Replication-deficient rabies vectors against rabies infection

复制缺陷型狂犬病载体对抗狂犬病感染

• 批准号: 8089358
• 负责人: JAMES P MCGETTIGAN
• 金额: $ 37.86万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089358
• 关键词: A Mouse; Active Immunization; Address; Animal Model; Animals; Applications Grants; Cessation of life; Child; Clinical Trials; Communicable Diseases; Data; Developed Countries; Developing Countries; Development; Disease; Dose; Effectiveness; Exposure to; Financial cost; Future; Generations; Genes; Goals; HIV-1; Healthcare; Human; Immune; Immune response; Immunity; Immunization; Immunization Schedule; Immunoglobulins; Inactivated Vaccines; Incidence; Infection; Kinetics; Laboratories; Life; Lyssavirus; Mesocricetus auratus; Modeling; Molecular; Mus; Neuraxis; Passive Immunization; Patients; Peripheral; Phosphoproteins; Populations at Risk; Prevention; Prophylactic treatment; Protocols documentation; Rabies; Rabies Vaccines; Rabies virus; Reporting; Research Infrastructure; Signal Transduction; Site; Speed; Suggestion; System; Testing; Time; United States; Vaccination; Vaccines; Veterinarians; Virus; Virus Diseases; animal rule; base; combat; cost; design; global health; immunogenic; immunogenicity; killings; lot production; meetings; novel; prevent; public health relevance; research study; response; therapy development; vector; vector vaccine

DESCRIPTION (provided by applicant): Rabies is a major global health issue that kills approximately 40,000 to 70,000 people per year and over 10 million people receive post-exposure prophylaxis (PEP) after exposure to potentially infected animals. Cost and compliance issues have greatly hampered the effectiveness of current vaccines. To confound this issue, current vaccines are not effective at preventing disease from several newly identified rabies related viruses. In addition, live rabies virus (RV) was recently discovered in a lot of vaccine that was supposed to contain inactivated RV. Taken together, the development of novel pre- and post-exposure vaccines is necessary to combat this global health issue. Since pre-exposure vaccination is reserved only for those at-risk populations, such as laboratory workers and veterinarians, PEP is the world-wide standard for human rabies prevention. Current PEPs are comprised of one dose of passive immunization (rabies immune globulin) along with five active immunizations with rabies vaccines. The experiments in this proposal are designed to test the hypothesis that replication-deficient RVs would make excellent rabies PEPs and will require only one to two doses. A hallmark of RV infection that makes PEP feasible is the relatively long period between the time of exposure at the peripheral site and the time when RV infects the central nervous system. As such, a rapid humoral response is absolutely required for a successful PEP. Therefore, the goal of this grant application to identify the most promising vector in small animal models [mice (Aim I) and Syrian hamsters, (Aim II)]. The responses and protection will be compared with animals inoculated with a commercially available inactivated RV vaccine. In summary, the development of a treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of human RV prevention and has the potential to save many lives and reduce costs in both developing and developed countries. In addition, this data will be useful for the development of replication-deficient RV vectors for vaccines against other infectious diseases, such as HIV-1. PUBLIC HEALTH RELEVANCE: The goal of this application is to develop safe and effective alternatives to the current human rabies post- exposure prophylaxis. The development of treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of rabies virus prevention, save lives and reduce costs in developing and developed countries.

描述（由申请方提供）：狂犬病是一个主要的全球健康问题，每年造成约40，000至70，000人死亡，超过1000万人在接触可能受感染的动物后接受暴露后预防（PEP）。成本和合规问题极大地阻碍了当前疫苗的有效性。为了混淆这个问题，目前的疫苗不能有效预防几种新发现的狂犬病相关病毒引起的疾病。此外，最近在许多本应含有灭活狂犬病病毒（RV）的疫苗中发现了活的RV。总之，开发新型暴露前和暴露后疫苗对于应对这一全球健康问题是必要的。由于暴露前疫苗接种仅适用于实验室工作人员和兽医等高危人群，因此PEP是预防人类狂犬病的全球标准。目前的PEP由一剂被动免疫（狂犬病免疫球蛋白）沿着五次狂犬病疫苗主动免疫组成。本提案中的实验旨在检验复制缺陷型RV将成为优秀的狂犬病PEP并且仅需要一到两个剂量的假设。使PEP可行的RV感染的标志是在外周部位暴露的时间与RV感染中枢神经系统的时间之间的相对较长的时间。因此，快速的体液反应是成功的PEP绝对需要的。因此，本资助申请的目标是在小动物模型[小鼠（Aim I）和叙利亚仓鼠（Aim II）]中确定最有前途的载体。将与接种市售灭活RV疫苗的动物进行应答和保护比较。总之，开发一种仅依赖于一到两剂疫苗而不是六次接种的治疗方法将大大提高人类RV预防的有效性，并有可能挽救许多生命并降低发展中国家和发达国家的成本。此外，这些数据将有助于开发复制缺陷型RV载体，用于预防其他传染病，如HIV-1。公共卫生关系：本申请的目的是开发安全有效的替代品，以替代目前的人狂犬病暴露后预防。开发仅依赖一至两剂疫苗而不是六次接种的治疗方法将大大提高狂犬病病毒预防的有效性，挽救生命并降低发展中国家和发达国家的成本。