Immune factors in vaccine-enhanced pandemic H1N1 influenza disease

描述（由申请方提供）：2009年H1N1流感大流行例证了动物流感病毒在缺乏交叉保护性免疫力的人群中出现的威胁。在2009-10年有值得注意的观察，免疫介质是严重的大流行性H1N1（panH 1 N1）病例的一个因素，在一些队列中，灭活的季节性三价疫苗增加了严重的panH 1 N1疾病的风险。在接种灭活H1猪流感病毒后，随后进行异源panH 1 N1攻击的猪中观察到类似的疾病增强现象。因此，我们的长期目标是阐明决定流感疫苗在感染抗原性不同的毒株后是否交叉保护或加重疾病的关键因素。我们的目标是在这个建议中，以确定哪些隔室的免疫反应和灭活疫苗中的病毒成分是不可或缺的疾病增强在接种疫苗的宿主感染异源泛H1N1。我们将通过一种实验方法来实现这些目标，该方法包括以下具体目标：（1）通过被动免疫来确定当猪感染异源panH 1 N1病毒时，灭活H1疫苗引发的抗体是否使猪易于增强疾病。(2)使用重组疫苗，确定疫苗株和panH 1 N1病毒包膜蛋白之间的错配是否足以导致panH 1 N1攻毒后疾病增强。这项拟议研究背后的基本原理是，它将回答在天然流感宿主中的重要问题，即抗原错配疫苗可以增强对人群的新型毒株感染的机制。这些结果还将把未来的机制研究重点放在关键病毒抗原（例如靶向的特定蛋白质和表位）和宿主免疫因子（例如导致粒细胞浸润的补体固定IgG; CTL介导的上皮细胞死亡）上。这些研究将具有重要意义，因为它们将为改进季节性疫苗的设计和交付提供新的标准，特别是当新菌株适应人类传播时的应急措施。实现既定目标并朝着我们的长期研究目标迈进，也将对破坏呼吸道病毒感染正常反应的新机制提供重要见解。在人类疾病研究的传统平台之外的动物模型中探索我们关于严重的、免疫相关的泛H 1 N 1疾病的问题，是理解一个困难的公共卫生问题的创新方法。

DESCRIPTION (provided by applicant): The 2009 H1N1 influenza pandemic exemplified the threat of animal influenza viruses emerging in a human population that lacks cross-protective immunity. There were notable observations in 2009-10 that immune mediators were a factor in severe pandemic H1N1 (panH1N1) cases and that an inactivated seasonal trivalent vaccine in some cohorts enhanced the risk of severe panH1N1 illness. A similar phenomenon of enhanced disease is observed in pigs after vaccination with an inactivated H1 swine influenza virus, followed by heterologous panH1N1 challenge. Therefore, our long-term goal is to elucidate the pivotal factors that determine if influenza vaccines cross-protect or exacerbate disease upon infection with antigenically divergent strains. Our objectives in this proposal are to identify which compartment of the immune response and which viral constituents in an inactivated vaccine are integral to disease enhancement in a vaccinated host infected with heterologous panH1N1. We will meet the objectives by an experimental approach that includes the following specific aims: (1) Determine by passive immunization if antibodies elicited by an inactivated H1 vaccine predispose pigs for enhanced disease when infected with the heterologous panH1N1 virus. (2) Using recombinant vaccines, determine if mismatch between viral envelope proteins of the vaccine strain and panH1N1 is sufficient to cause enhanced disease following panH1N1 challenge. The rationale behind the proposed study is that it will answer vital questions, in a natural influenza host, about the mechanisms by which an antigenically mismatched vaccine can enhance infection with a strain novel to the human population. The results will also focus future mechanistic studies into the critical viral antigens (e.g. specific proteins and epitopes targeted) and host immune factors (e.g. complement-fixing IgG leading to granulocyte infiltration; CTL-mediated epithelial cell death). These investigations will be significant because they will provide new criteria for improved seasonal vaccine design and delivery, especially for contingencies when novel strains adapt to circulate in humans. Achieving the stated aims and progressing toward our long-term research goal will also deliver significant insight into a novel mechanism that disrupts a normal response to viral infection of the respiratory tract. Probing our questions about severe, immune- related panH1N1 disease in an animal model outside conventional platforms of human disease research is an innovative approach to understanding a difficult public health problem.