Biomedicine, College of Public Health, Medical and Veterinary Sciences, and.
Australian Institute of Tropical Health and Medicine, James Cook University, Douglas, Queensland, Australia.
JCI Insight. 2023 Jul 24;8(14):e167464. doi: 10.1172/jci.insight.167464.
BACKGROUNDAntibody-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.METHODSTo 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.RESULTSInfluenza-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.CONCLUSIONThese 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 REGISTRATIONClinicalTrials.gov NCT02287467.FUNDINGFunding for this research was provided by subcontract 13XS134 under Leidos Biomedical Research Prime Contract HHSN261200800001E and HHSN261201500003I, NCI/NIAID.
背景
针对呼吸道病毒的抗体疗法越来越重要。INSIGHT 006 试验向因流感住院的患者给予抗流感高免疫静脉用免疫球蛋白（Flu-IVIG）。Flu-IVIG 治疗可改善流感 B 患者的结局，但对流感 A 无获益。
方法
为探究 Flu-IVIG 效用的潜在机制，采用 ELISA、基于珠子的多重分析和 NK 细胞激活分析，分析了因甲型或乙型流感病毒（IAV 或 IBV）感染而住院的患者的血清中抗体同种型/亚类和 Fcγ 受体（FcγR）结合情况。
结果
在接受 Flu-IVIG 输注的 IBV 和 IAV 感染患者中，流感特异性 FcγR 结合抗体升高。在 IBV 感染患者（n = 62）中，增加的 IgG3 和 FcγR 结合与更有利的结局相关。Flu-IVIG 治疗还可提高低水平抗-IBV Fc 功能抗体患者获得更有利结局的几率。更高的 FcγR 结合抗体与 IAV 感染患者的更不利结局相关（n = 50），且 Flu-IVIG 降低了低水平抗-IAV Fc 功能抗体患者获得有利结局的几率。
结论
这些详细的血清学分析提供了针对流感产生成功体液反应所需的抗体特征和机制的见解，表明针对 IBV 的而非 IAV 的、具有 Fc 介导功能的抗体可能有助于改善流感结局。这项工作将为开发改良的流感免疫疗法提供信息。
试验注册
ClinicalTrials.gov 注册号 NCT02287467。
资金
本研究的资金由分包合同 13XS134 提供，该合同是 Leidos Biomedical Research Prime 合同 HHSN261200800001E 和 HHSN261201500003I 的一部分，由 NCI/NIAID 资助。
