Adenovirus-vectored RSV vaccine not inhibited by maternal immunity

腺病毒载体 RSV 疫苗不受母体免疫力抑制

基本信息

批准号：
8463974
负责人：
Jason Graham Gall
金额：
$ 28.91万
依托单位：
GENVEC, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463974
关键词：
Adenovirus Vector Adenoviruses Adult Affect Age-Months Amino Acids Animal Model Animals Antibodies Attenuated CD8B1 gene Cell Line Cells Cercopithecidae Characteristics Child Childhood Chimera organism Collaborations Communicable Diseases Cotton Rats Cyclic GMP Development Disease Engineering Equilibrium Failure Formalin Funding General Population Generations Geographic Locations Goals HIV HIV vaccine Hospitalization Human Human Adenoviruses Immune Sera Immune response Immunity Immunization Immunobiology Infant Infection Life Malaria Vaccines Maternal antibody Methods Modeling Monkeys Morbidity - disease rate National Institute of Allergy and Infectious Disease Passive Immunity Passive Immunotherapy Phase Population Pre-Clinical Model Prevalence Prevention Probability Protein Subunits Proteins Pulmonary Pathology Recording of previous events Regimen Research Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory Tract Infections Respiratory syncytial virus Respiratory syncytial virus RSV F proteins Risk Safety Sampling Seroprevalences Serum Small Business Innovation Research Grant Subunit Vaccines Surface T cell response T-Lymphocyte Testing Time United States Upper Respiratory Infections Vaccination Vaccine Clinical Trial Vaccine Design Vaccines Viral Viral Antigens Virion Virus Virus Diseases Virus-like particle base clinical material experience immunogenicity improved in vivo killer T cell mortality neonate neutralizing antibody novel novel vaccines public health priorities public health relevance research clinical testing respiratory response success vaccine candidate vaccine development vector vector vaccine vector-induced

项目摘要

DESCRIPTION (provided by applicant): RSV is the leading viral cause of lower respiratory illness and hospitalization in young children, yet there isn't an approved vaccine. The vast majority of children infected with RSV suffer from a mild upper respiratory tract infection; however, severe lower respiratory infection develops in 20-30% of RSV-infected children, resulting in >130,000 pediatric hospitalizations annually in the United States. Given the degree of RSV-associated hospitalizations, morbidity, and mortality, the development of an RSV vaccine is a high public health priority. The history of failed RSV vaccines, such as formalin-inactivated virus, attenuated viruses, and purified protein subunit vaccines clearly shows the need for a new vaccine design. Fortunately, there are new vaccine designs based on understanding the immunobiology of natural RSV infection, the failed vaccines, and the safe and effective passive immunotherapy Synagistm. The new vaccine designs focus on inducing neutralizing antibodies for protection and cytolytic cellular responses to clear infection. The strategy for this SBIR was formulated on the recent demonstration of protection in animal models of RSV by adenoviral vector vaccines and the recognition of pre-existing immunity as an impediment to effective and safe immunization. GenVec's strategy to use a replication-defective adenovirus vectored vaccine for RSV is based on the clinically proven capability of adenovirus vectored vaccines to induce antibody, CD8+ T-cell, and Th1 type responses. These considerations resulted in the underlying hypothesis that maternal immunity in the neonate to both the vaccine vector and RSV can be circumvented by vaccine design. We have identified a non-human adenovirus vector, SAV7, that has been demonstrated to have comparable efficacy to Ad5 vectors in animal models of RSV protection. The human population should be na¿ve to the non-human adenovirus vector. We will be able to rapidly test the maternal immunity hypothesis in preclinical models, and with positive results, advance to human clinical testing. Our probability of success is increased by our experience with key RSV animal models, adenoviral vector vaccines, and our collaboration with a leader in the field of RSV research, Barney Graham, VRC, NIAID. The aims of the project are the verification of low human seroprevalence of the non-human adenovirus vectors and in vivo assessment (cotton rat model) of the effect of pre-existing immunity on vaccine vector-induced immune responses to RSV. Both human adenovirus immunity and passive RSV antibody immunity will be modeled. Successful completion of the aims and demonstration of no effect of pre-existing immunity on the immunogenicity of the SAV7 RSV vaccine vector will justify continuing the project to Phase II. Key aspects of Phase II would be pre-clinical testing of candidate vaccines in regimens appropriate for inducing protection against RSV in infants less than two months old and, subsequently, cGMP manufacture of clinical material. We estimate the additional time and funding necessary to bring this product to clinical testing after the completion of Phase I to be 3 years and 5 million dollars.

描述（由适用提供）：RSV是幼儿下呼吸道疾病和住院治疗的主要病毒原因，但没有批准的疫苗。感染RSV的绝大多数儿童患有轻度的上呼吸道感染。然而，在美国，20-30％的RSV感染儿童中有20-30％的下呼吸道感染发生，每年在美国导致130,000个儿科住院治疗。鉴于与RSV相关的住院，发病率和死亡率的程度，RSV疫苗的开发是高公共卫生的优先事项。 RSV疫苗失败的病史，例如福尔马林灭活病毒，减毒病毒和纯化的蛋白质亚基疫苗，清楚地表明了需要新的疫苗设计。幸运的是，基于了解天然RSV感染的免疫生物学，失败的疫苗以及安全有效的被动免疫疗法秘密疗法的新疫苗设计。新的疫苗设计着重于诱导中和抗体，以保护和细胞溶解细胞对清除感染的反应。该SBIR的策略是根据腺病毒载体疫苗在RSV动物模型中的最新保护中提出的，并识别预先存在的免疫AS是对有效和安全免疫的障碍。 Genvec使用复制缺陷型腺病毒载体疫苗进行RSV的策略是基于腺病毒载体疫苗诱导抗体，CD8+ T细胞和TH1型反应的临床证明的能力。这些考虑因素导致了一个基本的假设，即新生儿对疫苗载体和RSV的材料免疫可以通过疫苗设计可以规避。我们已经确定了非人类腺病毒载体SAV7，该载体已被证明具有与RSV保护动物模型中AD5矢量相当的效率。人口应纳入非人类腺病毒载体。我们将能够在临床前模型中迅速检验孕妇免疫假设，并取得积极的结果，可以促进人类的临床测试。我们在关键RSV动物模型，腺病毒载体疫苗以及与RSV研究领域的领导者Barney Graham，VRC，NIAID的领导者的合作方面增加了成功的可能性。该项目的目的是验证非人类腺病毒载体的低人类血清阳性和体内评估（棉花大鼠模型）对预先存在免疫组织化学对疫苗载体诱导的免疫反应对RSV的影响的影响。人类腺病毒免疫组织化学和被动RSV抗体免疫组织化学均可建模。成功完成目标和证明没有预先存在免疫对SAV7 RSV疫苗载体的免疫原性的影响将证明将项目继续前往第二阶段。第二阶段的关键方面是对适合诱导不到两个月大的婴儿进行保护的治疗方案的候选疫苗的临床前测试，随后，CGMP的临床材料生产。我们估计I阶段完成后，将该产品带入临床测试所需的额外时间和资金为3 年和500万美元。