Human Rabies Virus Vaccine Development

描述（申请人提供）：目前的人类狂犬病病毒（RV）疫苗如果以适当和及时的方式接种是有效的，因此，RV感染是一种疫苗可预防的疾病。然而，免疫方案很复杂，需要在数周甚至数月内多次接种。当前疫苗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，导致狂犬病继续成为全球健康威胁。世界卫生组织估计，RV 每年导致超过 55,000 人死亡，超过 1500 万人在接触可能受感染的动物后接受接触后预防 (PEP)。狂犬病多发生于儿童，在重要传染病中排名第七。此外，目前的疫苗是基于活 RV 的灭活，然而，最近在疫苗生产批次中发现了活 RV，导致国际疫苗召回和短缺，表明需要本质安全的人类 RV 疫苗。总而言之，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。 我们的总体目标是开发安全、廉价且有效的新型人类 RV 疫苗，作为工业化国家和发展中国家的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 是人类狂犬病预防的全球标准。我们假设矩阵 (M) 基因缺失的 RV 会导致病毒复制缺陷，从而成为出色的 RV PEP。除其他属性外，M 基因缺失的 RV 疫苗可引发与活 RV 疫苗相似的免疫反应，后者更有效且不同于灭活疫苗。重要的是，即使在 T 细胞和 B 细胞免疫缺陷的小鼠以及非人类灵长类动物中，这些复制缺陷病毒也非常安全。 M 基因缺失的 RV 成为我们在 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确定的最有前途的疫苗载体。我们相信，M 基因删除的 RV 将有利于 PEP 疫苗接种，减少接种次数，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。 为了实现我们的总体目标，提出了三个目标。目标 I 旨在使用第一阶段开发的方案制备 M 基因删除的 RV 的研究主种子，以在 Vero 细胞（药学上可接受的细胞基质）上恢复和繁殖 M 基因删除的 RV。 Aim II 旨在通过研究 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来评估其安全性和毒性。目标 III 是进一步评估我们的疫苗载体的免疫原性，并通过将病灶形成单位 (ffu) 与明确定义的 NIH RV 疫苗诱导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病毒疫苗效力测定。 总之，这项 II 期研究应完成 M 基因缺失 RV 的临床前测试，并支持一到两剂 RV 疫苗的开发。实现这些目标将使我们更接近于拯救生命并降低工业化国家和发展中国家的人类RV预防成本。 公共卫生相关性：本申请的目标是开发安全有效的替代方案来替代当前人类狂犬病暴露后预防。开发仅依靠一到两剂疫苗而不是五六次接种的治疗方法将大大提高发展中国家和发达国家狂犬病病毒预防的有效性，挽救生命并降低成本。

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. 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 five or six inoculations will greatly enhance the effectiveness of rabies virus prevention, save lives and reduced costs in developing and developed countries.