The interleukin-2 mutein, VIS171, was engineered to extend half-life and enhance selective binding and expansion of regulatory T cells (Tregs) expressing high levels of the trimeric interleukin-2 receptor. This study evaluated the effects of VIS171 on immune cell populations in nonhuman primates, focusing on its ability to selectively expand Tregs, and then characterized their phenotype during expansion and contraction. Naïve rhesus macaques were treated subcutaneously with VIS171, along with daily rapamycin. VIS171 was well tolerated with repeated administration. Tregs, identified as cluster of differentiation CD4+CD25+FoxP3+ or CD4+CD25+CD127lo cells, expanded significantly after treatment. Peak Treg expansion was evident in the peripheral circulation between days 5 and 7 postdose, with frequency and absolute counts markedly increasing from 4- to 6-fold after administration. In contrast, no significant effect was found in cytotoxic T lymphocyte populations, highlighting the specificity of VIS171 for expanding Tregs. Single-cell RNA sequencing revealed 3 distinct Treg clusters: resting (SELLhigh) Tregs and 2 Treg subsets with distinct activation and metabolic profiles (HACD4high and TIGIThigh). The transcriptomic profile of expanded Tregs was consistent, with an effector Treg signature associated with immunoregulatory function. Differentiation signature scores indicated preserved Treg functionality after expansion. These findings suggest that VIS171 with rapamycin promotes robust, selective, and durable Treg expansion, offering a strategy to enhance transplant tolerance without broad immunosuppression.

KEY POINTS:The phase 2 ENVISION trial evaluated efficacy and safety of intravenous sibeprenlimab, a selective A PRoliferation-Inducing Ligand inhibitor. Because the trial was conducted during the coronavirus disease 2019 pandemic, we assessed if sibeprenlimab affected humoral responses to coronavirus disease 2019 infection or vaccine. Sibeprenlimab treatment resulted in reduced pathogenic IgA and preserved protective humoral response to coronavirus disease 2019 vaccine and infection. BACKGROUND:In phase 2 ENVISION trial, sibeprenlimab, a selective A PRoliferation-Inducing Ligand inhibitor, significantly decreased proteinuria and stabilized eGFR in adults with IgA nephropathy. This exploratory substudy evaluated coronavirus disease 2019 (COVID-19) severity, severe acute respiratory syndrome coronavirus 2 (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 versus 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) after 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:A PRoliferation-Inducing Ligand 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. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:ClinicalTrials.gov, NCT04287985 .

Importance Dengue outbreaks are increasing in frequency and intensity. In the absence of any specific treatment, a pan-serotype recombinant monoclonal antibody (Dengue-mAb) was tested in adult patients with dengue as a therapeutic option. Objective To assess the safety and effect of a single dose of Dengue-mAb on dengue viremia at different dose levels among patients with dengue. Design, Setting, and Participants A phase 2, single-blind, randomized, placebo-controlled clinical trial was conducted from September 19, 2021, to May 13, 2023, at 12 hospitals in India. Study participants were aged 18 to 60 years with dengue and a history of fever onset within 48 hours. Key exclusion criteria were severe dengue, hemoglobin less than 10 g/dL, absolute neutrophil count less than 500/mm 3 , total leukocyte count less than 1500/mm 3 , platelet count less than 50 000/mm 3 , and any other clinically significant disorders. Data were analyzed from January 11, 2024, to March 26, 2024. Interventions Participants were randomly allocated 1:1:1:1:1 using an interactive web response system to receive 1 of 4 dose levels of Dengue-mAb (3, 5, 7, or 9 mg/kg) or placebo by slow intravenous infusion. Main Outcomes and Measures Primary outcomes were reduction in viremia at 24 hours and causally related serious adverse events (SAEs). Secondary outcomes were RNAemia, fever, and hematologic and pharmacokinetic parameters. Findings A total of 250 participants were randomized, with 50 participants in each group. The overall median age was 30 years (IQR, 24-37 years), and 180 participants (72.3%) were male. There were no causally related SAEs. The adjusted mean (SE) viral log reduction at 24 hours was significantly higher with Dengue-mAb—from 1.93 (0.23) with 3 mg/kg ( P = .04) to 2.35 (0.27) with 9 mg/kg ( P = .003)—compared with placebo (1.29 [0.22]), using a mixed model for repeated measures. Participants with detectable viremia (n = 32) at baseline were negative for dengue virus by 8 hours when treated with a 5- to 9-mg/kg dose of Dengue-mAb compared with 72 hours with placebo. Median time to fever clearance was 3.5 (95% CI, 1.0-24.0) hours (hazard ratio [HR], 2.6 [95% CI, 1.0-6.4]) with Dengue-mAb 5 mg/kg (n = 14) and 2.0 (95% CI, 0.5-6.0) hours (HR, 2.8 [95% CI, 1.2-6.8]) with Dengue-mAb 7 mg/kg (n = 14), compared with 26.8 (95% CI, 1.0-50.5) hours with placebo (n = 12). At 24 hours, between 13 of 14 participants (92.9%; 95% CI, 66.1%-99.8%) with Dengue-mAb (3 mg/kg), 14 of 14 participants (100.0%; 95% CI, 76.8%-100.0%) with Dengue-mAb (5 mg/kg and 7 mg/kg), and 16 of 17 participants (94.1%; 95% CI 71.3%-99.9%) with Dengue-mAb (9 mg/kg); and 7 of 12 participants (58.3%; 95% CI, 27.7%-84.8%) with placebo had fever clearance. Conclusions and Relevance In this randomized clinical trial, Dengue-mAb was safe and well tolerated. Dengue-mAb rapidly reduced dengue viremia and fever at doses of 5 mg/kg and 7 mg/kg, making this the first therapeutic against wild-type dengue virus to show preliminary efficacy in humans. Trial Registration Clinical Trial Registry-India Identifier: CTRI/2021/07/035290

Importance:Dengue outbreaks are increasing in frequency and intensity. In the absence of any specific treatment, a pan-serotype recombinant monoclonal antibody (Dengue-mAb) was tested in adult patients with dengue as a therapeutic option. Objective:To assess the safety and effect of a single dose of Dengue-mAb on dengue viremia at different dose levels among patients with dengue. Design, Setting, and Participants:A phase 2, single-blind, randomized, placebo-controlled clinical trial was conducted from September 19, 2021, to May 13, 2023, at 12 hospitals in India. Study participants were aged 18 to 60 years with dengue and a history of fever onset within 48 hours. Key exclusion criteria were severe dengue, hemoglobin less than 10 g/dL, absolute neutrophil count less than 500/mm3, total leukocyte count less than 1500/mm3, platelet count less than 50 000/mm3, and any other clinically significant disorders. Data were analyzed from January 11, 2024, to March 26, 2024. Interventions:Participants were randomly allocated 1:1:1:1:1 using an interactive web response system to receive 1 of 4 dose levels of Dengue-mAb (3, 5, 7, or 9 mg/kg) or placebo by slow intravenous infusion. Main Outcomes and Measures:Primary outcomes were reduction in viremia at 24 hours and causally related serious adverse events (SAEs). Secondary outcomes were RNAemia, fever, and hematologic and pharmacokinetic parameters. Findings:A total of 250 participants were randomized, with 50 participants in each group. The overall median age was 30 years (IQR, 24-37 years), and 180 participants (72.3%) were male. There were no causally related SAEs. The adjusted mean (SE) viral log reduction at 24 hours was significantly higher with Dengue-mAb-from 1.93 (0.23) with 3 mg/kg (P = .04) to 2.35 (0.27) with 9 mg/kg (P = .003)-compared with placebo (1.29 [0.22]), using a mixed model for repeated measures. Participants with detectable viremia (n = 32) at baseline were negative for dengue virus by 8 hours when treated with a 5- to 9-mg/kg dose of Dengue-mAb compared with 72 hours with placebo. Median time to fever clearance was 3.5 (95% CI, 1.0-24.0) hours (hazard ratio [HR], 2.6 [95% CI, 1.0-6.4]) with Dengue-mAb 5 mg/kg (n = 14) and 2.0 (95% CI, 0.5-6.0) hours (HR, 2.8 [95% CI, 1.2-6.8]) with Dengue-mAb 7 mg/kg (n = 14), compared with 26.8 (95% CI, 1.0-50.5) hours with placebo (n = 12). At 24 hours, between 13 of 14 participants (92.9%; 95% CI, 66.1%-99.8%) with Dengue-mAb (3 mg/kg), 14 of 14 participants (100.0%; 95% CI, 76.8%-100.0%) with Dengue-mAb (5 mg/kg and 7 mg/kg), and 16 of 17 participants (94.1%; 95% CI 71.3%-99.9%) with Dengue-mAb (9 mg/kg); and 7 of 12 participants (58.3%; 95% CI, 27.7%-84.8%) with placebo had fever clearance. Conclusions and Relevance:In this randomized clinical trial, Dengue-mAb was safe and well tolerated. Dengue-mAb rapidly reduced dengue viremia and fever at doses of 5 mg/kg and 7 mg/kg, making this the first therapeutic against wild-type dengue virus to show preliminary efficacy in humans. Trial Registration:Clinical Trial Registry-India Identifier: CTRI/2021/07/035290.

Background In phase 2 ENVISION trial, sibeprenlimab, a selective A PRoliferation-Inducing Ligand inhibitor, significantly decreased proteinuria and stabilized eGFR in adults with IgA nephropathy. This exploratory substudy evaluated coronavirus disease 2019 (COVID-19) severity, severe acute respiratory syndrome coronavirus 2 (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 () 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 versus 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) after 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 A PRoliferation-Inducing Ligand 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.Clinical Trial registry name and registration number: ClinicalTrials.gov, .

While at least 8 monoclonal and 3 polyclonal antibody products have been tested in clinical trials for the treatment of influenza, no products have been licensed, and most have stopped clinical development. The COVID-19 pandemic demonstrated that these approaches, especially monoclonal antibodies, may have unique potential in certain stages of disease and populations, especially in preventing severe disease in a population without preexisting immunity or in those with a limited capacity to mount an effective humoral immune response. This review summarizes past and ongoing efforts in using monoclonal and polyclonal antibodies for the treatment and prevention of influenza, focusing on products that have entered clinical trials and drawing lessons from COVID-19 to direct future efforts on these strategies.