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）是由蜱传脑炎组黄病毒引起的神经系统疾病，并导致高达60%的出现临床症状的个体死亡。幸存者往往表现出严重的长期神经系统后遗症。除了经典的病毒外，TBE病毒复合体还含有引起出血热的成员，有时还伴有神经系统症状。在流行地区，这种感染是通过媒介蜱自然传播的。然而，高传染性病毒也可以通过食物或以气溶胶形式传播。因此，TBE病毒疫苗的开发是NIH高度优先的生物防御项目（并且因此被列入NIAID生物防御研究议程中的B和C类病原体）。目前可获得的基于灭活全病毒的商业疫苗未在美国注册，显示出相当大的疫苗接种副作用，并且被标记为仅用于对抗毒性较低的中欧亚型。在先前的第I阶段SBIR项目中，在昆虫细胞中成功地产生了重组TBE亚基蛋白。当与现代佐剂一起使用时，重组蛋白在小鼠中显示出非常强的免疫原性。领先的制剂在西方和远东亚型TBE病毒的小鼠攻击模型中显示出良好的功效。此外，一项初步研究表明，领先的候选疫苗也能完全保护人们免受更远的鄂木斯克出血热病毒的侵害。在II期项目期间，将推进抗原生产，并实施必要的质量控制步骤，以随着生产规模的扩大而取得进展。这将包括在大鼠毒理学研究中明确定义的抗原的安全性试验。将进一步发展和标准化生物和物理化验，以评价对疫苗的反应。这些试验将用于记录主要疫苗制剂中抗原剂量的影响，并评价是否需要第三次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抗原与常规生产的灭活TBE病毒的效力。在改进疫苗制剂后，将评价小鼠对TBE复合物更远距离成员的保护效力。基于小鼠研究，将在非人灵长类动物中检测主要候选药物，以证明其安全性和免疫原性。将使用公认的小鼠被动保护研究间接证明在灵长类动物中的疗效。计划中的研究应完成临床前有效性要求，因此将是迈向新型TBE疫苗临床开发的重要一步。基于重组亚单位蛋白的安全有效的疫苗将可用于保护美国公民免受TBEV感染，而不需要大规模培养高感染性病毒。 公共卫生相关性-项目叙述：蜱传脑炎（TBE）病毒可引起严重的神经系统疾病或出血热，幸存者通常表现出严重的长期神经系统后遗症。目前可获得的基于灭活全病毒的商业疫苗未在美国注册，显示出相当大的疫苗接种副作用，并且标记为仅用于对抗毒力较低的中欧亚型。该项目旨在开发一种基于重组亚单位蛋白的安全有效的疫苗制剂，该疫苗制剂仅需要两次剂量即可提供针对TBE复合体所有成员的广泛保护，以保护美国公民免受世界各地流行地区的TBEV感染。