The current seasonal inactivated influenza vaccine protects only against a narrow range of virus strains as it triggers a dominant antibody response toward the hypervariable hemagglutinin (HA) head region. The discovery of rare broadly protective antibodies against conserved regions in influenza virus proteins has propelled research on distinct antigens and delivery methods to efficiently induce broad immunity toward drifted or shifted virus strains. Here, we report that adeno-associated virus (AAV) vectors expressing influenza virus HA or chimeric HA protected mice against homologous and heterologous virus challenges. Unexpectedly, immunization even with wild-type HA induced antibodies recognizing the HA-stalk and activating FcγR-dependent responses indicating that AAV-vectored expression balances HA head- and HA stalk-specific humoral responses. Immunization with AAV-HA partially protected also ferrets against a harsh virus challenge. Results from this study provide a rationale for further clinical development of AAV vectors as influenza vaccine platform, which could benefit from their approved use in human gene therapy.

中文翻译：

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腺相关病毒载体流感疫苗引发中和抗体和 Fcγ 受体激活抗体。

当前的季节性灭活流感疫苗仅针对一小部分病毒株提供保护，因为它会触发针对高变血凝素 (HA) 头部区域的显性抗体反应。罕见的针对流感病毒蛋白保守区域的广泛保护性抗体的发现推动了对不同抗原和递送方法的研究，以有效诱导对漂移或转移病毒株的广泛免疫。在这里，我们报告表达流感病毒 HA 或嵌合 HA 的腺相关病毒 (AAV) 载体保护小鼠免受同源和异源病毒攻击。出乎意料的是，即使使用野生型 HA 进行免疫也能诱导抗体识别 HA 茎并激活 FcγR 依赖性反应，表明 AAV 载体表达平衡了 HA 头部和 HA 茎特异性体液反应。用 AAV-HA 免疫也能部分保护雪貂免受严酷的病毒攻击。这项研究的结果为 AAV 载体作为流感疫苗平台的进一步临床开发提供了理论依据，这可能会受益于它们被批准用于人类基因治疗。