Vaccine-enhanced respiratory syncytial virus disease

描述(申请人提供)：1967年，呼吸道合胞病毒(RSV)福尔马林灭活疫苗使婴儿和儿童在接触RSV后在社区发展为一种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然不清楚。此外，针对这种病毒的灭活疫苗为什么会引起非保护性抗体还不清楚。自那以后，没有任何针对RSV的疫苗获得许可。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的保护性抗体反应所必需的。我们进一步假设，用非复制型RSV疫苗免疫RSV初生鼠可以激活没有亲和力成熟的B细胞，从而引起非保护性RSV特异性抗体反应。这种非保护性反应会导致免疫复合体在肺部形成和沉积，并加剧疾病。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): 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.