A Mucosal RSV Vaccine

粘膜 RSV 疫苗

• 批准号: 8392826
• 负责人: Kejian Yang
• 金额: $ 30万
• 依托单位: BIOMEDICAL RESEARCH MODELS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392826
• 关键词: Adjuvant; Animals; Antibodies; B-Lymphocytes; Biomedical Research; Blood group antigen f; Bronchiolitis; CD4 Positive T Lymphocytes; Cercopithecus pygerythrus; Cessation of life; Child; Clinical; Complex; Cotton Rats; Cyclic GMP; DNA; DNA Vaccines; Development; Disease; Dose; Drug Formulations; Elderly; Encapsulated; Family; Formalin; Funding; Grant; Hepatitis B Surface Antigens; Histopathology; Human Herpesvirus 2; Human respiratory syncytial virus; Immune; Immune response; Immunity; Immunization; Immunocompromised Host; Inactivated Vaccines; Inbred BALB C Mice; Incidence; Infant; Infection; Inflammatory; Inflammatory Response; Institutes; Iowa; Legal patent; Licensing; Liposomes; Lower Respiratory Tract Infection; Lower respiratory tract structure; Lung; Lung diseases; Mediating; Medical; Modeling; Morbidity - disease rate; Mucosal Immune Responses; Mus; Paramyxovirus; Pneumonia; Population; Process; Proteins; Public Health; Pulmonary Eosinophilia; Regimen; Request for Proposals; Respiratory Failure; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Safety; Saint Jude Children' s Research Hospital; Secretory Immunoglobulin A; Severity of illness; Sterility; Surface; T cell response; T-Lymphocyte; Technology; Testing; Toxicology; United States; United States Public Health Service; Universities; Vaccinated; Vaccination; Vaccines; Vaccinia virus; Virus; Virus Replication; base; cost; eosinophil; immunogenic; immunogenicity; immunopathology; member; mortality; mucosal vaccination; mucosal vaccine; neutralizing antibody; novel strategies; pathogen; phase 2 study; prevent; product development; protective efficacy; safety study; vaccination strategy; vaccine candidate; vaccine development; vector

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.

描述(申请人提供)：人类呼吸道合胞病毒(RSV)是副粘病毒家族中具有高度传染性的成员，可引起上呼吸道和下呼吸道感染。呼吸道合胞病毒感染是婴儿下呼吸道肺部疾病(毛细支气管炎、肺炎和呼吸衰竭)的主要原因，原因是病毒引起的呼吸道损伤和复杂的炎症过程，估计全世界每年有16万人死亡。RSV还会导致免疫受损人群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名婴儿因呼吸道合胞病毒肺炎或毛细支气管炎住院，造成的费用可能远远超过每年4亿美元。由于免疫原性低和/或出于安全原因，以前研制预防RSV介导性疾病的疫苗的尝试都没有成功。福尔马林灭活疫苗候选疫苗(FI-RSV)在随后自然感染RSV时导致严重疾病。接种疫苗的儿童被发现疾病严重程度增加，甚至在随后的RSV感染伴随肺嗜酸性粒细胞增多症时死亡。检测到严重的肺炎性反应，其特征是CD4+T细胞反应扭曲(无中和抗体)和嗜酸性粒细胞进入肺内。由于对安全有效的RSV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获得专利的粘膜疫苗接种平台，该平台已经显示出强大的免疫反应和对两种不同的粘膜挑战病毒的保护。这种强大的疫苗方案可以产生偏向Th1的、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)、系统免疫反应和完全的粘膜保护；2)在病毒攻击的动物中没有检测到免疫病理学或疫苗增强型疾病。该平台技术已获得两项专利。粘膜HSV-2疫苗的专利正在申请中，并将被授权给疫苗开发商进行进一步的产品开发。因此，这个黏膜疫苗平台是开发黏膜疫苗的理想候选者，该疫苗可以保护进入粘膜表面的病原体，就像RSV一样。利用这种获得专利的粘膜免疫策略，将开发一种安全有效的RSV疫苗。一个强大的科学团队由四个合作机构组成，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夫生物系统公司，他们将：1)制备和优化用于在BALB/c小鼠和棉花大鼠身上进行试验的疫苗配方，2)在小鼠和棉花大鼠鼻内感染RSV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)评估候选RSV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)。 公共卫生相关性：公共卫生服务(PHS)已经认识到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。开发一种安全有效的呼吸道合胞病毒(RSV)疫苗将为受到RSV感染威胁的婴儿和老年人提供保护。下呼吸道疾病发病率的减少将减少与感染直接相关的医疗费用。