Developing Avirulent Rabies Virus Vaccines

开发无毒狂犬病病毒疫苗

• 批准号: 6623317
• 负责人: ZHEN F FU
• 金额: $ 34.17万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623317
• 关键词: antiviral antibody; attenuated microorganism; biological models; communicable disease control; glycoproteins; host organism interaction; immunotherapy; laboratory mouse; microorganism immunology; neutralizing antibody; newborn animals; nonhuman therapy evaluation; rabies; rabies vaccines; rabies virus; recombinant virus; site directed mutagenesis; vaccine development; vector vaccine; virulence; virus genetics; virus protein; virus replication

DESCRIPTION: (Provided by Applicant) Rabies still presents a public health threat causing more than 70,000 human deaths each year. Humans get infected with the rabies virus mostly through bites from rabid domestic and wildlife animals. Controlling rabies virus infection in domestic and wildlife animals, therefore, not only reduces the mortality in these animals but also reduces the risks of human exposure. Pre-exposure vaccinations for people who are constantly at risk further prevent human rabies, as do post-exposure immunizations for people who are bitten by rabid or suspected rabid animals. Currently, inactivated rabies virus vaccines are used to immunize domestic animals, particularly pets. Purified and inactivated rabies virus vaccines are used for humans in the pre- or post-exposure settings. A recombinant vaccinia virus expressing rabies virus glycoprotein (VRG) has been used to control rabies in wildlife. Although these vaccines are effective, annual vaccinations are required to maintain adequate immunity in pets. For humans, multiple doses of the inactivated tissue culture vaccines are required to stimulate optimal immune responses. Furthermore, current tissue culture vaccines are expensive; thus most people in need of vaccinations (in developing countries) cannot afford them. Hence, there is a need to develop more efficacious and affordable rabies virus vaccines. We propose to develop avirulent live rabies virus vaccines by constructing mutant virus with reduced ability to spread in the nervous system (by mutation of the glycoprotein G) and with reduced rate of viral replication (by mutation and/or rearrangement of genes within the rabies virus genome). This will be accomplished by using the state-of-the-art reverse genetics technology. Our proposal is based on recent findings from us as well as others showing the following. 1) Mutation of the phosphorylated serine at 389 of the N to alanine reduced the rate of viral replication by more than five-fold and virus production by more than 10,000 times. 2) Mutation of the G at residue 333 reduced dramatically the virulence and pathogenicity of rabies virus. 3) Rearrangement of the genes within the vesicular stomatitis virus genome resulted in attenuation and enhancement of immune responses. The rationale for constructing mutated or rearranged rabies viruses is that such altered viruses most likely will be further attenuated than currently available attenuated rabies virus (still induce rabies in neonatal animals). If the further attenuated rabies viruses no longer causes diseases in animals at any age and by any route of inoculation, yet remain immunoqenic, they can be developed as modified live rabies vaccines for humans and animals.

描述：（由申请人提供）狂犬病仍然是一种公共卫生 每年造成7万多人死亡的威胁。人类会被感染 狂犬病病毒主要是通过狂犬病家庭和野生动物的叮咬传播的 动物控制家畜和野生动物的狂犬病病毒感染， 因此，不仅降低了这些动物的死亡率， 人体暴露的风险。接触前接种疫苗的人 经常处于危险中的人进一步预防人类狂犬病， 为被患狂犬病或疑似患狂犬病的动物咬伤的人接种疫苗。 目前，狂犬病病毒灭活疫苗用于免疫国内 动物，尤其是宠物。纯化和灭活狂犬病病毒疫苗 用于人类暴露前或暴露后的环境。的重组痘苗 表达狂犬病病毒糖蛋白（VRG）的病毒已被用于控制 野生动物狂犬病尽管这些疫苗有效， 以维持宠物足够的免疫力。对人类来说， 的灭活组织培养疫苗需要刺激最佳的 免疫反应。此外，目前的组织培养疫苗价格昂贵; 因此，大多数需要接种疫苗的人（在发展中国家） 负担得起。因此，有必要开发更有效和负担得起的 狂犬病毒疫苗我们建议研制出无毒的狂犬病活病毒 通过构建在病毒中传播能力降低的突变体病毒， 神经系统（通过糖蛋白G的突变），并降低了 病毒复制（通过狂犬病病毒内基因的突变和/或重排 病毒基因组）。这将通过使用最先进的反向 遗传学技术。我们的建议也是基于我们最近的发现 其他人则显示如下。1)磷酸化丝氨酸的突变 389的N-丙氨酸降低了病毒复制的速度， 病毒产量增加了10,000多倍。2)G突变 在残基333处，狂犬病病毒的毒力和致病性显著降低 病毒3)水泡性口炎病毒基因重排 基因组导致免疫应答的减弱和增强。的 构建突变或重排狂犬病病毒的基本原理是， 改变后的病毒很可能会比现有的病毒更弱 减毒狂犬病病毒（仍能在新生动物中诱发狂犬病）。如果 进一步减毒的狂犬病病毒在任何时候都不再引起动物疾病 年龄和通过任何途径接种，但仍保持免疫，他们可以 作为人类和动物的改良狂犬病活疫苗开发。