Role of F Protein Conformation in RSV Vaccine Efficacy

 描述（由申请方提供）：婴幼儿中的大多数急性病毒性呼吸道疾病是由呼吸道合胞病毒（RSV）引起的。该病毒还在老年人和免疫功能低下人群中引起严重疾病，并且是健康成人人群发病的重要原因。尽管这种病毒在世界范围内造成了巨大的疾病负担，但没有可用的疫苗。几个问题阻碍了RSV疫苗的开发。首先是安全。早期的福尔马林灭活疫苗（FI-RSV）刺激了弱的和不平衡的免疫反应，使婴儿在自然暴露于活病毒时容易患上更严重的疾病。第二个问题是许多候选疫苗未能刺激保护性免疫反应。第三个问题是自然感染和候选疫苗不能刺激长期的保护性记忆反应。所有这些问题最终是由于缺乏对参与刺激保护性以及持久的抗RSV免疫应答的机制的理解。该提议将检验RSV F蛋白的不同构象形式影响抗RSV免疫应答的性质的假设。目的是确定在病毒样颗粒上表达的RSV F蛋白的构象，其刺激高滴度中和抗体和保护性、长寿命和记忆性免疫应答，并了解负责产生这些应答的机制。为了验证这一假设，提出了四个目标。具体目标1：表征在小鼠和棉鼠中通过含有稳定的融合前或稳定的融合后F蛋白的VLP刺激的抗体的RSV F蛋白结合特性。具体目标二：为了阐明抗G抗体在小鼠和棉鼠中由含有RSV F蛋白的融合前形式的VLP和含有融合后形式的VLP诱导的中和滴度中的作用。具体目标3：表征作为母体免疫模型的RSV经历小鼠和棉鼠中对含有融合前和融合后形式F的VLP的免疫应答。具体目标4：以确定含有融合前和融合后F蛋白的VLP是否在小鼠和棉鼠中诱导RSV F蛋白特异性长寿命骨髓相关浆细胞（LLPC）和记忆B细胞。

 DESCRIPTION (provided by applicant): Most acute viral respiratory disease in infants and young children is due to respiratory syncytial virus (RSV). This virus also causes serious disease in elderly and immunocompromised populations and is a significant cause of morbidity in healthy adult populations. Despite the substantial disease burden due to this virus worldwide, there are no vaccines available. Several problems have impeded RSV vaccine development. First is safety. An early formalin-inactivated vaccine (FI-RSV), which stimulated weak and unbalanced immune responses, predisposed infants to more severe disease upon natural exposure to live virus. A second problem is the failure of many vaccine candidates to stimulate protective immune responses. A third problem is the failure of natural infection as well as vaccine candidates to stimulate long-lived, protective memory responses. All these problems are ultimately due to a lack of understanding of mechanisms involved in stimulation of protective as well as durable anti-RSV immune responses. This proposal will test the hypothesis that different conformational forms of RSV F protein impact the properties of anti-RSV immune responses. The goal is to define conformations of RSV F protein, expressed on virus-like particles, that stimulate high titer neutralizing antibodies and protective, long-lived and memory immune responses and to understand the mechanisms responsible for generation of these responses. To test the hypothesis, four aims are proposed. Specific Aim 1: to characterize the RSV F protein binding properties of antibodies stimulated in mice and in cotton rats by VLPs containing stabilized pre-fusion or stabilized post-fusion F protein. Specific Aim 2: to clarify th role of anti-G antibodies in the neutralization titers induced in mice and cotton rats by VLPs containing the pre-fusion form of the RSV F protein and VLPs containing the post-fusion form. Specific Aim 3: to characterize immune responses to VLPs containing pre- and post-fusion forms of F in RSV experienced mice and cotton rats as models for maternal immunization. Specific Aim 4: to determine if VLPs containing the pre-fusion and the post-fusion F proteins induce RSV F protein specific long-lived bone marrow associated plasma cells (LLPC) and memory B cells in both mice and cotton rats.