Flu-IGIP: Live attenuated influenza virus vaccines with improved stimulation of IgA responses

项目摘要 世界卫生组织（WHO）估计，季节性流感导致约10亿人感染， 世界上每年有500万例严重疾病，30万到50万人死亡。 接种疫苗是预防流感的第一道防线，但这些病毒不断变化的性质使 疫苗在一个季节后无效或对大流行毒株无效。因此，呼吁更广泛地 保护性流感病毒疫苗，其导致针对所有或几种流感病毒的保护， 持久免疫力在典型的流感感染后，在粘膜组织中检测到伊加和IgG应答。 水平，具有抗流感的中和活性。伊加反应被认为对预防 和/或控制无数的生殖器、肠道和呼吸道感染，包括流感。尤其是伊加 多聚体形式的分泌型伊加（sIgA）通常比IgG更具交叉反应性。伊加中和 由于它不能固定和激活补体级联反应，因此它可以杀死病原体而不引起炎症。在 相反，结合但不中和病毒的IgG反应（非保护性抗体）已经被联系起来， 免疫复合物介导的疾病。因此，旨在改善粘膜伊加反应的疫苗策略 对于增强和/或扩大针对抗原漂移变体的保护将是理想的， 同时最大限度地减少与次优抗体-抗原匹配、疾病增强或 免疫病理学迄今可用的流感疫苗尚未被设计成特异性上调 伊加应答和/或使伊加/IgG平衡向更显著的伊加应答倾斜，特别是在 气道的局限性。目前批准的或实验性的减毒活流感病毒疫苗是 被认为刺激粘膜和全身伊加和IgG以及T细胞介导的免疫，因为它们 更接近于自然病毒感染，但它们对促进伊加反应的相对影响不是 很好理解。IgA诱导蛋白（IGIP），最初在牛胃肠道中发现， 相关淋巴组织（GALT），正调节伊加的表达。我们假设 理想的流感疫苗是一种能有效刺激粘膜表面伊加以阻止病毒传播的疫苗。 到达目标细胞。我们进一步假设，产生IGIP的减毒活病毒（IGIP- LAIV）将上调针对流感攻击的粘膜伊加应答。因此， 申请开发疫苗策略，这将导致增强伊加反应后， 预防针据我们所知，不存在特异性促进伊加应答的流感疫苗， 保持对其他体液和T细胞保护性反应的有效刺激。IGIP-LAIV战略 在本申请中提出的是增强针对流感病毒的保护性伊加应答的第一次尝试。

Project Summary The Word Health Organization (WHO) estimates that seasonal influenza causes about one billion infections, 3- 5 million cases of severe disease, and between 300,000 and 500,000 deaths around the word every year. Vaccination is the first line of defense against influenza, but the ever-changing nature of these viruses make vaccines ineffective after a single season or against pandemic strains. Hence, the appeal for more broadly protective influenza virus vaccines that result in protection against all or several influenza viruses and long- lasting immunity. After a typical influenza infection, both IgA and IgG responses are detected at the mucosal level with neutralizing activity against influenza. IgA responses are considered of great significance to prevent and/or control a myriad of genital, intestinal, and respiratory infections, including influenza. IgA, particularly secretory IgA (sIgA) in its multiple multimeric forms is typically more cross-reactive than IgG. IgA neutralizes pathogens without causing inflammation because of its inability to fix and activate the complement cascade. In contrast, IgG responses that bind but do not neutralize the virus (non-protective antibodies) have been linked to immune complex–mediated disease. Thus, a vaccine strategy aimed at improving mucosal IgA responses against influenza would be ideal to enhance and/or broaden protection against antigenic drifted variants or clades while minimizing the risks associated with suboptimal antibody-antigen match, disease enhancement or immunopathology. The influenza vaccines available to date have not been designed to specifically upregulate IgA responses and/or tilt the IgA/IgG balance towards more prominent IgA responses, particularly within the confinements of the airway. Currently approved or experimental live attenuated influenza virus vaccines are thought to stimulate mucosal and systemic IgA and IgG as well as T-cell mediated immunity because they more closely resemble a natural virus infection, but their relative influence on promoting IgA responses is not well understood. The IgA-inducing protein (IGIP), initially characterized in the bovine gastrointestinal associated lymphoid tissue (GALT), was shown to positively regulate IgA expression. We hypothesize that an ideal influenza vaccine would be one that efficiently stimulates IgA at mucosal surfaces to stop the virus from ever reaching the target cells. We further hypothesize that a live attenuated virus that produces IGIP (IGIP- LAIV) will upregulate mucosal IgA responses against influenza challenge. It is therefore the goal of this application to develop a vaccine strategy that will result in enhanced IgA responses against influenza after vaccination. To our knowledge, no influenza vaccine exists that specifically promotes IgA responses while retaining efficient stimulation of other humoral and T-cell protective responses. The IGIP-LAIV strategy proposed in this application is the first attempt to enhance protective IgA responses against influenza viruses.