Recombinant Subunit Vaccine For Tick-Borne Encephalitis

蜱传脑炎重组亚单位疫苗

• 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
• 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

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）：蜱传脑炎（TBE）是一种由蜱传脑炎类黄病毒引起的神经系统疾病，导致高达 60% 出现临床症状的个体死亡。幸存者常常表现出严重的长期神经系统后遗症。除了经典病毒外，TBE 病毒复合体还包含有时引起出血热并伴有神经系统症状的成员。在流行地区，感染通过媒介蜱自然传播。然而，高度传染性的病毒也可以通过食物或雾化形式传播。因此，TBE病毒疫苗的开发是NIH高度优先的生物防御项目（因此被列入NIAID B类和C类病原体生物防御研究议程中。目前基于灭活全病毒的商业疫苗尚未在美国注册，显示出相当大的疫苗副作用，并且被标记为仅针对毒性较低的中欧亚型。在之前的第一阶段SBIR项目中，重组TBE亚基蛋白已在昆虫细胞中成功产生。当与现代佐剂一起使用时，该领先制剂在小鼠的西方和远东亚型 TBE 病毒攻击模型中显示出良好的功效。此外，一项初步研究表明，该领先的候选疫苗还可以提供针对 TBE 病毒的完全保护。更远亲的鄂木斯克出血热病毒 在第二阶段项目中，将推进抗原生产并实施必要的质量控制步骤，以扩大生产规模。这将包括在大鼠毒理学研究中对明确抗原进行安全性测试。用于评估疫苗反应的生物和物理测定将得到进一步开发和标准化。这些测定将用于记录主要疫苗配方中抗原剂量的影响，并评估是否需要第三次疫苗接种以实现完全保护（在不同的小鼠模型中）。另一项研究将比较重组 TBE 抗原与传统生产的灭活 TBE 病毒的效力。改进疫苗配方后，将评估小鼠对 TBE 复合体较远成员的保护功效。基于小鼠研究，主要候选药物将在非人类灵长类动物中进行测试，以证明安全性和免疫原性。将使用广为接受的小鼠被动保护研究来间接证明对灵长类动物的功效。计划中的研究应完成临床前功效要求，因此将是新型 TBE 疫苗临床开发的重要一步。基于重组亚基蛋白的安全有效的疫苗将有助于保护美国公民免受 TBEV 感染，而无需大规模培养高传染性病毒。 公共卫生相关性 - 项目叙述：蜱传脑炎 (TBE) 病毒会导致严重的神经系统疾病或出血热，幸存者通常会出现严重的长期神经系统后遗症。目前基于灭活完整病毒的商业疫苗尚未在美国注册，显示出相当大的疫苗副作用，并且被标记为仅针对毒性较低的中欧亚型。该项目旨在开发一种基于重组亚基蛋白的安全有效的疫苗制剂，只需两剂即可针对TBE复合体的所有成员提供广泛的保护，从而保护美国公民免受世界各地流行地区TBEV的感染。