Development of vaccination strategies to elicit broadly protective immunity against influenza

摘要 预防流感病毒感染最有效的措施是接种疫苗。然而，由于正在进行的 抗原性漂移，目前的流感疫苗需要每年重新配制才能提供足够的保护。此外， 接种流感疫苗后产生的免疫反应是针对不同毒株的，因此不能预防流感 新的季节性和大流行病毒，需要开发一种具有通用性的流感疫苗 获得针对不同流感病毒株的终身保护的能力。发展的主要目标是 对流感的保护性免疫是血凝素糖蛋白(HA)，它由两种不同的 功能区：参与病毒进入并受抗原漂移影响的球形头部，以及 茎结构域，高度保守，介导病毒融合。HA上的免疫优势抗原部位 Head能诱导高亲和力、菌株特异性的抗HA抗体反应，而与之相反，抗HA抗体 表位可以介导广泛的保护活性，但是免疫亚显性的。克服固有的 HA头部的免疫优势，并将免疫重新聚焦于保守的、交叉保护的表位，我们将 设计创新的马赛克HA蛋白免疫原，其中HA头部抗原位点将被沉默。我们的前辈 研究表明，接种HA：抗HA免疫复合物(ICs)可调节适应性 免疫球蛋白Fc结构域与γ表面Fc受体(FcγR)的特异性相互作用 效应器白细胞。我们的深入研究表明，特定的Fc-γ受体：CD23与B细胞和 FcγRIIA对树突状细胞(DC)的作用，对于诱导高亲和力Ig G反应和T细胞免疫至关重要。 分别进行了分析。基于这些知识，我们将利用这些途径来扩大特异性，增加亲和力 并选择对保守的流感表位进行长寿体液和细胞免疫。我们将设计和 嵌合型HAS和Fc基因工程抗HA免疫原的免疫原性评价 对特定的人FcγR类型具有选择性亲和力。这些研究将导致开发和临床前 评估疫苗接种策略以获得强大和持久的抗病毒免疫，这可能会改善 目前季节性疫苗的广度，但也可以用于开发新的下一代疫苗 通用流感病毒疫苗。

ABSTRACT The most effective measure for the prevention of influenza virus infection is vaccination. However, due to ongoing antigenic drift, current influenza vaccines need annual reformulation to provide sufficient protection. Furthermore, immune responses elicited upon influenza vaccination are strain-specific and fail to provide protection against novel seasonal and pandemic viruses, necessitating the development of a universal influenza vaccine with the capacity to elicit lifelong protection against diverse influenza virus strains. A major target for the development of protective immunity against influenza is the hemagglutinin glycoprotein (HA), which comprises two distinct functional domains: the globular head, which participates in viral entry and is subject to antigenic drift, and the stalk domain, which is highly conserved and mediates viral fusion. Immunodominant antigenic sites on the HA head elicit high-affinity, strain-specific anti-HA Ab responses, whereas in contrast, Abs against conserved epitopes can mediate broadly protective activity, but are immunosubdominant. To overcome the inherent immunodominance of the HA head and refocus immunity towards conserved, cross-protective epitopes, we will engineer innovative mosaic HA protein immunogens in which HA head antigenic sites will be silenced. Our prior research demonstrated that vaccination with HA:anti-HA IgG immune complexes (ICs) can modulate adaptive immunity through specific interactions of the Fc domain of the IgG with Fcγ receptors (FcγR) on the surface of effector leukocytes. Our in-depth studies revealed that engagement of specific FcγRs: CD23 on B-cells and FcγRIIa on dendritic cells (DCs), is critical for the induction of high-affinity IgG responses and T-cell immunity, respectively. Based on this knowledge, we will exploit these pathways to broaden specificity, increase affinity and select for long-lived humoral and cellular immunity to conserved influenza epitopes. We will design and evaluate the immunogenicity of IC-based immunogens comprising mosaic HAs and Fc-engineered anti-HA IgGs with selective affinity for specific human FcγR types. These studies will lead to the development and pre-clinical evaluation of vaccination strategies to elicit robust and long-lasting antiviral immunity, which could improve the breadth of current seasonal vaccines, but could also be employed in the development of novel, next-generation universal influenza virus vaccines.