Vaccine-enhanced respiratory syncytial virus disease

描述（由申请人提供）：呼吸道合胞病毒（RSV）是全球婴幼儿呼吸道感染的主要原因。在20世纪60年代，一种福尔马林灭活的RSV疫苗被开发出来，并在美国给婴儿和儿童接种，随后在社区爆发期间接种了RSV疫苗的儿童暴露于RSV，导致感染RSV的疫苗接种者的发病率和死亡率增加。这种疾病的发病机制从未得到澄清，目前仍没有获得许可的针对RSV的疫苗。最近，我们建立了小鼠增强型RSV疾病模型，将支气管收缩和肺炎、RSV疾病的特征性和严重表现以及婴儿和儿童的疫苗增强型RSV疾病作为疾病增强的主要相关因素，比较典型疾病和疫苗增强型疾病引起的疾病程度。利用该模型和受感染儿童的死后肺切片，我们发现肺中固定补体的免疫复合物的沉积在增强型RSV疾病的发病机制中起着至关重要的作用。然而，导致免疫复合物疾病的病理性抗体的产生是由于在RSV失活期间福尔马林破坏RSV关键保护性表位引起的，还是由RSV特异性促进的，以及与B细胞对firv反应缺乏亲和成熟相关的问题尚不清楚。此外，目前尚不清楚RSV保护性抗原(融合（F)和附着(G)蛋白）是否可以安全地用于亚单位疫苗，或者是否可以使用不同的RSV灭活方法或亚单位疫苗来避免疾病增强。我们建议研究疫苗增强的RSV疾病，并进一步开发一种安全的疫苗测试模型。我们提出以下具体目的：1)确定RSV灭活方法对疫苗增强型疾病是否重要。2)确定RSV F和G保护性抗原在疫苗增强疾病中的作用。3)确定疫苗增强型疾病是否与B细胞对firstv反应的亲和力成熟缺失相关，因此可以通过促进B细胞对firstv反应的亲和力成熟来预防。

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the leading cause of respiratory infections in infants and young children worldwide. In the 1960s, a formalin-inactivated RSV vaccine (FIRSV) was developed and administered to infants and children in the U.S. Subsequent exposure of vaccinated children to RSV during community outbreaks resulted in increased morbidity and mortality in vaccine recipients who contracted RSV. The mechanism of illness was never clarified and there is still no licensed vaccine against RSV. Recently, we established a mouse model of enhanced RSV disease that uses bronchoconstriction and pneumonia, characteristic and serious manifestations of RSV disease and vaccine-enhanced RSV disease in infants and children, as primary correlates of disease enhancement to compare degrees of illness elicited by typical and vaccine enhanced disease. Using this model and post-mortem lung sections from affected children we showed that deposition of immune complexes that fix complement in the lungs play a crucial role in the pathogenesis of enhanced RSV disease. However, whether development of pathologic antibodies leading to immune-complex disease is caused by formalin disruption of RSV critical protective epitopes during inactivation or promoted by an RSV-specific and problem associated with lack of affinity maturation of the B cell response to FIRSV is unknown. Furthermore, it is unclear if either or both RSV protective antigens (fusion (F) and attachment (G) proteins) can be used safely in subunit vaccines or whether disease-enhancement can be avoided using a different method of RSV inactivation or a subunit vaccine. We propose to examine vaccine-enhanced RSV disease and further develop a safe model for vaccine testing. We propose the following Specific Aims: 1) Determine whether the method of RSV inactivation is important for vaccine-enhanced disease. 2) Determine the role of RSV F and G protective antigens in vaccine-enhanced disease. 3) Determine whether vaccine-enhanced disease is associated with the lack of affinity maturation of the B cell response to FIRSV, and therefore can be prevented by promoting affinity maturation of the B cell response to FIRSV.