无头血凝素含有的流感病毒颗粒将免疫反应引导到更保守的表位。

Headless hemagglutinin-containing influenza viral particles direct immune responses toward more conserved epitopes.

机构信息

Department of Molecular Genetics and Microbiology, Duke University School of Medicine Durham, Durham, North Carolina, USA.

Duke Human Vaccine Institute, Duke University School of Medicine Durham, Durham, North Carolina, USA.

出版信息

J Virol. 2024 Oct 22;98(10):e0116624. doi: 10.1128/jvi.01166-24. Epub 2024 Sep 26.

Abstract

Seasonal influenza vaccines provide mostly strain-specific protection due to the elicitation of antibody responses focused on evolutionarily plastic antigenic sites in the hemagglutinin head domain. To direct the humoral response toward more conserved epitopes, we generated an influenza virus particle where the full-length hemagglutinin protein was replaced with a membrane-anchored, "headless" variant while retaining the normal complement of other viral structural proteins such as the neuraminidase as well as viral RNAs. We found that a single administration of a headless virus particle-based vaccine elicited high titers of antibodies that recognized more conserved epitopes on the major viral glycoproteins. Furthermore, the vaccine could elicit these responses even in the presence of pre-existing, hemagglutinin (HA) head-focused influenza immunity. Importantly, these antibody responses mediated protective, but non-neutralizing functions such as neuraminidase inhibition and antibody-dependent cellular cytotoxicity. Additionally, we show the vaccine can provide protection from homologous and heterologous challenges in mouse models of severe influenza without any measurable HA head-directed antibody responses. Thus, headless hemagglutinin containing viral particles may represent a tool to drive the types of antibody responses predicted to increase influenza vaccine breadth and durability.IMPORTANCECurrent seasonal influenza vaccines provide incomplete protection from disease. This is partially the result of the antibody response being directed toward parts of the virus that are tolerant of mutations. Redirecting the immune response to more conserved regions of the virus has been a central strategy of next-generation vaccine designs and approaches. Here, we develop and test a vaccine based on a modified influenza virus particle that expresses a partially deleted hemagglutinin protein along with the other viral structural proteins. We demonstrate this vaccine elicits antibodies that recognize the more conserved viral epitopes of the hemagglutinin stalk and neuraminidase protein to facilitate protection against influenza viruses despite a lack of classical viral neutralization activity.

摘要

季节性流感疫苗主要提供针对特定毒株的保护,这是由于其诱导的抗体反应主要针对血凝素头部结构域中进化上具有可塑性的抗原位点。为了使体液免疫反应针对更保守的表位,我们构建了一种流感病毒颗粒,其中全长血凝素蛋白被一种膜锚定的“无头”变体所取代,同时保留了其他病毒结构蛋白(如神经氨酸酶)和病毒 RNA 的正常组成。我们发现,单次给予基于无头病毒颗粒的疫苗能够诱导产生高滴度的抗体,这些抗体能够识别主要病毒糖蛋白上更保守的表位。此外,即使存在针对血凝素(HA)头部的预先存在的流感免疫,该疫苗也能够诱导这些反应。重要的是,这些抗体反应介导了保护性但非中和性的功能,如神经氨酸酶抑制和抗体依赖性细胞毒性。此外,我们还表明,该疫苗可在严重流感的小鼠模型中提供针对同源和异源挑战的保护,而不会引起可测量的针对 HA 头部的抗体反应。因此,含有无头血凝素的病毒颗粒可能代表一种工具,可驱动预期增加流感疫苗广度和持久性的抗体反应类型。

重要性

目前的季节性流感疫苗不能提供完全的疾病保护。这部分是由于抗体反应针对的是病毒中对突变具有耐受性的部分。将免疫反应重新定向到病毒的更保守区域一直是下一代疫苗设计和方法的核心策略。在这里,我们开发并测试了一种基于修饰的流感病毒颗粒的疫苗,该疫苗表达部分缺失的血凝素蛋白以及其他病毒结构蛋白。我们证明,尽管缺乏经典的病毒中和活性,该疫苗能够诱导产生识别血凝素茎和神经氨酸酶蛋白更保守病毒表位的抗体,从而促进对流感病毒的保护。

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