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

7.项目总结/摘要 脑炎性新世界甲病毒（NWAV），包括东部、委内瑞拉和西部马 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引起重大的周期性动物流行病爆发。 NWAV可引起严重的神经系统疾病，高达70%的病例会导致致命的脑炎， 幸存者的长期后遗症。随着最近的气候变化，携带蚊子的地理分布 非病毒性禽流感进一步增加了未来爆发的可能性。此外，对它们可能被用作 生物武器是有充分理由的，因为它们易于生产，传染性强，能够雾化， 诱发疾病的能力，导致E/VEEV的选择剂分类。尽管意识到这些 病毒存在近100年来，针对E/V/WEEV的许可人类疫苗仍然无法普遍使用。 开发下一代疫苗，可以安全有效地保护人类免受这些疾病的侵害。 迫切需要致病性甲病毒感染。该项目旨在开发一种交叉保护 基于包膜2（E2）和E1的连接的胞外域部分的重组亚单位E/V/WEEV疫苗 用SLA-LSQ（一种与皂苷QS-21组合的新型TLR 4激动剂）辅助的每种NWAV的蛋白质 在脂质体制剂中。所提出的方法提供了一种将安全稳定的疫苗提供给 使用可扩展的制造平台，结合 一种经证实的Th 1/Th 2平衡佐剂，通过两种途径增强稳健、有效和持久的免疫应答。 中和和非中和装置。拟议的NWAV疫苗是基于我们的高免疫原性 和用于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NWAV E2/E1亚单位免疫的小鼠产生高NAb 对E/V/WEEV的非选择剂菌株的滴度。该项目的具体目标是：1）评估 重组E/V/WEEV单亚基和组合亚基免疫原性和优化制剂 2）证明候选疫苗诱导具有SLA-LSQ佐剂的持久免疫应答的能力; 小鼠中的免疫应答;和3）证明候选疫苗在小鼠中的交叉保护效力 在NWAV的挑战。夏威夷生物技术公司和贝勒医学院将合作开发， 评估和推进这种新的三价NWAV候选疫苗。交叉保护的发展 重组亚单位疫苗，以保护对所有三个致病性NWAV将提供一个有价值的医疗 因此，我们需要采取措施，以防范这些脑炎甲病毒造成的巨大威胁。

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.