Vaccine-enhanced respiratory syncytial virus disease

描述（由申请方提供）：1967年，针对呼吸道合胞病毒（RSV）的福尔马林灭活疫苗引发婴儿和儿童在社区暴露于RSV后发生增强型下呼吸道疾病。37年后，这种增强型疾病的发病机制仍不清楚。此外，为什么针对该病毒的灭活疫苗会引发非保护性抗体尚不清楚。从那时起，没有针对RSV的疫苗被许可。我们使用一种新的增强型疾病小鼠模型来解决这些问题。我们假设RSV特异性B细胞的亲和力成熟是产生针对RSV的保护性抗体应答所必需的。我们进一步假设，用非复制型RSV疫苗免疫未感染RSV的小鼠激活了不经历亲和力成熟的B细胞，因此激发了非保护性RSV特异性抗体应答。这种非保护性反应导致免疫复合物形成和沉积在肺中并增强疾病。我们提出了以下具体目的：1）确定RSV灭活方法是否对疫苗增强的疾病重要。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FIRSV应答的亲和力成熟缺乏相关，因此可以通过促进B细胞对FIRSV应答的亲和力成熟来预防。

DESCRIPTION (provided by applicant): In 1967, the formalin-inactivated vaccine against respiratory syncytial virus (RSV) primed infants and children to develop an enhanced form of lower respiratory tract disease upon exposure to RSV in the community. Thirty-seven years later, the mechanism of illness of this enhanced disease remains unclear. Furthermore, why inactivated vaccines against this virus elicit non-protective antibody is not understood. No vaccine against RSV has been licensed since. We use a novel mouse model of enhanced disease to address these questions. We hypothesize that affinity maturation of RSV-specific B cells is required for development of a protective antibody response against RSV. We further hypothesize that immunization of RSV- naive mice with nonreplicating RSV vaccines activates B cells that do not undergo affinity maturation and therefore elicits a non-protective RSV-specific antibody response. This non-protective response results in immune complex formation and deposition in the lungs and enhanced disease. 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.