Pre-transplant vaccination against pulmonary viral infection

描述（由申请人提供）：造血细胞移植（HCT）后的感染性并发症是一个重要的医疗保健问题。HCT患者发生严重呼吸道感染的风险增加，其中呼吸道合胞病毒（RSV）感染是最常见的。在一般人群中，RSV感染是常见的，几乎每个人都在三岁之前感染。然而，对RSV的保护性免疫是不完全的，因为在整个生命中感染是常见的。在免疫功能正常的成年人中，这些通常表现出与普通感冒（鼻病毒）相似的症状。另一方面，在移植受者中，RSV的下呼吸道感染是死亡的重要原因。在拟议的研究中，我们将测试一种在移植后早期管理呼吸道感染的新方法。多年来，我们一直在开发针对呼吸道病毒（包括RSV）的经鼻给药灭活病毒疫苗。目前还没有获得许可的RSV疫苗，治疗方案也不太理想。造血细胞移植（HCT）患者是用作RSV疫苗接种的初始目标群体的理想患者群体。首先，HCT患者在移植后相对较短的时间内呼吸道感染RSV的风险最高。因此，成功的疫苗不一定需要提供长期保护。其次，即使对RSV的免疫力有微小的改善，也可能具有临床益处。第三，免疫经验丰富的成年人的疫苗接种不太可能导致与20世纪60年代福尔马林灭活的RSV疫苗相关的“疫苗增强的疾病”。为此，我们开发了一种新的同种异体HCT相关RSV感染模型。通常对RSV感染具有抗性的B6小鼠在异基因造血细胞移植（Allo-HCT）后显著更易感。我们将通过追求以下两个目标来研究移植前接种疫苗对抗RSV的潜在益处：目标1：确定活疫苗与灭活疫苗对RSV易感性的免疫原性和有效性目标2：询问移植后对RSV的免疫机制，这些研究将使我们能够确定在造血细胞/骨髓移植之前给患者接种疫苗是否可以预防移植后的呼吸道感染，移植期

DESCRIPTION (provided by applicant): Infectious complications following hematopoietic cell transplant (HCT) are a significant healthcare problem. HCT patients are at increased risk for developing severe respiratory infections, of which respiratory syncytial virus (RSV) infection is among the most common. In the general population, infection with RSV is common, with nearly everyone infected by three years of age. However, protective immunity to RSV is incomplete, in that infections throughout life are commonplace. In immunocompetent adults, these typically present with symptoms similar to the common cold (rhinovirus). In transplant recipients, on the other hand, lower respiratory tract infection with RSV is a significant cause of death. In the proposed studies, we will test a new method to manage respiratory infection in the early post-transplant period. For several years, we have been developing nasally administered, inactivated viral vaccines against respiratory viruses, including RSV. No licensed vaccine currently exists for RSV, and therapeutic options are less than optimal. Hematopoitic cell transplant (HCT) patients are an ideal patient population to serve as an initial target population for RSV vaccination. First, HCT patients are at highest risk for respiratory infection with RSV for a relatively short time period after transplant. Thus, a successful vaccine would not necessarily need to provide long-term protection. Second, even a small improvement in immunity to RSV is likely to be of clinical benefit. Third, vaccination of immunologically experienced adults is unlikely to lead to "vaccine- enhanced disease" associated with formalin-inactivated RSV vaccines in the 1960's. To this end, we have developed a novel model of allogeneic HCT- associated RSV infection. B6 mice, normally resistent to RSV infection are dramatically more susceptible following allogeneic hematopoietic cell transplant (Allo-HCT). We will investigate the potential benefit of pre-transplant vaccination against RSV via pursuing the following two Aims: Aim 1: Determine the immunogenicity and efficacy of live versus inactivated pre-transplant vaccination on RSV susceptibility Aim 2: Interrogate the mechanisms of post-transplant immunity to RSV Together, these studies will allow us determine whether vaccinating patients prior to hematopoietic cell/ bone marrow transplant can prevent respiratory infection in the post-transplant period.