Immune factors in vaccine-enhanced pandemic H1N1 influenza disease

描述（由申请人提供）：2009年H1N1流感大流行举例说明了动物流感病毒在缺乏交叉保护免疫的人群中出现的威胁。2009- 2010年有值得注意的观察结果表明，免疫介质是导致严重甲型H1N1流感大流行病例的一个因素，在一些队列中，季节性三价灭活疫苗增加了患严重甲型H1N1流感的风险。在猪接种灭活的H1猪流感病毒后，在异源panH1N1攻毒后，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分化菌株时是交叉保护还是加重疾病的关键因素。我们在本提案中的目标是确定免疫反应的哪个区室和灭活疫苗中的哪些病毒成分对感染异源panH1N1的接种宿主的疾病增强是不可或缺的。我们将通过一种实验方法来实现目标，其中包括以下具体目标：(1)通过被动免疫确定由灭活H1疫苗引发的抗体是否使猪在感染异源panH1N1病毒时易患增强疾病。(2)利用重组疫苗，确定疫苗株的病毒包膜蛋白与甲型h1n1流感病毒的不匹配是否足以引起甲型h1n1流感病毒攻击后疾病的增强。提出这项研究的基本原理是，它将在天然流感宿主中回答关于抗原不匹配疫苗如何增强人类新菌株感染的机制的重要问题。这些结果还将使未来的机制研究集中在关键的病毒抗原（如特异性蛋白和靶向表位）和宿主免疫因子（如补体固定IgG导致粒细胞浸润；ctl介导的上皮细胞死亡）上。这些调查将具有重要意义，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，特别是在新菌株适应在人类中传播的意外情况下。实现既定目标并朝着我们的长期研究目标前进，也将为破坏呼吸道病毒感染的正常反应的新机制提供重要的见解。在传统的人类疾病研究平台之外，在动物模型中探讨我们关于严重的、与免疫相关的甲型h1n1流感的问题，是理解一个困难的公共卫生问题的一种创新方法。

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. PUBLIC HEALTH RELEVANCE: In situations such as the 2009 H1N1 influenza pandemic, most of the human population lacks immunological protection against a newly circulating influenza virus. Immunity induced by previous strains with distinct antigenic properties can sometimes exacerbate infection with the new strain. The proposed study has clear relevance to public health because it will investigate host and viral factors in this phenomenon. Results may lead to improved design of seasonal influenza vaccines for contingencies when novel animal strains adapt to humans.