Developing Avirulent Rabies Virus Vaccines

开发无毒狂犬病病毒疫苗

• 批准号: 6464738
• 负责人: ZHEN F FU
• 金额: $ 24.22万
• 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/6464738
• 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）狂犬病仍然是一个公共卫生问题 威胁每年造成 70,000 多人死亡。人类被感染 狂犬病病毒主要通过患有狂犬病的家畜和野生动物的叮咬传播 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，而且还减少了 人体暴露的风险。适合以下人群的暴露前疫苗接种 持续处于危险之中进一步预防人类狂犬病，暴露后也是如此 为被患有狂犬病或疑似患有狂犬病的动物咬伤的人进行免疫接种。 目前，国内免疫接种均采用灭活狂犬病病毒疫苗。 动物，特别是宠物。纯化和灭活的狂犬病病毒疫苗是 用于处于暴露前或暴露后环境中的人类。重组牛痘 表达狂犬病病毒糖蛋白（VRG）的病毒已被用来控制 野生动物中的狂犬病。尽管这些疫苗有效，但每年都要接种疫苗 需要保持宠物足够的免疫力。对于人类来说，多次剂量 需要灭活的组织培养疫苗来刺激最佳效果 免疫反应。此外，目前的组织培养疫苗价格昂贵； 因此，大多数需要疫苗接种的人（在发展中国家）无法 负担得起。因此，需要开发更有效、更经济的方法 狂犬病病毒疫苗。我们建议开发无毒活狂犬病病毒 通过构建在体内传播能力降低的突变病毒来开发疫苗 神经系统（通过糖蛋白 G 的突变）并且降低了 病毒复制（通过狂犬病基因内的突变和/或重排） 病毒基因组）。这将通过使用最先进的逆向来完成 遗传学技术。我们的建议也是基于我们最近的发现 正如其他人显示的那样。 1) 磷酸化丝氨酸突变 第389章 丙氨酸的N使病毒复制速度降低超过 5倍，病毒产量增加10,000倍以上。 2）G的突变 333位残基显着降低了狂犬病的毒力和致病性 病毒。 3) 水泡性口炎病毒内基因的重排 基因组导致免疫反应减弱和增强。这 构建突变或重排的狂犬病病毒的基本原理是 改变的病毒很可能比目前可用的病毒进一步减毒 减毒狂犬病病毒（仍会在新生动物中诱发狂犬病）。如果 进一步减毒的狂犬病病毒不再引起动物疾病 年龄和任何接种途径，但仍保持免疫原性，它们可以 开发为人类和动物的改良狂犬病活疫苗。