (mAbs) to SARS-CoV-2 are clinically efficacious when administered early, decreasing hospitalization and mortality in patients with mild or moderate COVID-19. We investigated the effects of receiving mAbs (bamlanivimab alone and bamlanivimab and etesevimab together) after SARS-CoV-2 infection on the endogenous immune response., Methods: Longitudinal serum samples were collected from patients with mild or moderate COVID-19 in the BLAZE-1 trial who received placebo (n=153), bamlanivimab alone [700 mg (n=100), 2800 mg (n=106), or 7000 mg (n=98)], or bamlanivimab (2800 mg) and etesevimab (2800 mg) together (n=111). A multiplex Luminex serology assay measured antibody titers against SARS-CoV-2 antigens, including SARS-CoV-2 protein variants that evade bamlanivimab or etesevimab binding, and SARS-CoV-2 pseudovirus neutralization assays were performed., Results: The antibody response in patients who received placebo or mAbs had a broad specificity. Titer change from baseline against a receptor-binding domain mutant (Spike-RBD E484Q), as well as N-terminal domain (Spike-NTD) and nucleocapsid protein (NCP) epitopes were 1.4 to 4.1 fold lower at day 15-85 in mAb recipients compared with placebo. Neutralizing activity of day 29 sera from bamlanivimab monotherapy cohorts against both spike E484Q and beta variant (B.1.351) were slightly reduced compared with placebo (by a factor of 3.1, p=0.001, and 2.9, p=0.002, respectively). Early viral load correlated with the subsequent antibody titers of the native, unmodified humoral response (p<0.0001 at Day 15, 29, 60 and 85 for full-length spike)., Conclusions: Patients with mild or moderate COVID-19 treated with mAbs develop a wide breadth of antigenic responses to SARS-CoV-2. Small reductions in titers and neutralizing activity, potentially due to a decrease in viral load following mAb treatment, suggest minimal impact of mAb treatment on the endogenous immune response., Competing Interests: Authors LZ, JP, SB, MDa, TNVT, MC, JF, PV, DP, AN, NK, RH, and RB are all employees and shareholders of Eli Lilly and Company. MDo reports receiving grants from Eli Lilly and Company, and Novartis; and receiving consulting fees from Moderna, Tillotts, SQZ, AzurRx, Partner Therapeutics, and ORIC Pharmaceuticals; and has Neoleukin Therapeutics stock. PC reports receiving consulting fees from Eli Lilly and Company and Gilead; and receiving payment or honoraria from Rockpointe, Frontier Collaborative, CME Outfitter, and Physician Education Resource. RG reports receiving consulting fees from Eli Lilly and Company, GSK Pharmaceuticals, and Gilead Sciences; and receiving payment or honoraria from Gilead Sciences. GH reports receiving grants from Eli Lilly and company, Gilead, Viiv, Janssen, and Proteus; receiving consulting fees from Gilead, Viiv, and Janssen; and receiving payment or honoraria from Rockpointe, CME Outfitter, Simply Speaking, and Clinical Care Options. The authors declare that this study received funding from Eli Lilly and Company. The funder had the following involvement with the study: study design, data analysis, decision to publish, and preparation of the manuscript., (Copyright © 2021 Zhang, Poorbaugh, Dougan, Chen, Gottlieb, Huhn, Beasley, Daniels, Ngoc Vy Trinh, Crisp, Freitas, Vaillancourt, Patel, Nirula, Kallewaard, Higgs and Benschop.)