RSV Upper Airway Infection and Otitis Media

描述（申请人提供）：呼吸道合胞病毒（RSV）是婴幼儿和老年人下呼吸道感染的主要原因，RSV引起的细支气管炎和肺炎是幼儿住院的主要原因。多年来，一直在积极寻找一种安全有效的疫苗来预防初生婴儿中的原发性RSV感染，尽管RSV疫苗开发的进展受到病毒的不寻常生物学以及在20世纪60年代中期福尔马林灭活的全病毒疫苗制剂的试验期间疫苗增强疾病的影响的阻碍。建立RSV免疫的问题由于以下事实而复杂化：虽然中和抗体的存在通常对肺部感染具有保护作用，但在整个生命中上呼吸道的再感染是规律。获得性免疫应答不能保护上呼吸道的观察结果已经很好地建立，但还没有很好地理解。虽然上呼吸道疾病不会危及生命，但它仍然是一个非常重要的健康问题，因为RSV已被证明是导致儿童细菌性中耳炎（OM）的主要病毒病原体。由于RSV是OM的主要触发因素，并且临床数据显示幼儿频繁再感染，因此我们假设开发针对RSV感染的有效疫苗将对OM的发生产生显著影响。在该资助的第一个周期中，我们开发了RSV上呼吸道感染的小鼠和灰鼠模型，并使用这些模型测试了新的RSV候选疫苗：表达RSV F蛋白的重组纽卡斯尔病病毒载体。我们已经发现用该构建体的粘膜引发在两种啮齿动物模型中都具有保护性，并且现在希望探索这种保护的机制以及该疫苗在病毒和细菌共感染后抑制细菌OM的能力。我们的具体目标是：1）确定针对RSV的免疫是否可以在灰鼠模型中保护免受细菌共感染; 2）定义上呼吸道保护的相关性;和3）确定RSV感染增强细菌OM的宿主易感性的机制。 最近的研究发现，婴儿和幼儿的中耳炎或耳部感染总是由病毒和细菌有机体感染引起的。导致耳朵感染的细菌通常生活在鼻子里，直到孩子感冒才成为问题。一旦孩子感染病毒，宿主的防御能力就会受损，通常无害的细菌就会引起疾病。有一种称为RSV的感冒病毒反复感染儿童，并且在大多数患有耳部感染的儿童中发现。我们的研究小组已经发现了一种针对这种病毒的新疫苗，并希望测试对RSV的免疫力是否可以防止导致细菌性耳部感染的过程。

DESCRIPTION (provided by applicant): Respiratory Syncytial Virus (RSV) is a major cause of lower respiratory tract infection in infants and the elderly, and bronchiolitis and pneumonia caused by RSV are the primary reason for hospitalization of young children. For many years there has been an active search to find a safe and effective vaccine to prevent primary RSV infection in naWve infants, although progress in RSV vaccine development has been hampered by the unusual biology of the virus as well as the legacy of vaccine-enhanced illness during trials of a formalin-inactivated whole virus vaccine preparation in the mid 1960's. The problem of establishing RSV immunity is complicated by the fact that while the presence of neutralizing antibody is generally protective against pulmonary infection, re-infection of the upper airway throughout life is the rule. The observation that adaptive immune response fails to protect the upper airway is well established, but not well understood. While upper airway disease is never life threatening, it is nonetheless a very important health problem as RSV has been shown to be the predominant viral pathogen predisposing children to bacterial otitis media (OM). Since RSV is a major trigger for OM, and clinical data show frequent reinfection in young children, we hypothesize that development of an effective vaccine targeting RSV infection will have a significant impact on the occurrence of OM. In the first cycle of this grant we have developed both murine and chinchilla models of RSV upper airway infection, and have used these to test a new RSV vaccine candidate: a recombinant Newcastle disease virus vector expressing the RSV F protein. We have found that mucosal priming with this construct is protective in both rodent models, and now wish to explore both the mechanism of this protection as well as the ability of this vaccine to inhibit bacterial OM following viral and bacterial co- infection. Our specific aims are these: 1) Determine whether immunization against RSV can protect against bacterial co-infection in the chinchilla model; 2) Define the correlates of upper airway protection; and 3) Determine the mechanisms by which RSV infection enhances host susceptibility of bacterial OM. Recent studies have found that otitis media, or ear infections, in babies and young children are always caused by infection with both a viral and a bacterial organism. The bacteria that cause ear infections normally live in the nose, and are not a problem until the child catches a cold. Once the child has a virus infection, the host defenses are damaged, and normally harmless bacteria then cause disease. There is one cold virus called RSV which infects children over and over and is found in the majority of children with ear infections. Our group has found a new vaccine against this virus, and want to test whether immunity to RSV can protect against the process that causes bacterial ear infections.