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Developing Avirulent Rabies Virus Vaccines

开发无毒狂犬病病毒疫苗

基本信息

批准号：
7900063
负责人：
ZHEN F FU
金额：
$ 28.65万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900063
关键词：
Ablation Adjuvant Adverse effects Animals Arts Attenuated Bite Brain Cell Culture Techniques Cells Cessation of life Characteristics Cloning Developing Countries Disadvantaged Dose Engineering Funding Genes Genome Glycoproteins Goals Growth Human Immune Immune response Immunization Immunoglobulins In Vitro Inactivated Vaccines Infection Inflammatory Interferons Life Mediating Microglia Mus Mutation Natural Killer Cells Nervous system structure Neuraxis Nucleoproteins Prevention Public Health Rabies Rabies virus Recombinants Recruitment Activity Research Research Personnel Risk Spinal Cord T-Lymphocyte Testing Time Up-Regulation Vaccination Vaccines Viral Physiology Virulence Virulent Virus Virus Diseases Wild Animals base chemokine chemokine receptor exposed human population genetic technology immunogenicity in vivo innovation killings macrophage mortality mutant novel pet animal positional cloning prevent programs recombinant virus tissue culture

项目摘要

DESCRIPTION (provided by applicant): Rabies still presents a public health threat causing more than 70,000 human deaths each year. Humans are infected with rabies virus (RV) mostly through bites from rabid domestic or wild animals. Controlling RV infection in domestic and wildlife animals, therefore not only reduces the mortality in these animals but also reduces the risk of human exposure. Pre-exposure vaccinations for people who are constantly at risk further prevent human rabies, as do post-exposure immunization for people who are bitten by rabid or suspected rabied animals. Currently, inactivated RV vaccines are used to immunize domestic pet animals. Purified and inactivated RV vaccines are used for humans in pre- or post-exposure settings. Although inactivated RV vaccines are efficacious, they have problems. First and for most, multiple doses of vaccines over a long period of time are required to stimulate protective immune responses. Furthermore, current tissue culture vaccines are expensive, thus most people in need of vaccination (in developing countries) cannot afford them. Hence, there is a need to develop more efficacious and affordable RV vaccines. In the previous funding period, we made constructs with mutation on both the glycoprotein and the nucleoprotein, resulting in reduced ability to replicate and spread in the nervous system. Here we propose to continue developing avirulent live RV vaccines by constructing mutant RV with enhanced ability to induce innate immune responses (by inserting IFN or chemokine genes into the RV genome), using the state-of-the-art reverse genetics technology. Our proposal is based on our recent findings. Attenuated RV induces strong innate immune responses, particularly IFN and chemokines, thus limiting virus spread within the CNS. The rationale for construction of recombinant RV expressing IFN or chemokines is that such altered RV most likely will have enhanced immunogenicity and can be used as live avirulent vaccines for humans and animals. Furthermore, induction of innate immune responses will not only have a direct anti-viral functions, but also recruit inflammatory cells that can kill infected cells. Such characterists will make these recombinant RV vaccines particularly suitable for post-exposure treatment.

描述（由申请人提供）：狂犬病仍然构成公共健康威胁，每年导致超过 70,000 人死亡。人类主要通过患有狂犬病的家畜或野生动物咬伤而感染狂犬病病毒（RV）。因此，控制家畜和野生动物的RV感染不仅可以降低这些动物的死亡率，还可以降低人类接触RV的风险。对经常处于危险之中的人进行暴露前疫苗接种可以进一步预防人类狂犬病，对被狂犬病或疑似狂犬病动物咬伤的人进行暴露后免疫也可以进一步预防人类狂犬病。目前，灭活RV疫苗用于对家养宠物进行免疫。纯化和灭活的 RV 疫苗用于人类暴露前或暴露后的情况。尽管灭活RV疫苗有效，但也存在问题。首先，对于大多数人来说，需要在很长一段时间内注射多剂疫苗来刺激保护性免疫反应。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）负担不起。因此，需要开发更有效、更实惠的 RV 疫苗。在之前的资助期间，我们制作了糖蛋白和核蛋白均发生突变的构建体，导致神经系统中复制和传播的能力降低。在这里，我们建议使用最先进的反向遗传学技术，通过构建具有增强诱导先天免疫反应能力的突变型RV（通过将干扰素或趋化因子基因插入RV基因组）来继续开发无毒活RV疫苗。我们的建议是基于我们最近的发现。减毒的 RV 会诱导强烈的先天免疫反应，特别是干扰素和趋化因子，从而限制病毒在中枢神经系统内的传播。构建表达 IFN 或趋化因子的重组 RV 的基本原理是，这种改变的 RV 很可能具有增强的免疫原性，并可用作人类和动物的无毒活疫苗。此外，诱导先天免疫反应不仅具有直接的抗病毒功能，而且还可以招募炎症细胞来杀死受感染的细胞。这些特性将使这些重组 RV 疫苗特别适合暴露后治疗。

项目成果

期刊论文数量（34）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Enhancement of blood-brain barrier permeability is required for intravenously administered virus neutralizing antibodies to clear an established rabies virus infection from the brain and prevent the development of rabies in mice.

DOI：
10.1016/j.antiviral.2014.07.013
发表时间：
2014-10
期刊：
ANTIVIRAL RESEARCH
影响因子：
7.6
作者：
Huang, Chien-Tsun;Li, Zhenguang;Huang, Ying;Zhang, Guoqing;Zhou, Ming;Chai, Qingqing;Wu, Hua;Fu, Zhen F.
通讯作者：
Fu, Zhen F.

Characterization of conformation-specific monoclonal antibodies against rabies virus nucleoprotein.

DOI：
10.1007/s00705-010-0709-x
发表时间：
2010-08
期刊：
ARCHIVES OF VIROLOGY
影响因子：
2.7
作者：
Jiang, Yan;Luo, Yonghuang;Michel, Frank;Hogan, Robert J.;He, Ying;Fu, Zhen F.
通讯作者：
Fu, Zhen F.

Recombinant rabies viruses expressing GM-CSF or flagellin are effective vaccines for both intramuscular and oral immunizations.

DOI：
10.1371/journal.pone.0063384
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Zhou M;Zhang G;Ren G;Gnanadurai CW;Li Z;Chai Q;Yang Y;Leyson CM;Wu W;Cui M;Fu ZF
通讯作者：
Fu ZF

Complete genome sequence of a street rabies virus isolated from a dog in Nigeria.

DOI：
10.1128/genomea.00214-12
发表时间：
2013-01
期刊：
Genome announcements
影响因子：
0
作者：
Zhou M;Zhou Z;Kia GS;Gnanadurai CW;Leyson CM;Umoh JU;Kwaga JP;Kazeem HM;Fu ZF
通讯作者：
Fu ZF

Role of chemokines in the enhancement of BBB permeability and inflammatory infiltration after rabies virus infection.