Preclinical-Clinical Paramyxovirus Vaccine Development

描述（由申请人提供）：本提案的长期目标是获得安全有效的疫苗，以预防儿童最常见的呼吸道病毒，即呼吸道合胞病毒和人类副流感病毒，1型和3型。尽管它们在流行病学上具有重要意义，但目前还没有针对这些病原体的疫苗。本文提出小鼠1型副流感病毒仙台病毒是其人类同源物（人类1型副流感病毒；hPIV1）的有效疫苗。基于我们之前在非人灵长类动物中证明了SV诱导的对hPIV1的保护作用，以及通过反向遗传学获得的SV cDNA的初步成功，我们提出SV可以作为hPIV1的有效疫苗和其他副粘病毒抗原的疫苗骨干。

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.