A Mucosal RSV Vaccine

描述（由申请人提供）：人呼吸道合胞病毒（RSV）是副粘病毒家族的一种高传染性成员，可引起上呼吸道和下呼吸道感染。由于病毒引起的气道损伤和复杂的炎症过程，呼吸道合胞病毒感染是婴儿下呼吸道肺部疾病（细支气管炎、肺炎和呼吸衰竭）的主要原因，全世界每年估计有16万人死亡。呼吸道合胞病毒还会导致免疫功能低下人群和老年人发病和死亡。在美国，估计每年有70,000至125,000名婴儿因呼吸道合胞病毒肺炎或细支气管炎住院，每年的费用可能远远超过4亿美元。由于免疫原性低和/或出于安全原因，以前研制疫苗以预防rsv介导的疾病的尝试都没有成功。福尔马林灭活疫苗候选物（FI-RSV）在随后自然感染RSV后诱导严重疾病。发现接种疫苗的儿童在随后的RSV感染并肺嗜酸性粒细胞增多后，疾病严重程度增加，甚至死亡。检测到严重的肺部炎症反应，其特征是CD4+ t细胞反应偏斜（在缺乏中和抗体的情况下）和嗜酸性粒细胞在肺部的内流。由于对安全有效的呼吸道合胞病毒疫苗的需求尚未得到满足，迫切需要新的方法。我们已经开发了一种专利的粘膜疫苗接种平台，该平台已经证明了针对两种不同的粘膜挑战病毒的有效免疫反应和保护。这种强大的疫苗方案可以产生Th1偏向，广泛和有效的体液，粘膜和T细胞反应，包括大量的粘膜分泌IgA和CTL。我们的专利免疫方案的独特之处在于：1)在不使用任何病毒载体和/或有毒佐剂的情况下，提高了粘膜（特别是粘膜中和抗体）、全身免疫反应和完整的粘膜保护；2)在病毒攻毒动物中未发现免疫病理或疫苗增强疾病。该平台技术已获得两项专利。粘膜HSV-2疫苗专利正在申请中，并被授权给疫苗开发商进行进一步的产品开发。因此，这种粘膜疫苗平台是开发粘膜疫苗的理想候选者，该疫苗可以防止病原体进入粘膜表面，就像RSV的情况一样。利用这一获得专利的粘膜免疫策略，将开发出安全有效的RSV疫苗。一个强大的科学团队包括四个合作机构，包括：生物医学研究模型公司、圣裘德儿童研究医院、爱荷华大学和西格莫维尔生物系统公司。1)制备和优化BALB/c小鼠和棉花大鼠的疫苗配方，2)进行RSV鼻内感染小鼠和棉花大鼠的免疫原性和保护研究，3)测试免疫保护和交叉亚型保护的持久性，4)评估RSV候选疫苗在BALB/c小鼠和棉花大鼠模型中的安全性（肺组织病理学）。

DESCRIPTION (provided by applicant): Human respiratory syncytial virus (RSV) is a highly infectious member of the paramyxovirus family causing upper and lower respiratory tract infections. RSV infection is the leading cause of pulmonary disease of the lower respiratory tract (bronchiolitis, pneumonia and respiratory failure) in infants due to virus-induced airway damage and complex inflammatory processes and responsible for an estimated 160,000 deaths annually worldwide. RSV also causes morbidity and mortality to the immunocompromised and elderly populations. In the United States, an estimated 70,000 to 125,000 infants are hospitalized annually with RSV pneumonia or bronchiolitis resulting in costs that may well exceed US$400 million annually. Because of either low immunogenicity and/or for safety reasons, previous attempts to formulate a vaccine to prevent RSV-mediated disease have not been successful. The formalin-inactivated vaccine candidate (FI-RSV) induced severe disease upon subsequent natural infection with RSV. Vaccinated children were found to suffer from enhanced disease severity and even death upon subsequent RSV infection concomitant with pulmonary eosinophilia. Severe lung inflammatory responses characterized by a skewed CD4+ T-cell response (in the absence of neutralizing antibodies) and the influx of eosinophils in the lung were detected. Because of the unmet need of a safe and effective RSV vaccine, novel approaches are desperately needed. We have developed a patented mucosal vaccination platform that has demonstrated potent immune responses and protection against two different, mucosally challenged viruses. This powerful vaccine regimen can generate a Th1 biased, broad and potent humoral, mucosal and T cell responses including substantial mucosal secretory IgA and CTL. The uniqueness of our patented immunization regimen are:1) both mucosal (especially mucosal neutralizing antibodies), systemic immune responses and complete mucosal protection were raised without using any virus vectors and/or toxic adjuvants; 2) no immunopathology or vaccine- enhanced diseases have been detected in virus challenged animals. Two patents on the platform technology have been granted. Mucosal HSV-2 vaccine patents are pending and being licensed to a vaccine developer for further product development. Therefore, this mucosal vaccine platform is an ideal candidate for developing a mucosal vaccine that protects against pathogens which enter at mucosal surfaces, as is the case for RSV. Using this patented mucosal immunization strategy, a safe and effective RSV vaccine will be developed. A strong scientific team involves four collaborating Institutes including: Biomedical Research Models, Inc., St. Jude Children's Research Hospital, University of Iowa and Sigmovir Biosystem, Inc. will: 1) prepare and optimize vaccine formulations to be tested in both BALB/c mice and cotton rats, 2) perform immunogenicity and protection studies in both mice and cotton rats of RSV intranasal infection, 3) test the durability of immune protection and the cross-subtype protection, 4) evaluate the safety (pulmonary histopathology) of the RSV vaccine candidate in both BALB/c mouse and the cotton rat models.