Humoral Response to COVID-19 Vaccines and Infection During Sibeprenlimab Treatment of IgA Nephropathy

Background: In phase 2 ENVISION trial, sibeprenlimab, a selective A PRoliferation-Inducing Ligand (APRIL) inhibitor, significantly decreased proteinuria and stabilized eGFR in adults with IgA nephropathy. This exploratory substudy evaluated COVID-19 severity, SARS-CoV-2–specific antibody responses to vaccine and infection, and circulating B-cell populations in patients with IgA nephropathy treated with sibeprenlimab or placebo. Methods: Participants enrolled in ENVISION (NCT04287985) received 12 monthly intravenous infusions of sibeprenlimab (2, 4, or 8 mg/kg) or placebo. COVID-19 infection and vaccination data were recorded for all participants. In a substudy, serum IgG responses to SARS-CoV-2 spike protein, its receptor binding domain (RBD), and nucleocapsid antigen were assessed, with further analysis of serum IgM and IgA and salivary IgA against RBD in a subset of participants. Circulating T cells and B-cell subsets were analyzed by flow cytometry. Results: Overall, symptomatic COVID-19 incidence was comparable between groups (33.3% sibeprenlimab vs 44.7% placebo), indicating no observable excess risk of COVID-19 infection with sibeprenlimab. Of 155 participants, 72 (sibeprenlimab n=52; placebo n=20) consented to the substudy. Within the substudy, COVID-19 seroconversion rates were 100% for IgG against SARS-CoV-2 RBD (IgG-RBD) following vaccination or infection. Peak IgG-RBD titers after mRNA vaccination exceeded protective thresholds in all COVID-19–naive sibeprenlimab recipients, and IgG-RBD durability was comparable between sibeprenlimab and placebo. COVID-19–specific IgG, IgA, and IgM antibody responses to infection were preserved, and IgA-RBD responses detected in saliva suggested preservation of mucosal immunity with sibeprenlimab. No meaningful perturbations in B or T cells were observed. Conclusions: APRIL inhibition with sibeprenlimab reduced pathogenic IgA while preserving mucosal immunity and systemic antibody responses to COVID-19 vaccination and infection. The absence of B-cell perturbations and the apparent absence of an increased risk of impaired vaccine response suggest that sibeprenlimab may not confer clinically significant immunosuppressive risks; the substudy’s size and exploratory design preclude definitive conclusions, warranting further evaluation.