Rational design of a respiratory syncytial virus vaccine to prevent asthma

描述（由申请人提供）：婴幼儿呼吸道合胞病毒（RSV）严重下呼吸道感染（LRTIs）与未发生严重RSV下呼吸道感染的同龄儿童相比，后续复发性喘息、气道高反应性（AHR）和哮喘的发生率高25-80%。一些严重的呼吸道合胞病毒下呼吸道感染可以识别出那些在遗传上易患老年哮喘的婴儿，但流行病学研究和动物模型表明，严重的呼吸道合胞病毒下呼吸道感染也可能特别有助于哮喘的发生。事实上，目前已有足够的证据表明，通过预防严重的RSV下呼吸道感染，RSV保护性疫苗在降低儿童哮喘发病率方面具有潜在作用。有趣的是，与支持卫生假说的大量证据一致，婴儿时期的上呼吸道感染（URTIs）已被证明可以降低儿童哮喘和AHR的发病率。此外，流行病学数据、动物模型研究和我们实验室的初步数据支持这样的假设，即合理设计的RSV减毒鼻内活疫苗（模拟RSV URTI）可能有助于调节宿主的免疫发展并预防哮喘的发生。来自其他人和我们实验室的数据表明，RSV及其主要保护性抗原融合(F)蛋白可以引发长期的自然T调节（nTreg）淋巴细胞反应，可能是通过myd88依赖性激活，负向调节哮喘发病。此外，我们实验室的动物和人类数据表明，RSV可以下调呼吸道中TLR4的表达。在典型的屋尘螨（HDM）疾病模型中，呼吸道上皮中TLR4的表达对于哮喘的开始至关重要。因此，如果我们建议研究的所有这些观察结果得到证实，考虑到上述效果的RSV疫苗的基本原理设计可能会改变儿童哮喘的前景：1)防止RSV LRTI的促哮喘作用，2)“成熟”宿主免疫。了解RSV疫苗和病毒糖蛋白对哮喘发病的保护作用，以及它们的风险调节机制，可以为设计一种同时针对两种关键儿科疾病的儿科疫苗提供理论依据。我们的具体目标是：确定呼吸道合胞病毒表面糖蛋白F和G的鼻内免疫是否调节哮喘的发生。目标2。确定RSV F疫苗是否通过Tlr2激活和下调呼吸道上皮Tlr4表达来扩大nTregs，从而减少哮喘的发生。目标3。确定cptsRSV248-404免疫是否能预防哮喘的发生。

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) severe lower respiratory tract infections (LRTIs) in infants and young children associate with 25-80% greater subsequent rates of recurrent wheezing, airways hyperreactivity (AHR) and asthma compared to same age children not experiencing severe RSV LRTIs. Some of these severe RSV LRTIs may identify those infants genetically predisposed to develop asthma at older age, but epidemiological studies and animal models suggest that severe RSV LRTIs may also specifically contribute to asthma inception. In fact, enough evidence exists today to consider a potential role for protective RSV vaccines in decreasing pediatric asthma rates by preventing severe RSV LRTI. Interestingly, and in line with the overwhelming evidence supporting the Hygiene Hypothesis, upper respiratory tract infections (URTIs) during infancy have been shown to decrease the rates of pediatric asthma and AHR. Moreover, epidemiological data, studies in animal models, and preliminary data from our laboratory support the hypothesis that a rationally designed live attenuated intranasal (IN) RSV vaccine (mimicking an RSV URTI) may contribute to modulate the development of immunity in the host and prevent asthma inception. Data from others and our laboratory show that RSV and its main protective antigen, the fusion (F) protein, can elicit a long-lived natural T regulatory (nTreg) lymphocyte response, presumably through Myd88-dependent activation, negatively modulating asthma inception. In addition, animal and human data from our laboratory demonstrate that RSV can downregulate TLR4 expression in the respiratory tract. TLR4 expression in the respiratory epithelium is critical for the inception f asthma in the classic house dust mite (HDM) model of disease. Therefore, if all these observations - which we propose to study- are confirmed, rationale design of an RSV vaccine considering the aforementioned effects, may change the landscape of pediatric asthma by: I) protecting against the pro-asthmatic effects of RSV LRTI, and 2) "maturing" host immunity. Understanding the protective effects of RSV vaccines and the virus glycoproteins against the inception of asthma, and their mechanisms of risk modulation, can lead to the rationale design of a pediatric vaccine working simultaneously against two critical pediatric diseases. Our Specific Aims are: Aim 1. Determine whether intranasal immunization using RSV surface glycoproteins F and G modulates the inception of asthma. Aim 2. Determine whether RSV F vaccines decrease inception of asthma by expanding nTregs through Tlr2 activation and downregulation of Tlr4 expression in respiratory epithelium. Aim 3. Determine whether IN immunization with cptsRSV248-404 prevents the inception of asthma.