Development, Production and Testing of VLP based Respiratory Syncytial Virus (RSV

描述（由申请方提供）：本提案的目的是开发一种安全有效的基于病毒样颗粒（VLP）的呼吸道合胞病毒（RSV）疫苗，以预防由该病原体引起的疾病。RSV在婴儿、儿童和老年人中引起的呼吸道疾病具有全球经济和公共卫生影响。最近的一项全球估计[5]表明，超过3300万5岁以下儿童患有RSV相关下呼吸道感染（ALRI），每年至少有300万人住院，约199，000人死于该疾病。在美国，CDC估计有超过126，000例RSV相关的儿科住院治疗，每年的费用超过9亿美元。目前没有疫苗获得许可，对该疾病的治疗有限;预防性干预依赖于对有感染风险的婴儿给予中和单克隆抗体（Synagis）和支持性护理。安全有效的疫苗将是最理想和最具成本效益的预防性干预措施。然而，迄今为止，这种疫苗的产生尚未实现，并且其发展受到20世纪60年代生产的福尔马林灭活疫苗引起的疾病增强的阻碍。其他方法并不成功，甚至是危险的。在这里，我们建议开发和测试展示RSV抗原的病毒样颗粒作为创建安全有效的RSV疫苗的策略。VLP是野生型病毒颗粒的模拟物，但不包含病毒遗传物质，使其无法复制或引起感染。VLP表面上天然抗原的颗粒性质和冗余阵列激发免疫系统的更大识别。我们已经成功地产生了天然RSV-VLP，其显示表面刺突并类似于野生型病毒。我们的基于RSV的VLP候选疫苗通过共表达蛋白质M、F和SH或M、F或M、F和G以及另外的组合来产生。将在动物模型中评估它们诱导的免疫应答的类型和程度以及RSV-VLP候选疫苗提供的效力。为了实现这些目标，我们设计了三个具体目标：具体目标I：产生和表征展示呼吸道合胞病毒表面的病毒样颗粒（VLP）antigens.in替代组合物F、F+SH、F+G和F+SH+G具体目标II：评价免疫原性（免疫应答的质量和幅度）引起的RSV-在呼吸道合胞病毒感染的小鼠模型中，本发明涉及RSV-VLP疫苗的安全性特征以及由RSV-VLP疫苗的替代组合物提供的保护功效。将通过在小鼠中增加疫苗剂量来重新评估选定的候选物。此外，启动稳定细胞系的开发，以连续生产首选VLP疫苗。具体目标三：将在呼吸道合胞病毒感染的棉鼠模型中重新测试证明功效、效力和安全性的VLP组合物，以探索在两种RSV感染模型中的功效。这些研究将支持SBIR II期提案，并向FDA提交IND申请。

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a safe and efficacious virus-like particle (VLP) based-respiratory syncytial virus (RSV) vaccine to prevent the disease caused by this pathogen. The respiratory illnesses provoked by RSV in infants, children and the elderly are of global economical and public health impact. A recent worldwide estimate [5] indicates that over 33 million children under the age of five suffer RSV associated lower respiratory infections (ALRI) and at least 3 million are hospitalized and approximately 199,000 die of the disease each year. In the US, the CDC estimates that there are over 126,000 RSV associated pediatric hospitalizations at a cost of over $900 million per year. There is no vaccine currently licensed and treatments for the disease are limited; a prophylactic intervention relies on administering a neutralizing monoclonal (Synagis) to infants at risk of infection and to supportive care. A safe and effective vaccine would be the most desirable and cost effective preventive intervention. However, to date the creation of such a vaccine has not been attained and its development hindered by the enhancement of disease provoked by a formalin-inactivated vaccine produced in the 1960's. Other approaches have not proven successful and even dangerous. Here, we propose to develop and test a virus-like particle displaying RSV antigens as a strategy to create a safe and effective RSV vaccine. VLPs are mimics of wild type virus particles but do not contain viral genetic material making them unable to replicate or cause infection. The particulate nature and redundant array of native antigen on the surface of the VLP incites a greater recognition by the immune system. We have successfully produced native RSV-VLPs that display surface spikes and resemble wild type virus. Our RSV based VLP candidate vaccines are created by co-expressing the proteins M, F and SH or M, F or M, F and G as well as additional combinations. The type and magnitude of the immune response they induce as well as the efficacy afforded by the RSV-VLP candidate vaccines will be assessed in animal models. To fulfill these goals, we have designed three specific aims: Specific aim I: Produce and characterize virus-like particles (VLPs) displaying respiratory syncytial virus surface antigens.in alternative compositions F, F+SH, F+G and F+SH+G Specific aim II: Evaluate the immunogenicity (quality and magnitude of the immune response) elicited by the RSV-VLP vaccine and establish safety profile as well as the protective efficacy afforded by alternative compositions of RSV-VLP vaccines in a mouse model of respiratory syncytial virus infection. Selected candidates will be reevaluated by escalating doses of vaccine in mice. Also, initiate development of stable cell lines for the continuous production of the preferred VLP vaccine. Specific aim III: The VLP composition demonstrating efficacy, potency and safety will be retested in the cotton rat model of respiratory syncytial virus infection seeking probe of efficacy in two model of RSV infection. These studies will support a SBIR Phase II proposal and pursue an IND application with the FDA.