Developing Vertebrate-Specific Replication-Defective Dengue Virus as Novel Single-CycleDengue Vaccine Candidate

开发脊椎动物特异性复制缺陷型登革热病毒作为新型单周期登革热候选疫苗

• 批准号: 10384489
• 负责人: XIAOWU PANG
• 金额: $ 29.85万
• 依托单位: TENGEN BIOMEDICAL CO.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-21 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384489
• 关键词: 6 year old; Address; Animal Experiments; Animal Model; Antibody-Dependent Enhancement; Arboviruses; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Cell Line; Cells; Cellular Immunity; Child; Clinical Trials; Complementary DNA; DNA; Data; Defective Viruses; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dependence; Development; Epidemic; Evaluation; Female; Flavivirus; Formulation; Foundations; Generations; Goals; Hand; Hospitalization; Humoral Immunities; Immune response; Immunity; Immunologics; Inactivated Vaccines; Incubated; Insecta; Investigation; K562 Cells; Lead; Membrane Proteins; Modeling; Mus; Persons; Phase; Phenotype; Production; Public Health; RNA; Recording of previous events; Risk; Safety; Serotyping; Serum; Site; Subunit Vaccines; System; T cell response; Testing; Universities; Vaccinated; Vaccines; Viral; Viral Vaccines; Virus; Virus Replication; Zika Virus; base; commercial application; cost; immunogenicity; male; mindfulness; mouse model; nonhuman primate; novel; pathogen; phase 1 study; preclinical trial; prevent; programs; protective efficacy; receptor; reverse genetics; scale up; severe dengue; universal vaccine; vaccine access; vaccine candidate; vaccine development; vaccine trial

Developing Vertebrate-Specific Replication-Defective Dengue Virus as a Novel Single-Cycle Dengue Vaccine Candidate Abstract With an estimated minimum of 390 million dengue virus (DENV) infections per year, the DENV epidemic was listed as one of the world's top 10 public health threats by WHO in 2019. At present, there is no specific treatment. A universal vaccine is urgently needed. DENV vaccine development's unique challenge is that a dengue vaccine must induce long-term protection against all four serotypes simultaneously. Historically, tetravalent live attenuated viral vaccines have shown that it is difficult to achieve balanced immunity to all four serotypes. Also, inactivated virus vaccines can't confer long-term immunity to prevent potential antibody-dependent enhancement (ADE). Mindful of these obstacles, we have investigated single-cycle, pseudoinfectious DENVs as vaccine candidates to induce balanced long-term immunity against all four serotypes. A significant impediment to this approach is that replicating pseudoinfecious DENVs usually require complicated and low-efficient packaging cells, making the scale-up production difficult and costly. Thus, towards the overall goal of developing a safe, effective, and affordable DENV vaccine, we converted dual-tropic DENVs into artificial insect-specific viruses to overcome the dependence on packaging cells to produce a single-cycle virus vaccine. These vertebrate-specific replication-defective DENVs (VSRD-DENV) were generated by optimizing the furin cleavage site in viral pre-membrane protein (prM). Preliminary animal experiments with VSRD-DENV1 and VSRD-DENV2 demonstrated that the VSRD-DENVs induced robust protective immunity with inherent high safety levels in mice. Based on these highly promising preliminary results and considering the urgent need for an effective dengue vaccine, Tengen Biomedical Co. and Howard University have teamed up to accelerate the evaluation of the VSRD-DENVs-based dengue vaccine. To achieve this goal, we propose to generate and characterize VSRD-DENV3 and VSRD-DENV4 vaccine candidate viruses. We will then perform a comprehensive analysis of the immunogenicity and protective efficacy of tetravalent VSRD-DENVs in a sensitive AG129 mouse model. Successful completion of these proposed studies will enable the dengue vaccine candidate into non-human primate testing and establish a platform for developing vaccines for other important flaviviruses.

开发脊椎动物特异性复制缺陷登革热病毒 一种新型的单周期登革热疫苗候选者 抽象的 估计每年至少有3.9亿登革热病毒（DENV）感染， DENV流行病被列为世界上十大公共卫生威胁之一 2019年。目前没有具体的治疗方法。迫切需要一种通用疫苗。 DENV疫苗开发的独特挑战是登革热疫苗必须诱发 长期保护所有四种血清型。从历史上看，四价 活病毒疫苗的活衰减表明很难实现平衡的免疫力 到所有四种血清型。同样，灭活的病毒疫苗不能赋予长期免疫力 防止潜在的抗体依赖性增强（ADE）。注意这些障碍， 我们已经调查了单周期，伪感染的DENV作为候选疫苗 对所有四种血清型都施加平衡的长期免疫力。一个重大障碍 对这种方法是复制伪胸部的DENV通常需要复杂的 和低效率的包装单元，使扩大生产变得困难且昂贵。 因此，要建立安全，有效且负担得起的DENV的总体目标 疫苗，我们将双面热带DENV转换为人造昆虫特异性病毒 克服对包装细胞产生单周期病毒疫苗的依赖性。 这些脊椎动物特异性复制缺陷DENV（VSRD-DENV）被生成 通过优化病毒前膜蛋白（PRM）中的脂蛋白裂解位点。初步的 通过VSRD-denv1和VSRD-denv2进行的动物实验表明 VSRD-DENVS诱导了稳健的保护免疫，并具有固有的高安全水平 老鼠。基于这些高度有希望的初步结果，并考虑紧急 需要有效的登革热疫苗，Tengen Biomedical Co.和Howard University 已经合作加速了基于VSRD-DENVS的登革热的评估 疫苗。为了实现这一目标，我们建议生成和表征VSRD-denv3 和VSRD-DENV4疫苗候选病毒。然后，我们将进行全面的 分析四位价值VSRD-denvs的免疫原性和保护性 敏感的AG129小鼠模型。这些拟议的研究成功完成将 使登革热疫苗候选者进入非人类灵长类动物测试并建立 为其他重要黄病毒开发疫苗的平台。