Recombinant Subunit Vaccine For Tick-Borne Encephalitis

描述(申请人提供)：森林脑炎(TBE)是由森林脑炎组的黄病毒引起的一种神经系统疾病，可导致高达60%出现临床症状的患者死亡。幸存者通常会出现严重的长期神经后遗症。除了经典病毒外，TBE病毒复合体还包含一些成员，这些成员有时会导致出血热，有时还会伴随神经症状。在流行地区，这种感染是通过媒介蚤自然传播的。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，开发TBE病毒疫苗是NIH高度优先的生物防御项目(并因此被列入NIAID针对B类和C类病原体的生物防御研究议程。目前可用的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，并被贴上标签，仅用于针对毒力较低的中欧亚型。在前一期SBIR项目中，成功地在昆虫细胞中生产了重组TbE亚单位蛋白。当与现代佐剂一起使用时，重组蛋白在小鼠身上表现出非常强的免疫原性。领先的配方在西方和远东亚型TBE病毒的小鼠攻击模型中显示出良好的疗效。此外，一项初步研究表明，领先的候选疫苗也对更远亲的鄂木斯克出血热病毒提供了完全的保护。在第二阶段项目期间，将推进抗原制造，并实施必要的质量控制步骤，以随生产规模的扩大而进步。这将包括在老鼠毒理学研究中对明确定义的抗原进行安全性测试。评估疫苗反应的生物和物理测试将进一步发展和标准化。这些检测将被用来记录主要疫苗配方中抗原剂量的影响，并评估(在不同的小鼠模型中)实现完全保护的第三次疫苗接种的必要性。另一项研究将比较重组TBE抗原和常规生产的灭活TBE病毒的效力。在改进疫苗配方后，将评估小鼠对TBE复合体中更远成员的保护效果。基于对小鼠的研究，领先的候选药物将在非人类灵长类动物身上进行测试，以证明其安全性和免疫原性。在灵长类动物中的疗效将通过在小鼠身上进行公认的被动保护研究来间接证明。计划中的研究将完成临床前的疗效要求，因此将是迈向新型TBE疫苗临床开发的重要一步。一种基于重组亚单位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，而不需要大规模培养高传染性病毒。 公共卫生相关性-项目描述：森林脑炎(TBE)病毒会导致严重的神经系统疾病或出血热，幸存者通常会表现出严重的长期神经后遗症。目前可用的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，并被贴上标签，仅用于针对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配方，该重组亚单位蛋白只需两剂即可提供广泛的保护，以抵御TBE复合体的所有成员，以保护美国公民在世界各地的流行地区免受TBEV感染。

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.