Human Rabies Virus Vaccine Development

描述（由申请方提供）：狂犬病是一个重大的全球健康问题，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（RIG））]沿着五次灭活狂犬病疫苗主动免疫组成。本提案中的实验旨在检验以下假设：基质（M）基因缺失的RV疫苗载体将产生仅需要一到两剂的优异RV PEP。值得注意的是，由于这种载体缺乏其五个必需基因中的一个，因此它是复制缺陷型的，并且非常安全。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，我们将在仅一剂或两剂M缺失RV疫苗载体后测量小鼠中诱导的体液免疫应答的动力学。将这些应答与接种当前6剂灭活疫苗方案的小鼠进行比较。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极大地提高人类RV预防的有效性，从而在发达国家和发展中国家产生潜在的挽救生命和降低成本的疫苗。公共卫生相关性：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。

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 who 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 PEP is comprised of one dose of passive immunization [(rabies immune globulin (RIG)] along with five active immunizations with inactivated rabies vaccines. The experiments in this proposal are designed to test the hypothesis that a matrix (M) gene-deleted RV vaccine vector would make an excellent RV PEP that requires only one to two doses. Of note, since this vector lacks one of its five essential genes, it is replication-deficient and very safe. 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, we will measure the kinetics of the induced humoral immune response in mice after only one or two doses of the M- deleted RV vaccine vector. The responses will be compared with mice inoculated with the current six-dose inactivated vaccine regimen. 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, resulting in potential life-saving and cost-reducing vaccines in both developed and developing countries. 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 reduced costs in developing and developed countries.