Human Rabies Virus Vaccine Development

描述(申请人提供)：狂犬病是一个主要的全球健康问题，每年导致约40,000至70,000人死亡，超过1000万人在接触潜在感染的动物后接受暴露后预防措施(PEP)。成本和合规问题极大地阻碍了当前疫苗的有效性。为了解决这个问题，目前的疫苗在预防几种新发现的狂犬病相关病毒方面并不有效。此外，最近在许多本应含有灭活RV的疫苗中发现了活狂犬病病毒(RV)。综上所述，开发新的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限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世界标准。目前的PEP包括一剂被动免疫[(狂犬病免疫球蛋白(RIG)])以及五种用灭活狂犬病疫苗进行的主动免疫。这项建议中的实验旨在测试一种假设，即基质(M)基因缺失的轮状病毒疫苗载体将产生只需要一到两剂的极好的轮状病毒PEP。值得注意的是，由于该载体缺少其五个必需基因中的一个，因此它是复制缺陷的，非常安全。轮状病毒感染使PEP可行的一个标志是，在外周部位暴露的时间和轮状病毒感染中枢神经系统的时间之间的时间相对较长。因此，快速的体液反应绝对是成功的PEP所必需的。因此，我们将测量M缺失的轮状病毒疫苗载体仅接种一或两剂后小鼠诱导的体液免疫反应的动力学。这些反应将与接种目前六剂灭活疫苗方案的小鼠进行比较。总而言之，开发一种只需一到两剂疫苗而不是六剂疫苗的治疗方法将极大地提高人类轮状病毒预防的有效性，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：该应用程序的目标是开发安全有效的替代方案，以替代目前的人类暴露后狂犬病预防措施。在发展中国家和发达国家，开发只需一到两剂疫苗而不是六剂疫苗的治疗方法，将极大地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 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.