Understanding the treatment benefit of hyperimmune anti-influenza intravenous immunoglobulin (Flu-IVIG) for severe human influenza
Hillary A. Vanderven, … , Stephen J. Kent, for the INSIGHT FLU-IVIG Study Group
Hillary A. Vanderven, … , Stephen J. Kent, for the INSIGHT FLU-IVIG Study Group
Published June 8, 2023
Citation Information: JCI Insight. 2023;8(14):e167464. https://doi.org/10.1172/jci.insight.167464.
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Clinical Research and Public Health Immunology Infectious disease

Understanding the treatment benefit of hyperimmune anti-influenza intravenous immunoglobulin (Flu-IVIG) for severe human influenza

Abstract

BACKGROUND Antibody-based therapies for respiratory viruses are of increasing importance. The INSIGHT 006 trial administered anti-influenza hyperimmune intravenous immunoglobulin (Flu-IVIG) to patients hospitalized with influenza. Flu-IVIG treatment improved outcomes in patients with influenza B but showed no benefit for influenza A.METHODS To probe potential mechanisms of Flu-IVIG utility, sera collected from patients hospitalized with influenza A or B viruses (IAV or IBV) were analyzed for antibody isotype/subclass and Fcγ receptor (FcγR) binding by ELISA, bead-based multiplex, and NK cell activation assays.RESULTS Influenza-specific FcγR-binding antibodies were elevated in Flu-IVIG–infused IBV- and IAV-infected patients. In IBV-infected participants (n = 62), increased IgG3 and FcγR binding were associated with more favorable outcomes. Flu-IVIG therapy also improved the odds of a more favorable outcome in patients with low levels of anti-IBV Fc-functional antibody. Higher FcγR-binding antibody was associated with less favorable outcomes in IAV-infected patients (n = 50), and Flu-IVIG worsened the odds of a favorable outcome in participants with low levels of anti-IAV Fc-functional antibody.CONCLUSION These detailed serological analyses provide insights into antibody features and mechanisms required for a successful humoral response against influenza, suggesting that IBV-specific, but not IAV-specific, antibodies with Fc-mediated functions may assist in improving influenza outcome. This work will inform development of improved influenza immunotherapies.TRIAL REGISTRATION ClinicalTrials.gov NCT02287467.FUNDING Funding for this research was provided by subcontract 13XS134 under Leidos Biomedical Research Prime Contract HHSN261200800001E and HHSN261201500003I, NCI/NIAID.

Authors

Hillary A. Vanderven, Deborah N. Wentworth, Win Min Han, Heidi Peck, Ian G. Barr, Richard T. Davey Jr., John H. Beigel, Dominic E. Dwyer, Mamta K. Jain, Brian Angus, Christian T. Brandt, Analia Mykietiuk, Matthew G. Law, James D. Neaton, Stephen J. Kent, for the INSIGHT FLU-IVIG Study Group

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Figure 1

Flow diagram depicting the subset of patients from the INSIGHT 006 Flu-IVIG clinical trial who underwent detailed serological analyses.

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Flow diagram depicting the subset of patients from the INSIGHT 006 Flu-I...
Of the 308 participants included in the primary analysis, 84 (27%) had influenza B and 224 (73%) had influenza A. Of the 84 participants with influenza B, 64 patients (21% of total participants) were infected with a B/Yamagata lineage influenza virus. Of the 224 participants with influenza A, 73 patients (24% of total participants) were infected with an A/H1N1 influenza virus. Based on sample availability, serological analyses were performed with 62 sera samples from B/Yamagata-infected patients (20% of total participants) and 50 sera samples from A/H1N1-infected patients (16% of total participants). In the analyzed B/Yamagata-infected participants, 29 were infused with placebo and 33 infused with Flu-IVIG. In the analyzed A/H1N1-infected participants, 26 received placebo and 24 received Flu-IVIG.