Human Rabies Virus Vaccine Development

人类狂犬病病毒疫苗的开发

• 批准号: 8199749
• 负责人: JAMES P MCGETTIGAN
• 金额: $ 41.4万
• 依托单位: MOLECULAR TARGETING TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199749
• 关键词: Adult; Animals; Antibody Formation; Apoptosis; B-Lymphocytes; Biodistribution; Biological Assay; Cells; Cessation of life; Child; Clinical; Communicable Diseases; Complex; Data; Data Protection; Developed Countries; Developing Countries; Development; Disease; Dose; Effectiveness; Engineering; Evaluation; Exposure to; Financial cost; Future; Generations; Genes; Genetic; Goals; Healthcare; Histopathology; Human; Immune; Immune response; Immunity; Immunization; Immunization Schedule; Immunoglobulins; Inactivated Vaccines; Incidence; Infection; International; Laboratories; Life; Mus; Organ; Passive Immunization; Pathology; Patients; Phase; Populations at Risk; Preparation; Prevention; Procedures; Prophylactic treatment; Protocols documentation; Rabies; Rabies Vaccines; Rabies virus; Regimen; Reporting; Research; Research Infrastructure; Risk; Safety; Seeds; Site; Suggestion; System; Technology; Testing; Time; Tissues; Toxic effect; Transfection; Translating; United States National Institutes of Health; Vaccination; Vaccine Production; Vaccines; Vero Cells; Veterinarians; Viral Vaccines; Virus; Virus Diseases; Virus Replication; World Health Organization; base; combat; cost; global health; human mortality; immunogenicity; killings; lot production; neurovirulence; new technology; next generation; nonhuman primate; novel; novel vaccines; phase 1 study; phase 2 study; positional cloning; potency testing; pre-clinical; research clinical testing; safety study; safety testing; therapy development; vaccine candidate; vaccine development; vaccine-induced immunity; vector vaccine; viral DNA

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.

说明(申请人提供)：如果以适当和及时的方式接种，目前的人类狂犬病病毒(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，免疫方案很复杂，需要在几周内多次接种，在某些情况下需要几个月。目前疫苗的高成本和缺乏遵从性，以及狂犬病和狂犬病相关病毒的重新出现和出现，有助于使狂犬病继续成为全球健康威胁。世界卫生组织估计，每年有超过55000人死于轮状病毒，超过1500万人在接触潜在感染的动物后接受暴露后预防措施(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体轮状病毒灭活的，然而，最近在大量生产的疫苗中发现了活体轮状病毒，导致了国际上的疫苗召回和短缺，这表明需要本质上安全的人类轮状病毒疫苗。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。我们的总体目标是开发安全、廉价和有效的新型人轮状病毒疫苗，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全球标准。我们假设，使病毒复制缺陷的基质(M)基因缺失的RV将成为优秀的RV PEP。在其他属性中，M基因缺失的轮状病毒疫苗引起的免疫反应类似于活的轮状病毒疫苗，后者比灭活疫苗更有效，不同于灭活疫苗。重要的是，这些复制缺陷病毒即使在T细胞和B细胞免疫缺陷的小鼠和非人类灵长类动物中也是非常安全的。M基因缺失的RV成为我们在第一阶段研究中确定的最有希望的疫苗载体，与我们在小鼠非人类灵长类动物中的其他初步免疫原性和保护数据相结合。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方案减少到一剂或两剂免疫方案。为实现我们的总目标，提出了三个目标。目的利用第一阶段建立的方案在Vero细胞(一种药学上可接受的细胞底物)上恢复和繁殖M基因缺失的RV，以制备M基因缺失RV的研究母本种子。目的研究M基因缺失轮状病毒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，以评价其安全性和毒性。目的III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)与明确定义的轮状病毒疫苗诱导的免疫和保护的NIH效力试验相关联，定义或建立一种新的可接受的复制缺陷病毒疫苗效价测定方法。总之，这项第二阶段研究应该完成M基因缺失轮状病毒的临床前测试，并支持一到两剂轮状病毒疫苗的开发。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。 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。开发仅依靠一到两剂疫苗而不是五六种疫苗的治疗方法，将极大地提高狂犬病病毒预防的有效性，挽救生命，降低发展中国家和发达国家的成本。