Cross-Protective Multivalent Vaccine for Tick-Borne Flaviviruses

项目摘要/摘要 NIH/NIAID 2017年战略计划专门针对促进能够提供 缓解新出现和再次出现的疾病构成的威胁的解决方案。壁虱传播的黄病毒 (TBFV)组包括一些重要的人类病原体，这些病原体会导致严重的神经或 属于B类或C类优先病原体的出血性疾病。TBFV被认为是 新出现或重新出现的病原体由于人类感染人数的增加，扩大 它们的地理分布，以及新病毒的出现。此外，不同病毒的数量 TBFV小组构成了挑战。有两种已获许可的森林脑炎病毒(TBEV)疫苗 欧洲。这些疫苗基于TBEV的欧洲毒株(TBEV-EU)，虽然它们提供了 一定程度的交叉中和，但不是所有的TBFV都被覆盖。此外，这些疫苗并不是 在美国获得许可，在加拿大不再提供。一种多价疫苗的开发 提供针对多种致病TBFV的交叉保护将具有重要价值，并符合 NIH/NIAID开发多价交叉保护技术的优先事项。我们已经证明了 TBFV重组包膜亚单位蛋白(R80E)的两种组合可提供保护作用 在小鼠挑战模型中有不同范围的TBFV。此外，使用血清进行被动转移研究 用r80E蛋白组合免疫的小鼠证实了抗体在保护中的作用 抵御病毒挑战。这个IIB阶段的应用建立在我们最初开发多价 针对这一组病毒提供广泛交叉保护的TBFV疫苗。拟议的研究 目的是1)优化疫苗配方；2)中试生产抗原；3)进行前期试验 与FDA会面；以及4)进行效力和毒性测试，以确定 最终的TBFV疫苗配方。随着这些努力的成功完成，我们将定位于 推动多组分TBFV疫苗进入cGMP生产活动并走向临床 评估。

Project Summary/Abstract The NIH/NIAID 2017 Strategic Plan is specifically directed at promoting research that can provide solutions to mitigate the threat posed by emerging and re-emerging diseases. The tick-borne flavivirus (TBFV) group includes a number of important human pathogens that result in serious neurological or hemorrhagic diseases that are either Category B or C priority pathogens. The TBFVs are considered to be emerging or re-emerging pathogens due to increases in the number of human infections, the expansion of their geographic distribution, and emergence of new viruses. Additionally, the number of different viruses in the TBFV group poses challenges. There are two licensed Tick-borne encephalitis virus (TBEV) vaccines in Europe. These vaccines are based on the European strains of TBEV (TBEV-Eu), and while they provide some level of cross-neutralization, not all of the TBFV are covered. Furthermore, these vaccines are not licensed in the U.S. and are no longer available in Canada. The development of a multivalent vaccine that provides cross-protection against multiple pathogenic TBFVs would be of great value and is in line with the priorities of NIH/NIAID to develop multivalent and cross-protective technologies. We have demonstrated that two combinations of TBFV recombinant envelope subunit proteins (r80E) can provide protection against a diverse range of TBFV in a mouse challenge model. Additionally, passive transfer studies using serum from mice immunized with combinations of the r80E protein confirm the role of antibodies in protection against virus challenge. This Phase IIB application builds upon our initial efforts to develop a multivalent TBFV vaccine that provides broad cross-protection against viruses in this group. The proposed research aims to 1) optimizing the vaccine formulation; 2) produce pilot lots of the antigens; 3) conduct a pre-IND meeting with the FDA; and 4) conduct potency and toxicity testing to establish the suitability and safety of the final TBFV vaccine formulation. With the successful completion of these efforts, we will be positioned to advance a multicomponent TBFV vaccine into a cGMP manufacturing campaign and toward clinical evaluation.