Preclinical-Clinical Paramyxovirus Vaccine Development

描述（由申请方提供）：本提案的长期目标是获得安全有效的疫苗，用于预防儿童最常见的呼吸道病毒，即呼吸道合胞病毒和人副流感病毒1型和3型。尽管它们在流行病学上很重要，但这些病原体还没有疫苗。在该项目中，提出鼠1型副流感病毒仙台病毒是其人同源病毒（人1型副流感病毒; hPIV 1）的有效疫苗。基于我们先前在非人灵长类动物中对SV诱导的针对hPIV 1的保护的证明以及通过反向遗传学获得的操纵SV cDNA的初步成功，我们提出SV可以作为hPIV 1的有效疫苗和作为额外副粘病毒抗原的疫苗骨架。 SJCRH的副粘病毒疫苗项目整合了临床前和临床研究，并涉及传染病系、病毒学系和免疫学系的成员。这种综合的多学科方法对于最终确定可靠预测副粘病毒疫苗效力的免疫学和病毒学特征至关重要。该计划包括3个项目：项目1 -重组仙台病毒作为一种新型副粘病毒疫苗（PORTNER）;项目2 -啮齿动物模型中的免疫应答和疫苗效力（HURWITZ）;和项目3 -临床和灵长类副粘病毒疫苗评估（SLOBOD）。该计划的优势在于仙台病毒作为疫苗骨干的优势，以及为实现统一目标而共同努力的研究人员的经验、技能和多样性。最终，该计划将产生（1）候选呼吸道病毒疫苗;（2）包括12种重组仙台病毒疫苗的试剂（根据靶基因同一性和表达模式而不同）、单克隆抗体、hPIV-3和RSV的纯化重组蛋白;和（3）可用于副粘病毒疫苗开发研究的信息，包括对这些最常见呼吸道病毒持久免疫的T和B细胞研究。总之，这一综合性计划成功的可能性很高，衡量标准是鉴定出保护性和安全的呼吸道病毒疫苗。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to obtain safe and effective vaccines for the prevention of the most common respiratory viruses of childhood, namely respiratory syncytial virus and human parainfluenza viruses, type 1 and 3. In spite of their epidemiologic importance, no vaccines exist for these pathogens. In this program it is proposed that the murine type 1 parainfluenza virus, Sendai virus, is an effective vaccine for its human cognate (human parainfluenza virus type 1; hPIV1). Based on our previous demonstration of SV-induced protection against hPIV1 in non-human primates and preliminary success in manipulating the cDNA of SV obtained through reverse genetics, we propose that SV can serve as an effective vaccine for hPIV1 and as a vaccine backbone for additional paramyxoviral antigens. The Paramyxovirus Vaccine Program at SJCRH integrates pre-clinical and clinical research and involves members of the Departments of Infectious Diseases, the Division of Virology and the Department of Immunology. This integrated, multidisciplinary approach is essential to ultimately determine the immunologic and virologic features that reliably predict paramyxovirus vaccine efficacy. The Program consists of 3 Projects: Project 1 - Recombinant Sendai virus as a novel paramyxovirus vaccine (PORTNER); Project 2 - Immune response and vaccine efficacy in a rodent model (HURWITZ); and Project 3 - Clinical and primate paramyxovirus vaccine evaluation (SLOBOD). The strengths of the Program are based in the strength of Sendai virus as a vaccine backbone and in the experience, skills and diversity of the assembled investigators working together towards a unified objective. Ultimately, this program will yield (1) a candidate respiratory virus vaccine; (2) reagents including a panel of 12 recombinant Sendai virus vaccines (differing according to target gene identity and mode of expression), monoclonal antibodies, purified recombinant proteins of hPIV-3 and RSV; and (3) information which can be applied to the study of paramyxovirus vaccine development, including T and B cell studies of durable immunity to these most common respiratory viruses. Taken together, this comprehensive program has a high likelihood of success, measured as the identification of protective and safe respiratory virus vaccines.