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，3- 每年全世界有500万例严重疾病，30万至50万人死亡。 接种疫苗是预防流感的第一道防线，但这些病毒的不断变化的性质使 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，可预防所有或几种流感病毒，并长期有效 永久豁免权。在典型的流感感染后，在粘膜中检测到IgA和Ig G反应 具有中和流感活性的水平。免疫球蛋白反应被认为对预防 和/或控制无数的生殖器、肠道和呼吸道感染，包括流感。IGA，特别是 分泌型免疫球蛋白A(SIgA)具有多种多聚体形式，通常比免疫球蛋白具有更强的交叉反应。IGA中和 不会引起炎症的病原体，因为它不能修复和激活补体级联。在……里面 相比之下，结合但不能中和病毒的免疫球蛋白反应(非保护性抗体)已被联系在一起 免疫复合体介导的疾病。因此，旨在改善粘膜免疫球蛋白A反应的疫苗策略 预防流感将是增强和/或扩大对抗原漂移变体或 同时最大限度地减少与抗体-抗原匹配不佳、疾病增强或 免疫病理学。到目前为止，可用的流感疫苗还没有被设计成专门上调 免疫球蛋白应答和/或使免疫球蛋白/免疫球蛋白平衡向更突出的免疫球蛋白应答倾斜，特别是在 对呼吸道的限制。目前批准的或正在试验的减毒活流感病毒疫苗有 认为可以刺激粘膜和系统的免疫球蛋白A和免疫球蛋白G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IgA反应的相对影响并不是 很好理解。IgA诱导蛋白(IGIP)，最初在牛的胃肠道中具有特征 相关淋巴组织(GALT)对IgA的表达有正向调节作用。我们假设一个 理想的流感疫苗应该是一种能有效刺激粘膜表面的IgA以阻止病毒传播的疫苗。 曾经到达过目标细胞。我们进一步假设，产生IGIP(IGIP-)的减毒活病毒 LAIV)将上调黏膜对流感的免疫球蛋白A应答。因此，它的目标是 申请开发疫苗策略，以增强对流感的免疫球蛋白A反应 接种疫苗。据我们所知，目前还没有专门促进IgA反应的流感疫苗 保持对其他体液和T细胞保护反应的有效刺激。IGIP-LAIV战略 在这项申请中提出的是第一次尝试增强对流感病毒的保护性IgA反应。

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.