Recombinant Subunit Vaccine For Tick-Borne Encephalitis

蜱传脑炎重组亚单位疫苗

基本信息

批准号：
8143373
负责人：
DAVID E CLEMENTS
金额：
$ 99.35万
依托单位：
HAWAII BIOTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2012-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8143373
关键词：
Adjuvant Adverse effects Animal Model Antigens Area Asia Biological Biological Assay Categories Cause of Death Cell Line Cells Clinical Clinical Pathology Clinical assessments Complement Complex Development Distant Dose Drug Formulations Eastern Europe Encephalitis Enzyme-Linked Immunosorbent Assay Europe European Evaluation Flavivirus Food Formalin Goals Guidelines Hemagglutination Human Humoral Immunities Hybridomas Immune Sera Immune response In Vitro Inbreeding Individual Infection Insecta Japanese Encephalitis Vaccines Kyasanur Forest disease virus Label Licensing Macaca mulatta Measures Methods Military Personnel Modeling Mouse Strains Mus National Institute of Allergy and Infectious Disease Neurologic Omsk hemorrhagic fever virus Passive Immunization Performance Phase Primates Production Protein Subunits Quality Control Rattus Recombinant Proteins Recombinants Recommendation Regimen Research Research Proposals Russia Safety Schedule Serum Small Business Innovation Research Grant Subunit Vaccines Survivors Symptoms Technology Testing Tick-Borne Encephalitis Tick-Borne Encephalitis Virus Tick-Borne Encephalitis Viruses Ticks Toxic effect Toxicology United States National Institutes of Health Vaccination Vaccines Viral Hemorrhagic Fevers Virulent Virus Virus Diseases Work aerosolized base biodefense cell bank clinical efficacy dosage immunogenicity improved in vitro Assay in vivo member mouse model nervous system disorder neurotropic nonhuman primate novel novel vaccines pathogen pre-clinical protective efficacy protein expression protein purification public health relevance research and development response safety testing sample fixation scale up stability testing success vaccine candidate vaccine development vaccine efficacy vaccine safety vector

Adjuvant Adverse effects Animal Model Antigens Area Asia Biological Biological Assay Categories Cause of Death Cell Line Cells Clinical Clinical Pathology Clinical assessments Complement Complex Development Distant Dose Drug Formulations Eastern Europe Encephalitis Enzyme-Linked Immunosorbent Assay Europe European Evaluation Flavivirus Food Formalin Goals Guidelines Hemagglutination Human Humoral Immunities Hybridomas Immune Sera Immune response In Vitro Inbreeding Individual Infection Insecta Japanese Encephalitis Vaccines Kyasanur Forest disease virus Label Licensing Macaca mulatta Measures Methods Military Personnel Modeling Mouse Strains Mus National Institute of Allergy and Infectious Disease Neurologic Omsk hemorrhagic fever virus Passive Immunization Performance Phase Primates Production Protein Subunits Quality Control Rattus Recombinant Proteins Recombinants Recommendation Regimen Research Research Proposals Russia Safety Schedule Serum Small Business Innovation Research Grant Subunit Vaccines Survivors Symptoms Technology Testing Tick-Borne Encephalitis Tick-Borne Encephalitis Virus Tick-Borne Encephalitis Viruses Ticks Toxic effect Toxicology United States National Institutes of Health Vaccination Vaccines Viral Hemorrhagic Fevers Virulent Virus Virus Diseases Work aerosolized base biodefense cell bank clinical efficacy dosage immunogenicity improved in vitro Assay in vivo member mouse model nervous system disorder neurotropic nonhuman primate novel novel vaccines pathogen pre-clinical protective efficacy protein expression protein purification public health relevance research and development response safety testing sample fixation scale up stability testing success vaccine candidate vaccine development vaccine efficacy vaccine safety vector

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项目摘要

DESCRIPTION (provided by applicant): Tick-borne encephalitis (TBE) is a neurological disease caused by Flaviviruses of the tick-borne encephalitis group and causes death in up to 60% of the individuals developing clinical symptoms. Survivors often show severe long-term neurological sequelae. In addition to the classical viruses, the TBE complex of viruses also contains members that cause hemorrhagic fevers sometimes in combination with neurological symptoms. The infection is naturally transmitted via vector ticks in endemic areas. However, the highly infective viruses can also be transmitted via food or in aerosolized form. Therefore, development of a TBE virus vaccine is a NIH high-priority biodefense project (and as such listed in the NIAID Biodefense research agenda for category B and C pathogens. Currently available commercial vaccines based on inactivated whole virus are not registered in the U.S., show considerable vaccination side-effects and are labeled for use only against the less virulent Central European subtype. In the previous phase I SBIR project recombinant TBE subunit proteins were successfully produced in insect cells. The recombinant proteins showed very potent immunogenicity in mice when used with modern adjuvants. The leading formulations showed good efficacy in the mouse challenge models of Western and Far Eastern subtype TBE viruses. In addition, a preliminary study demonstrated that the leading vaccine candidate also confers complete protection against the more distantly related Omsk Hemorrhagic Fever virus. During the phase II project, the antigen manufacturing will be advanced and the necessary quality control steps implemented to progress with the scale-up of production. This will include safety testing of well-defined antigen in a rat toxicology study. Biological and physical assays to evaluate the response to the vaccines will be further developed and standardized. Those assays will be used to document the effect of antigen dosage in the leading vaccine formulation and evaluate the need for a third vaccination to achieve complete protection (in different mouse models). Another study will compare the potency of the recombinant TBE antigen with that of conventionally produced inactivated TBE virus. After refining the vaccine formulation, protective efficacy in mice against the more distant members of the TBE complex will be evaluated. Based on mouse studies the leading candidate will be tested in non-human primates to demonstrate safety and immunogenicity. Efficacy in primates will be demonstrated indirectly using well accepted passive protection studies in mice. The planned studies should complete the pre-clinical efficacy requirements and would therefore be an important step towards the clinical development of a novel TBE vaccine. A safe and efficacious vaccine based on recombinant subunit proteins would provide useful in protecting U.S. citizens from TBEV infection without the need of large-scale culture of highly infectious virus. PUBLIC HEALTH RELEVANCE - PROJECT NARRATIVE: Tick-borne encephalitis (TBE) viruses cause severe neurological disease or hemorrhagic fevers and survivors often show severe long-term neurological sequelae. Currently available commercial vaccines based on inactivated whole virus are not registered in the U.S., show considerable vaccination side-effects and are labeled for use only against the less virulent Central European subtype. This project is aimed to develop a safe and efficacious vaccine formulation based on a recombinant subunit protein which requires only two doses to provide broad protection against all members of the TBE complex to protect U.S. citizens from TBEV infection in endemic areas around the world.

描述（由申请人提供）：tick传播脑炎（TBE）是由tick传播脑炎组的黄病毒引起的神经系统疾病，并导致多达60％的患者死亡。幸存者经常表现出严重的长期神经后遗。除经典病毒外，病毒复合物还包含有时会与神经系统症状结合使用的成员。感染是通过流行区域的矢量滴答自然传播的。但是，高度感染性病毒也可以通过食物或雾化形式传播。因此，开发TBE病毒疫苗是NIH的高优先级生物化项目（如在NIAID BiodeFense研究的B和C类病原体的日程中所述。当前基于非活化的整个病毒的商业疫苗目前可用的商业疫苗在美国注册并不相当多，以前的疫苗接种量不多。重组蛋白在昆虫细胞中成功产生。重组蛋白在与现代辅助物中使用时，在小鼠中表现出非常有效的免疫原性。病毒。在II期项目中，抗原制造将得到发展，并实施必要的质量控制步骤，以随着生产规模而进行。这将包括对大鼠毒理学研究中定义明确的抗原的安全测试。评估对疫苗反应的生物学和物理测定将进一步开发和标准化。这些测定法将用于记录抗原剂量在领先的疫苗配方中的影响，并评估第三次疫苗接种以实现完全保护的需求（在不同的小鼠模型中）。另一项研究将比较重组TBE抗原的效力与传统产生的TBE病毒的效力。在完善疫苗配方后，将评估小鼠对TBE复合物更遥远成员的保护效果。根据小鼠研究，将在非人类灵长类动物中测试领先的候选人，以证明安全性和免疫原性。使用小鼠中公认的被动保护研究，将间接证明灵长类动物的功效。计划的研究应满足临床前的功效要求，因此将是迈向新型疫苗临床发展的重要一步。基于重组亚基蛋白的安全有效的疫苗将提供有助于保护美国公民免受TBEV感染的有用，而无需大规模的高度感染性病毒培养。公共卫生相关性 - 项目叙事：tick传播脑炎（TBE）病毒引起严重的神经系统疾病或出血性发烧，幸存者经常出现严重的长期神经系统后遗症。目前，基于灭活整个病毒的商业疫苗在美国没有注册，显示出相当大的疫苗接种副作用，并被标记为仅用于对中欧较不毒性的中欧亚型的使用。该项目的目的是基于重组亚基蛋白来开发安全有效的疫苗配方，该蛋白只需要两种剂量才能为TBE建筑群的所有成员提供广泛的保护，以保护美国公民免受世界各地的TBEV感染。