Adenovirus Vectors for Respiratory Syncytial Virus Vaccination

用于呼吸道合胞病毒疫苗接种的腺病毒载体

• 批准号: 7620101
• 负责人: Jason Graham Gall
• 金额: $ 30万
• 依托单位: GENVEC, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620101
• 关键词: Adenovirus Vector; Adenoviruses; Animal Model; Animals; Antibodies; Antigens; Attenuated; Biodistribution; Blood group antigen f; CD8B1 gene; Cell Line; Cells; Child; Communicable Diseases; Cotton Rats; Cytotoxic T-Lymphocytes; Data; Decision Making; Development; Disease; Dose; Equilibrium; Evaluation; Formalin; Generations; Genes; Goals; HIV; HIV vaccine; Histopathology; Hospitalization; Human; Immune; Immune response; Immunity; Immunization; Immunobiology; Infection; Influenza; Injection of therapeutic agent; Interferon Type II; Interleukin-4; Interleukin-5; Intramuscular; Lead; Lower Respiratory System; Lung; Malaria; Measures; Methods; Modeling; Mus; Nose; Passive Immunotherapy; Pathology; Pattern; Phase; Preparation; Protein Subunits; Proteins; Pulmonary Pathology; Recombinants; Research; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Route; Safety; Serotyping; Serum; Small Business Innovation Research Grant; Subunit Vaccines; T-Lymphocyte; Testing; Th2 Cells; Time; Transgenes; Treatment Protocols; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; base; cytokine; cytotoxic; efficacy testing; innovation; killer T cell; mouse model; neutralizing antibody; novel; novel vaccines; particle; pre-clinical; preclinical efficacy; preclinical safety; prophylactic; public health relevance; research clinical testing; respiratory; response; safety study; safety testing; vaccine candidate; vaccine development; vaccine efficacy; vector; Adenovirus Vector; Adenoviruses; Animal Model; Animals; Antibodies; Antigens; Attenuated; Biodistribution; Blood group antigen f; CD8B1 gene; Cell Line; Cells; Child; Communicable Diseases; Cotton Rats; Cytotoxic T-Lymphocytes; Data; Decision Making; Development; Disease; Dose; Equilibrium; Evaluation; Formalin; Generations; Genes; Goals; HIV; HIV vaccine; Histopathology; Hospitalization; Human; Immune; Immune response; Immunity; Immunization; Immunobiology; Infection; Influenza; Injection of therapeutic agent; Interferon Type II; Interleukin-4; Interleukin-5; Intramuscular; Lead; Lower Respiratory System; Lung; Malaria; Measures; Methods; Modeling; Mus; Nose; Passive Immunotherapy; Pathology; Pattern; Phase; Preparation; Protein Subunits; Proteins; Pulmonary Pathology; Recombinants; Research; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Route; Safety; Serotyping; Serum; Small Business Innovation Research Grant; Subunit Vaccines; T-Lymphocyte; Testing; Th2 Cells; Time; Transgenes; Treatment Protocols; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; base; cytokine; cytotoxic; efficacy testing; innovation; killer T cell; mouse model; neutralizing antibody; novel; novel vaccines; particle; pre-clinical; preclinical efficacy; preclinical safety; prophylactic; public health relevance; research clinical testing; respiratory; response; safety study; safety testing; vaccine candidate; vaccine development; vaccine efficacy; vector

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the leading viral cause of lower respiratory illness and hospitalization in young children and has long been recognized as a priority disease for a vaccine. RSV presents many challenges for vaccine efficacy. Over the nearly 40 years since the failed formalin-inactivated RSV vaccine great strides have been made in understanding the appropriate immune responses for protection versus immunopotentiation. Vaccine-evoked protection against RSV-induced disease of the lower respiratory system must include antibody and CD8+ cytolytic T- cells. Of equal or greater importance, the vaccine must not stimulate interleukin (IL)-4 and IL-5, indicators of a TH2 CD4+ response. IL-4 has been shown to immunopotentiate while the TH1-associated cytokine interferon-gamma and CD8+ T-cells have been correlated with protection without enhanced lung pathology. Thus, we propose that vaccination will be effective if there is induction of balanced helper and killer T-cell responses to a key RSV antigen. Adenovirus vectors (advectors) have shown promise as vaccines for infectious diseases. Preclinical and clinical testing of replication-defective advector vaccines with potent expression of the encoded antigen is underway for HIV, Ebola, Influenza, and other diseases. Advectors are capable of stimulating Th1 helper and cytolytic CD8+ responses and neutralizing antibody to the vectored antigen. The overall goal of this SBIR application is to test whether immunization with novel advector vaccine candidates for RSV stimulate neutralizing antibody and virus-specific Th1 CD4+ and CD8+ T-cells without Th2 CD4+. We will build novel recombinant adenovirus vectors that express the RSV F protein to high levels. GenVec has cell lines to construct advectors based on different serotypes of adenovirus, which provides advectors that can be used in prime-boost regimens and circumvent pre-existing anti-vector immunity. These same cell lines facilitate the construction of advectors that express transgenes that are cytotoxic or inhibit advector replication. Additionally, GenVec's cell line has been used as the cell substrate for the generation and manufacturing of an advector-based HIV vaccine that is now in phase II clinical testing. The advectors will be tested for the pattern of immune response evoked to RSV, for efficacy against RSV challenge, and for lung histopathology. Both cotton rat and murine models will be used to fully characterize RSV protection, safety, and the immune response. From the phase I portion of this proposal key immunological and safety data will be generated to enable decision-making for advancement to phase II. In the phase II portion, lead adenovectors will be chosen for additional preclinical efficacy testing, preclinical safety testing, and manufacturing in preparation for clinical testing. PUBLIC HEALTH RELEVANCE: Respiratory syncytial virus (RSV) is the leading viral cause of lower respiratory illness and hospitalization in young children and has long been recognized as a priority disease for a vaccine. We propose a method of vaccination that will induce an antibody and balanced helper and killer T-cell response against RSV without causing enhanced disease. In phase I we will generate novel replication-deficient adenovirus vectors that express F protein and test them for safety, generation of appropriate immune responses, and protection against RSV.

描述（由申请人提供）：呼吸道合胞病毒（RSV）是幼儿下呼吸道疾病和住院治疗的主要病毒原因，长期以来一直被认为是疫苗的优先疾病。 RSV提出了疫苗功效的许多挑战。自从失败的福尔马林灭活RSV疫苗失败以来，已经在理解适当的免疫反应与免疫抑制后取得了长足进步近40年。疫苗引起的针对RSV诱导的下呼吸系统疾病的保护必须包括抗体和CD8+细胞溶解T细胞。具有相等或更大的重要性，疫苗不得刺激TH2 CD4+响应的指标刺激白介素（IL）-4和IL-5。 IL-4已被证明可以免疫剂量，而Th1相关的细胞因子干扰素 - 伽马和CD8+ T细胞与保护无关，而没有增强的肺病理学。因此，我们建议，如果对键RSV抗原的均衡辅助辅助者和杀手T细胞反应诱导疫苗接种将是有效的。腺病毒载体（Advectors）已显示出有望作为传染病的疫苗。对艾滋病毒的临床前和临床检测，具有有效的编码抗原的临床缺陷式抗原疫苗正在进行HIV，正在进行中 埃博拉病毒，流感和其他疾病。向前器能够刺激Th1辅助器和细胞溶解CD8+反应以及对矢量抗原的抗体中和。该SBIR应用的总体目标是测试用于RSV的新型Advector疫苗的免疫是否刺激中和抗体和病毒特异性TH1 CD4+和CD8+ T细胞，而无需TH2 CD4+。我们将建立新型的重组腺病毒载体，将RSV F蛋白表达高水平。 GenVEC具有基于腺病毒的不同血清型构建对流的细胞系，该腺病毒提供了可以用于素促进型方案并规避预先存在的抗载体免疫力的授予器。这些相同的细胞系促进了表达细胞毒性或抑制对流复制的跨基因的构造。此外，Genvec的细胞系已被用作基于Advector的HIV疫苗的生成和生产的细胞底物，该疫苗现在正在II期临床测试中。将测试对流的对RSV的免疫反应模式，针对RSV挑战的功效以及肺部组织病理学的功效。棉花大鼠和鼠模型均可用来充分表征RSV保护，安全性和免疫反应。从本提案的第一阶段开始，将生成关键的免疫和安全数据，以实现决策，以促进第二阶段。在第二阶段的部分中，将选择铅酰化剂进行其他临床前疗效测试，临床前安全测试和制造以准备临床 测试。 公共卫生相关性：呼吸综合病毒（RSV）是幼儿下呼吸道疾病和住院治疗的主要病毒原因，长期以来一直被认为是疫苗的优先疾病。我们提出了一种疫苗接种方法，该方法将诱导抗体，平衡的助手和杀手T细胞对RSV的反应，而不会引起疾病增强。在第一阶段，我们将生成新颖的不缺陷腺病毒载体，以表达F蛋白，并测试它们的安全性，适当的免疫反应以及对RSV的保护。