A Mucosal RSV Vaccine

描述（由申请方提供）：人呼吸道合胞病毒（RSV）是副粘病毒家族的一种高感染性成员，可引起上呼吸道和下呼吸道感染。RSV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，原因是病毒诱导的气道损伤和复杂的炎症过程，估计每年全球有160，000人死亡。RSV还导致免疫功能低下和老年人群的发病率和死亡率。在美国，估计每年有70，000至125，000名婴儿因RSV肺炎或细支气管炎住院，导致每年的费用可能远远超过4亿美元。由于低免疫原性和/或出于安全性原因，先前尝试配制疫苗以预防RSV介导的疾病尚未成功。福尔马林灭活候选疫苗（FI-RSV）在随后的RSV自然感染后诱导严重疾病。发现接种疫苗的儿童在随后的RSV感染伴随肺嗜酸性粒细胞增多时，疾病严重程度加重，甚至死亡。检测到严重的肺部炎症反应，其特征在于偏斜的CD 4 + T细胞反应（在不存在中和抗体的情况下）和肺部嗜酸性粒细胞流入。由于对安全有效的RSV疫苗的需求未得到满足，迫切需要新的方法。 我们已经开发出一种专利的粘膜疫苗接种平台，该平台已证明对两种不同的粘膜攻击病毒具有有效的免疫应答和保护作用。这种强有力的疫苗方案可以产生Th 1偏向的、广泛和有效的体液、粘膜和T细胞应答，包括大量的粘膜分泌型伊加和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/或毒性佐剂的情况下产生粘膜（特别是粘膜中和抗体）、全身免疫应答和完全粘膜保护; 2）在病毒攻击的动物中未检测到免疫病理学或疫苗增强的疾病。该平台技术已获得两项专利。粘液瘤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，该粘膜疫苗平台是用于开发粘膜疫苗的理想候选物，该粘膜疫苗保护免于在粘膜表面进入的病原体，如RSV的情况。 使用这种专利的粘膜免疫策略，将开发安全有效的RSV疫苗。一个强大的科学团队涉及四个合作研究所，包括：生物医学研究模型公司，圣裘德儿童研究医院，爱荷华州大学和Sigmovir生物系统公司。威尔：1）制备并优化待在BALB/c小鼠和棉鼠中测试的疫苗制剂，2）在RSV鼻内感染的小鼠和棉鼠中进行免疫原性和保护研究，3）测试免疫保护的持久性和交叉亚型保护，4）在BALB/c小鼠和棉鼠模型中评估RSV疫苗候选物的安全性（肺组织病理学）。 公共卫生相关性：公共卫生服务（PHS）已认识到RSV引起的重大公共卫生问题。由于RSV感染引起的发病率和死亡率的严重性以及缺乏安全有效的RSV疫苗，迫切需要开发新的RSV疫苗接种方法。开发安全有效的呼吸道合胞病毒（RSV）疫苗将为受RSV感染威胁的婴儿和老年人群提供保护。下呼吸道疾病发病率的降低将减少与感染直接相关的医疗费用。

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. PUBLIC HEALTH RELEVANCE: The Public Health Service (PHS) has recognized the significant public health issues caused by RSV. Due to the seriousness of RSV infection caused morbidity and mortality and the lack of a safe and effective RSV vaccine, development of novel approaches to RSV vaccination is desperately needed. The development of a safe and effective Respiratory Syncytial Virus (RSV) vaccine would provide protection to infants and elderly populations under the threat of RSV infection. The reduced incidence of disease in the lower respiratory tract would reduce the amount of medical costs directly associated with the infection.