Development of a Cross-Protective New World Encephalitic Alphavirus Subunit Vaccine

7.项目摘要/摘要 脑炎新世界甲型病毒(NWAVs)，由东部、委内瑞拉和西部马组成 脑炎病毒(EEEV、VEEV和WeEV)是由蚊子通过啮齿动物传播的 或鸟类宿主，并在美洲的马和人类中造成重大的周期性流行性疫情暴发。 NWAVs可导致严重的神经系统疾病，高达70%的病例会导致致命的脑炎，而且显著 幸存者的长期后遗症。随着最近的气候变化，蚊子携带的地质重新分布 NWAVs进一步增加了未来暴发的可能性。此外，对它们潜在用途的担忧 生物武器是有充分根据的，因为它们易于生产，传染性强，能够气雾化，以及 诱发疾病的能力，导致E/VEEV的选择试剂分类。尽管意识到了这些 近100年来，获得许可的针对E/V/Weev的人类疫苗仍然无法普遍使用。 下一代疫苗的开发可以安全有效地保护人类免受这些疾病的影响 致病性甲型病毒感染是迫切需要的。该项目寻求开发一种交叉保护 基于E_2和E_1膜外区连接的重组E/V/WeeV亚单位疫苗 新的TLR4激动剂SLA-LSQ与皂苷QS-21结合后每个NWAV的蛋白质 在脂质体配方中。建议的方法提供了一种将安全和稳定的疫苗输送到 使用可扩展的制造平台保护所有三个NWAV免受感染，与 一种成熟的Th1/Th2平衡佐剂，通过以下两种途径诱导强大、有效和持久的免疫反应 中和和非中和手段。建议的NWAV疫苗是基于我们高度免疫原性的 以及针对密切相关的基孔肯雅病毒(CHIKV)的完全保护性临床前E2/E1候选疫苗。 新的初步数据表明，用NWAVE2/E1亚基免疫的小鼠产生高NAB 对E/V/Weev非选择药剂株的效价。该项目的具体目标是：1)评估 重组E/V/WeeV单亚基和联合亚基的免疫原性及配方优化 含有SLA-LSQ佐剂的蛋白质；2)展示候选疫苗诱导持久 小鼠的免疫反应；以及3)证明候选疫苗在小鼠中的交叉保护效果 在NWAV挑战赛上。夏威夷生物技术公司和贝勒医学院将合作开发， 评估和推进这一新的三价NWAV候选疫苗。一种交叉保护装置的研制 针对所有三种致病NWAV的重组亚单位疫苗将提供一种有价值的医学 防范这些脑型字母病毒构成的相当大威胁的对策。

7. Project Summary/Abstract The encephalitic New World alphaviruses (NWAVs), consisting of Eastern, Venezuelan and Western Equine Encephalitis Viruses (EEEV, VEEV and WEEV, respectively), are transmitted by mosquitoes through rodent or bird hosts and have caused significant periodic epizootic outbreaks in equines and humans in the Americas. NWAVs can cause severe neurological disease, with fatal encephalitis in up to 70% of cases, and significant long-term sequelae in survivors. With recent climate changes, geological redistribution of mosquitoes carrying NWAVs further enhances the potential for future outbreaks. Moreover, concern over their potential use as bioweapons is well-founded due to their ease of production, high infectivity, ability for aerosolization, and capacity to induce disease, resulting in select agent classification for E/VEEV. Despite awareness of these viruses for nearly 100 years, licensed human vaccines against E/V/WEEV remain unavailable for general use. The development of next-generation vaccines that can safely and effectively protect humans against these pathogenic alphavirus infections are urgently needed. This project seeks to develop a cross-protective recombinant subunit E/V/WEEV vaccine based on the linked ectodomain portions of Envelope 2 (E2) and E1 proteins of each NWAV adjuvanted with SLA-LSQ, a novel TLR4 agonist combined with the saponin QS-21 in a liposomal formulation. The proposed approach provides a means to deliver a safe and stable vaccine to protect against infection by all three NWAVs using a scalable manufacturing platform that, in combination with a proven Th1/Th2 balanced adjuvant, elicits a robust, efficacious and durable immune response through both neutralizing and non-neutralizing means. The proposed NWAV vaccine is based on our highly immunogenic and fully protective pre-clinical E2/E1 candidate vaccine for the closely related Chikungunya virus (CHIKV). New preliminary data demonstrates that mice immunized with the NWAV E2/E1 subunits generate high NAb titers to non-select agent strains of E/V/WEEV. The Specific Aims of this project are: 1) evaluate the immunogenicity and optimize formulations of individual and combined recombinant E/V/WEEV subunit proteins with SLA-LSQ adjuvant; 2) demonstrate the ability of the candidate vaccine to induce a durable immune response in mice; and 3) demonstrate the cross-protective efficacy of the candidate vaccine in mice upon NWAV challenge. Hawaii Biotech and the Baylor College of Medicine will collaborate to develop, evaluate and advance this novel trivalent NWAV vaccine candidate. The development of a cross-protective recombinant subunit vaccine to protect against all three pathogenic NWAVs would provide a valuable medical countermeasure to safeguard against the considerable threat posed by these encephalitic alphaviruses.