A novel approach for developing inactivated chikungunya virus vaccine

开发灭活基孔肯雅病毒疫苗的新方法

基本信息

批准号：
9303272
负责人：
Anuj Sharma
金额：
$ 23.23万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-23 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9303272
关键词：
Address Adherence Adult Aedes Aerosols Affect Alphavirus Americas Animal Model Antibodies Antioxidants Attenuated Biological Preservation Cell Culture Techniques Chikungunya virus Clinical Trials Complex Country Deinococcus radiodurans Diagnosis Disease Outbreaks Dose Elements Emerging Communicable Diseases Epidemic Epitopes Europe FDA approved Formalin Gamma Rays Glycoproteins Goals Herd Immunity Human Immunization Immunocompetent Inactivated Vaccines Indian Ocean Islands Individual Infection Interferon-alpha Ionizing radiation Manganese Medical Methods Monoclonal Antibodies Morbidity - disease rate Mus Nature Neonatal North America Outcome Pharmaceutical Preparations Phase II Clinical Trials Population Preparation Production Prophylactic treatment Quality of life Radiation Radiation induced damage Regimen Reporting Research Residual state Risk Running Southeastern Asia Structural Protein Surface Testing Therapeutic Time Travel United States Vaccines Venezuelan Equine Encephalitis Virus Viral Viral Envelope Proteins Viral Genome Virion Virulence Virus Virus Diseases Virus Inactivation aqueous attenuation bacterial resistance chikungunya cost design env Gene Products experimental study fighting follow-up immunogenic immunogenicity in vivo inorganic phosphate irradiation mouse model novel novel strategies oxidative damage pathogen genome productivity loss protective efficacy protein degradation radiation resistance radioresistant seroconversion southeast Asian vaccine candidate vector virus envelope

项目摘要

Chikungunya virus (CHIKV) is an emerging infectious disease virus that has caused large scale outbreaks in the last decade, some of these are ongoing. The cost of decade long chikungunya outbreak, including medical and productivity loss, runs in billions of dollars. There are no licensed CHIKV vaccine or specific threapeutic drugs against CHIKV. United States Army had developed a live attenuated strain of CHIKV, CHIKV181/25, which in spite of demonstrating excellent immunogenicity failed in clinical trials due to residual virulence in some of the vaccinees. Similar outcome of residual virulence has also been reported in some other cases of attenuated alphavirus vaccine candidates. Therefore, it is unlikely that a live attenuated alphavirus will get FDA approval as vaccine for human application. There is a renewed focus on generating inactivated or highly attenuated chimeric CHIKV vaccine candidates. In this study, a novel approach for generating γ-radiation-inactivated CHIKV vaccine will be tested γ-radiation. Hypothesis will be tested first by evaluating the complete inactivation of CHIKV in cell culture, and in-vivo in sensitive neonatal mice, so as to rule out the protection of infectivity of CHIKV by MDP complex during exposure with γ-radiation. Second, epitope integrity of inactivated CHIKV will be evaluated using monoclonal antibodies against the virus envelope glycoproteins. Immunogenic potential in terms of induction of anti-CHIKV antibody will be evaluated in immunocompetent C57BL6 mice. Protective efficacy of inactivated CHIKV will be evaluated in- vivo in adult A129 (IFNα/βR-/-) mice model of CHIKV infection. Single immunization potential of inactivated CHIKV will also be evaluated. CHIKV infections spread rapidly during an outbreak. Single immunization will result in short and thereby, better adherence to immunization regimen that would be needed to develop protective immunivty against the virus, and will help in fighting the explosive nature of CHIKV outbreak. Long-term goal of the proposed research is to develop a safe and effective CHIKV-vaccine candidate. The current ongoing outbreak of CHIKV has shown potential to spread to the previously CHIKV-naïve regions of the globe such as the North Americas. In absence of an effective anti-CHIKV drug, vaccine, and any herd immunity in its population, CHIKV outbreak in the contiguous North Americas will be devastating.

基孔肯雅病毒（Chikv）是一种新兴的传染病病毒，已引起大规模的在过去的十年中，其中一些正在进行中。十年长的chikungunya的成本爆发，包括医疗和生产力损失，持续数十亿美元。没有持牌的CHIKV疫苗或针对Chikv的特异性药物。美国陆军有开发了CHIKV的活菌株Chikv181/25，尽管证明了这一点由于残留病毒在某些的临床试验中，出色的免疫原性失败了疫苗。在其他一些情况下，还报道了残留病毒的类似结果降低了α病毒疫苗的候选。因此，活着的人不太可能 Alphavirus将获得FDA批准作为人类应用的疫苗。重点是产生灭活或高度衰减的嵌合CHIKV疫苗候选物。在这项研究中，将测试生成γ-辐射灭活的CHIKV疫苗的新方法。假设将首先通过评估CHIKV在细胞培养中的完全失活，以下测试，和体内敏感的新生小鼠，以排除CHIKV感染的保护 MDP复合物与γ辐射暴露期间。第二，灭活的Chikv的表位完整性将使用针对病毒包膜糖蛋白的单克隆抗体评估。在诱导抗ChIKV抗体方面，将评估免疫原性的潜力免疫能力C57BL6小鼠。将评估灭活的CHIKV的保护效率成年A129（IFNα/βR - / - ）小鼠CHIKV感染模型的体内。单个免疫潜力还将评估灭活的CHIKV。 CHIKV感染在暴发。单个免疫将导致短暂，从而更好地遵守免疫为病毒开发受保护的免疫所需的疗法，将有助于与Chikv爆发的爆炸性作斗争。拟议研究的长期目标是发展一个安全有效的Chikv-Vaccine候选人。 Chikv目前正在持续的爆发已经显示出传播到地球以前未来地区的潜力北美。在没有有效的抗chiKV药物的情况下，疫苗和任何牛群免疫抑制它的人口，连续北美的Chikv爆发将是毁灭性的。