Replication-deficient rabies vectors against rabies infection

描述（由申请人提供）：狂犬病是一个主要的全球健康问题，每年造成约4万至7万人死亡，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现有疫苗的有效性。使这一问题更加复杂的是，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，近年来在许多被认为含有灭活狂犬病病毒的疫苗中发现了活狂犬病病毒（RV）。总之，开发新型暴露前和暴露后疫苗对于解决这一全球健康问题是必要的。由于暴露前疫苗接种仅针对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包括一剂被动免疫（狂犬病免疫球蛋白）和五剂主动免疫（狂犬病疫苗）。本提案中的实验旨在验证一种假设，即复制缺陷的RVs可以制造出优秀的狂犬病pep，并且只需要一到两次剂量。使PEP可行的RV感染的一个标志是在暴露于外周部位的时间和RV感染中枢神经系统的时间之间有相对较长的时间。因此，成功的PEP绝对需要快速的体液反应。因此，本拨款申请的目标是在小动物模型[小鼠（Aim I）和叙利亚仓鼠（Aim II）]中确定最有希望的载体。这些反应和保护作用将与接种市售灭活疫苗的动物进行比较。总之，开发一种仅依靠一至两剂疫苗而不是六剂疫苗的治疗方法将大大提高人类RV预防的有效性，并有可能在发展中国家和发达国家挽救许多生命并降低成本。此外，这些数据将有助于开发复制缺陷RV载体，用于针对其他传染病（如HIV-1）的疫苗。公共卫生相关性：本应用的目的是开发安全有效的替代目前人类狂犬病暴露后预防方法。在发展中国家和发达国家，开发只需要一到两剂疫苗而不是六剂疫苗的治疗方法将大大提高狂犬病病毒预防的有效性，挽救生命并降低成本。

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.