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

交叉保护性新世界脑炎甲病毒亚单位疫苗的研制

• 批准号: 10696914
• 负责人: DAVID E CLEMENTS
• 金额: $ 20.43万
• 依托单位: HAWAII BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-07 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696914
• 关键词: Acute; Adjuvant; Aerosols; Agonist; Alphavirus; Alphavirus Infections; Americas; Antibody Response; Antibody titer measurement; Antigens; Area; Attenuated; Awareness; Biotechnology; Birds; Blood; Brain; C-terminal; Cells; Centers for Disease Control and Prevention (U.S.); Chikungunya virus; Classification; Collaborations; Combined Vaccines; Culicidae; DNA; Data; Dengue Virus; Department of Defense; Development; Disease; Disease Outbreaks; Dose; Drosophila genus; Encephalitis; Equus caballus; Family; Fever; Formalin; Formulation; Glycoproteins; Goals; Hawaii; Headache; Health; Human; Immune response; Immunize; Inactivated Vaccines; Inbred BALB C Mice; Individual; Infection; Insecta; Investigational Drugs; Laboratories; Licensing; Licensure; Link; Lymphopenia; Malaise; Measures; Medicine; Military Personnel; Modeling; Mus; Myalgia; National Institute of Allergy and Infectious Disease; Nausea; Pathogenicity; Periodicals; Phase; Phase I Clinical Trials; Production; Protein Subunits; Proteins; Public Health; QS21; Recombinant Vaccines; Recombinants; Research; Risk; Rodent; Saponins; Subunit Vaccines; Survivors; System; TLR4 gene; Testing; Time; Tissues; Togaviridae; United States Food and Drug Administration; Vaccines; Venezuelan; Venezuelan Equine Encephalitis Virus; Viral; Viral Vector; Viremia; Virus; Virus Diseases; Virus-like particle; West Nile virus; Western Equine Encephalitis Virus; aerosolized; biothreat; bioweapon; climate change; college; design; epizootic; future outbreak; immunogenic; immunogenicity; interest; liposomal formulation; long-term sequelae; manufacture; medical countermeasure; nervous system disorder; neutralizing antibody; novel; novel vaccines; pandemic potential; pandemic preparedness; pre-clinical; preclinical study; programs; protective efficacy; prototype; response; success; technology platform; transmission process; vaccine candidate; vaccine development; vaccine formulation

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.

7。项目摘要/摘要 脑新世界alphaviruess（NWAVS），由东部，委内瑞拉和西马组成 脑炎病毒（分别EEEV，VEEV和WEEV）通过啮齿动物传播 或鸟类托管，并在美国的马和人类中引起了大量的周期性爆发。 NWAV会引起严重的神经系统疾病，在多达70％的病例中致命性脑炎，并且重要 幸存者的长期后遗症。随着近期气候变化，携带蚊子的地质重新分布 NWAVS进一步增强了未来爆发的潜力。此外，关注他们的潜在用途 生物武器由于其易于生产，高感染率，雾化能力和 诱导疾病的能力，导致E/VEEV的精选剂分类。尽管意识到这些 对E/V/WEEV的持牌人疫苗已有近100年的病毒仍然无法使用。 可以安全有效地保护人类免受这些疫苗的下一代疫苗的开发 迫切需要致病性α病毒感染。该项目旨在发展一个交叉保护 重组亚基E/V/WEEV疫苗基于信封2（E2）和E1的链接外域部分 每个NWAV佐剂的蛋白质与Sla-lsq，一种新型TLR4激动剂，与皂苷QS-21结合 在脂质体配方中。拟议的方法提供了一种将安全稳定的疫苗传递给 使用可扩展的制造平台防止所有三个NWAV的感染 经过验证的TH1/TH2平衡佐剂，通过两者都会引起坚固，有效和耐用的免疫反应 中和和非中和手段。提出的NWAV疫苗基于我们的高度免疫原性 以及密切相关的Chikungunya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亚基免疫的小鼠会产生高NAB E/V/WEEV的非选择剂菌株的滴度。该项目的具体目的是：1）评估 免疫原性并优化单个和联合重组E/V/WEEV亚基的配方 具有SLA-LSQ辅助的蛋白质； 2）证明候选疫苗诱导耐用的能力 小鼠的免疫反应； 3）证明候选疫苗在小鼠中的交叉保护功效 在NWAV挑战中。夏威夷生物技术和贝勒医学院将合作发展， 评估并推进这种新型三价NWAV疫苗候选者。交叉保护的发展 重组亚基疫苗可预防所有三种致病性NWAV，将提供有价值的医学 保护这些脑α病毒所构成的巨大威胁的对策。