Human Rabies Virus Vaccine Development

描述（由申请方提供）：如果以适当和及时的方式接种，目前的人狂犬病病毒（RV）疫苗是有效的，因此，RV感染是一种疫苗可预防的疾病。然而，免疫接种程序很复杂，需要在数周内多次接种，有时需要数月。与当前疫苗相关的高成本和缺乏合规性，以及狂犬病和狂犬病相关病毒的重新出现和出现，有助于使狂犬病成为全球健康威胁。世界卫生组织估计，RV每年造成超过55，000人死亡，超过1500万人在接触可能受感染的动物后接受暴露后预防（PEP）。狂犬病在重要传染病中排名第七，因为它经常发生在儿童中。此外，目前的疫苗是基于活RV的灭活，然而，最近在一个疫苗生产批次中发现了活RV，导致国际疫苗召回和短缺，这表明需要本质安全的人RV疫苗。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。 我们的总体目标是为工业化国家和发展中国家开发安全、廉价和有效的新型人类RV疫苗，作为暴露前和暴露后疫苗。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。我们假设基质（M）基因缺失的RV，使病毒复制缺陷，将使优秀的RV PEP。在其他属性中，M基因缺失的RV疫苗引发与活RV疫苗相似的免疫应答，其更有效并且不同于灭活疫苗。重要的是，这些复制缺陷型病毒甚至在T细胞和B细胞免疫缺陷型小鼠和非人灵长类动物中也非常安全。在I期研究中，结合我们在小鼠非人灵长类动物中的其他初步免疫原性和保护数据，M基因缺失的RV成为我们最有前途的疫苗载体。我们相信M基因缺失的RV将有利于PEP疫苗接种，将接种次数从目前的五剂主动免疫和一剂被动免疫的标准方案减少到一剂或两剂免疫方案。 为实现我们的总体目标，提出了三个目标。目的I旨在使用I期期间开发的方案制备M基因缺失RV的研究主种子，以在Vero细胞（药学上可接受的细胞基质）上回收和繁殖M基因缺失RV。目的二是通过研究M基因缺失RV在小鼠体内的生物分布、组织病理学、遗传稳定性、热稳定性和神经毒力，评价M基因缺失RV的安全性和毒性。目的III是进一步评估我们的疫苗载体的免疫原性，并通过将焦点形成单位（ffu）与定义良好的NIH RV疫苗诱导的免疫和保护效力测试相关联，定义或建立一种新的可接受的复制缺陷型病毒疫苗的效力测试。 总之，这项II期研究应完成M基因缺失RV的临床前试验，并支持1 - 2剂RV疫苗的开发。实现这些目标将使我们更接近于在工业化国家和发展中国家拯救生命和降低人类RV预防成本。

DESCRIPTION (provided by applicant): Current human rabies virus (RV) vaccines are effective if administered in an appropriate and timely manner and therefore, RV infection is a vaccine-preventable disease. However, immunization protocols are complex, requiring multiple doses over a period of weeks and in some cases months. High costs and the lack of compliance associated with current vaccines, and the re-emergence and emergence of rabies and rabies- related viruses, helps to keep rabies a global health threat. The World Health Organization estimates RV kills over 55,000 people per year and over 15 million people receive post-exposure prophylaxis (PEP) after exposure to potentially infected animals. Rabies is ranked seventh in important infectious diseases since it often occurs in children. In addition, current vaccines are based on the inactivation of live RV, however, live RV was recently discovered in a production lot of vaccine, resulting in an international vaccine recall and shortage indicating intrinsically safe human RV vaccines are needed. Taken together, the development of novel pre- and post-exposure vaccines is necessary to combat this global health issue. Our overall goal is to develop new human RV vaccines that are safe, inexpensive and effective as pre- and post-exposure vaccines for both industrialized and developing countries. Since pre-exposure vaccination is reserved only for those at-risk populations, such as laboratory workers and veterinarians, PEP is the worldwide standard for human rabies prevention. We hypothesize that a matrix (M) gene-deleted RV, which renders the virus replication-deficient, will make excellent an RV PEP. Among other attributes, M-gene deleted RV vaccines elicit immune responses similar to that from live RV vaccines, which are more potent and different from inactivated vaccines. Importantly, these replication-deficient viruses are also very safe even in T- and B- cell immune-deficient mice and in non-human primates. The M gene-deleted RV emerged as our most promising vaccine vector identified during Phase I studies in conjunction with our other preliminary immunogenicity and protection data in mice non-human primates. We believe M-gene deleted RVs will benefit PEP vaccination reducing the number of inoculations from the current standard regimen of five doses of active and one dose of passive immunization to a one- or two-dose immunization protocol. Three Aims are proposed to achieve our overall goal. Aim I is directed towards preparing a research master seed of the M gene-deleted RV using protocols developed during Phase I to recover and propagate M gene-deleted RVs on Vero cells (a pharmaceutically acceptable cell substrate). Aim II is directed towards assessing the safety and toxicity of the M gene-deleted RV by studying its biodistribution, histopathology, genetic stability, thermal stability and neurovirulence in mice. Aim III is to further evaluate immunogenicity our vaccine vector, and to define or establish a new acceptable potency assay for the replication-deficient virus vaccine by correlating focus forming units (ffu) to the well-defined NIH potency test of RV vaccine-induced immunity and protection. In summary, this Phase II study should finalize pre-clinical testing of the M gene-deleted RV and support the development of a one- to two-dose RV vaccine. Achieving these Aims will bring us closer to saving lives and reducing the cost of human RV prevention in both industrialized and developing countries.