Adenovirus Vectors for Respiratory Syncytial Virus Vaccination

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对疫苗效力提出了许多挑战。在福尔马林灭活的RSV疫苗失败后的近40年里，在理解适当的免疫反应是保护还是免疫增强方面取得了巨大进展。疫苗对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。同样重要或更重要的是，疫苗不能刺激白细胞介素(IL)-4和IL-5，这是TH2 CD4+反应的指标。IL-4已被证明具有免疫增强作用，而th1相关的细胞因子干扰素- γ和CD8+ t细胞与保护作用相关，但没有增强肺部病理。因此，我们提出，如果对一种关键的RSV抗原诱导平衡的辅助和杀伤t细胞反应，疫苗接种将是有效的。腺病毒载体（vector）已显示出作为传染病疫苗的前景。目前正在对具有编码抗原强效表达的复制缺陷载体疫苗进行临床前和临床试验，

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.