Vaccine-enhanced respiratory syncytial virus disease

描述(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。20世纪60年代，一种福尔马林灭活RSV疫苗(FIRSV)被开发出来，并用于美国的婴儿和儿童。随后，在社区暴发期间，接种疫苗的儿童暴露于RSV，导致感染RSV的疫苗接受者的发病率和死亡率增加。疾病的机制一直没有弄清楚，也仍然没有获得许可的RSV疫苗。最近，我们建立了一种增强型呼吸道合胞病毒病的小鼠模型，以呼吸道合胞病毒病和肺炎、呼吸道合胞病毒病的特征和严重表现以及疫苗增强型呼吸道合胞病毒病在婴幼儿中的特点和严重程度作为疾病加重的主要相关因素，以比较典型和疫苗强化病引起的疾病程度。利用这一模型和受影响儿童的尸检肺切片，我们证明了肺内固定补体的免疫复合体的沉积在RSV增强型疾病的发病机制中发挥了关键作用。然而，导致免疫复合体疾病的病理抗体的产生是由福尔马林破坏RSV关键保护表位在灭活过程中引起的，还是由RSV特异性的促进引起的，以及与B细胞对FIRSV的反应缺乏亲和力成熟有关的问题尚不清楚。此外，目前还不清楚是否有一种或两种RSV保护性抗原(融合(F)和附着(G)蛋白)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。我们建议检查疫苗增强型RSV疾病，并进一步开发疫苗测试的安全模型。我们提出了以下具体目标：1)确定RSV灭活方法对于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型疾病中的作用。3)确定疫苗增强型疾病是否与B细胞对FIRSV的反应缺乏亲和力成熟有关，因此可以通过促进B细胞对FIRSV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.