School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
mBio. 2020 Mar 3;11(2):e00027-20. doi: 10.1128/mBio.00027-20.
Anti-galactose-α-1,3-galactose (anti-α-Gal) antibody is naturally expressed at a high level in humans. It constitutes about 1% of immunoglobulins found in human blood. Here, we designed a live attenuated influenza virus vaccine that can generate α-Gal epitopes in infected cells in order to facilitate opsonization of infected cells, thereby enhancing vaccine-induced immune responses. In the presence of normal human sera, cells infected with this mutant can enhance phagocytosis of human macrophages and cytotoxicity of NK cells Using a knockout mouse strain that allows expression of anti-α-Gal antibody , we showed that this strategy can increase vaccine immunogenicity and the breadth of protection. This vaccine can induce 100% protection against a lethal heterosubtypic group 1 (H5) or group 2 (mouse-adapted H3) influenza virus challenge in the mouse model. In contrast, its heterosubtypic protective effect in wild-type or knockout mice that do not have anti-α-Gal antibody expression is only partial, demonstrating that the enhanced vaccine-induced protection requires anti-α-Gal antibody upon vaccination. Anti-α-Gal-expressing knockout mice immunized with this vaccine produce robust humoral and cell-mediated responses upon a lethal virus challenge. This vaccine can stimulate CD11b pulmonary dendritic cells, which are known to be crucial for clearance of influenza virus. Our approach provides a novel strategy for developing next-generation influenza virus vaccines. Influenza A viruses have multiple HA subtypes that are antigenically diverse. Classical influenza virus vaccines are subtype specific, and they cannot induce satisfactory heterosubtypic immunity against multiple influenza virus subtypes. Here, we developed a live attenuated H1N1 influenza virus vaccine that allows the expression of α-Gal epitopes by infected cells. Anti-α-Gal antibody is naturally produced by humans. In the presence of this antibody, human cells infected with this experimental vaccine virus can enhance several antibody-mediated immune responses Importantly, mice expressing anti-α-Gal antibody can be fully protected by this H1N1 vaccine against a lethal H5 or H3 virus challenge. Our work demonstrates a new strategy for using a single influenza virus strain to induce broadly cross-reactive immune responses against different influenza virus subtypes.
抗半乳糖-α-1,3-半乳糖（抗-α-Gal）抗体在人体内高水平自然表达。它约占人类血液中发现的免疫球蛋白的 1%。在这里，我们设计了一种减毒流感病毒疫苗，可在感染细胞中产生α-Gal 表位，以促进感染细胞的调理作用，从而增强疫苗诱导的免疫反应。在正常人类血清存在的情况下，感染这种突变体的细胞可以增强人巨噬细胞的吞噬作用和 NK 细胞的细胞毒性。使用允许表达抗-α-Gal 抗体的基因敲除小鼠品系，我们表明该策略可以提高疫苗的免疫原性和保护范围。该疫苗可在小鼠模型中诱导对致死性异源亚型 1（H5）或 2（鼠适应 H3）流感病毒挑战的 100%保护。相比之下，在没有抗-α-Gal 抗体表达的野生型或基因敲除小鼠中，其异源保护作用是部分的，表明增强的疫苗诱导的保护作用需要接种疫苗时的抗-α-Gal 抗体。用这种疫苗免疫表达抗-α-Gal 的基因敲除小鼠，在致命病毒挑战下可产生强大的体液和细胞介导反应。该疫苗可刺激已知对清除流感病毒至关重要的 CD11b 肺树突状细胞。我们的方法为开发下一代流感病毒疫苗提供了一种新策略。甲型流感病毒有多种具有不同抗原性的 HA 亚型。经典的流感病毒疫苗是亚型特异性的，它们不能诱导对多种流感病毒亚型的满意异源免疫力。在这里，我们开发了一种减毒的 H1N1 流感病毒疫苗，允许感染细胞表达α-Gal 表位。抗-α-Gal 抗体是人体自然产生的。在这种抗体存在的情况下，感染这种实验疫苗病毒的人细胞可以增强几种抗体介导的免疫反应。重要的是，表达抗-α-Gal 抗体的小鼠可以完全免受这种 H1N1 疫苗的致命 H5 或 H3 病毒挑战的影响。我们的工作展示了一种使用单一流感病毒株诱导针对不同流感病毒亚型的广泛交叉反应性免疫反应的新策略。
