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

基本信息

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
项目类别：
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

项目摘要

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型登革热病毒新型单周期登革热候选疫苗抽象的据估计，每年至少有 3.9 亿登革热病毒 (DENV) 感染者 DENV疫情被世界卫生组织列为全球十大公共卫生威胁之一 2019年。目前尚无特效治疗方法。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导同时对所有四种血清型提供长期保护。历史上，四价减毒活病毒疫苗已表明很难实现平衡免疫所有四种血清型。此外，灭活病毒疫苗不能赋予对病毒的长期免疫力。防止潜在的抗体依赖性增强（ADE）。考虑到这些障碍，我们研究了单周期假传染性 DENV 作为候选疫苗诱导针对所有四种血清型的平衡长期免疫力。一个重大障碍这种方法的缺点是复制假性感染 DENV 通常需要复杂的封装单元效率低下，导致大规模生产困难且成本高昂。因此，朝着开发安全、有效和负担得起的 DENV 的总体目标疫苗，我们将双热带 DENV 转化为人造昆虫特异性病毒克服生产单周期病毒疫苗对包装细胞的依赖。生成了这些脊椎动物特异性复制缺陷型 DENV (VSRD-DENV) 通过优化病毒前膜蛋白 (prM) 中的弗林蛋白酶切割位点。初步的 VSRD-DENV1 和 VSRD-DENV2 的动物实验表明 VSRD-DENVs 诱导了强大的保护免疫力，具有固有的高安全水平老鼠。基于这些非常有希望的初步结果并考虑到紧迫的需要一种有效的登革热疫苗，Tengen Biomedical Co. 和霍华德大学联手加速基于 VSRD-DENV 的登革热评估疫苗。为了实现这一目标，我们建议生成并表征 VSRD-DENV3 和 VSRD-DENV4 疫苗候选病毒。然后我们将进行全面的四价 VSRD-DENV 的免疫原性和保护功效分析敏感AG129小鼠模型。成功完成这些拟议的研究将使登革热候选疫苗能够进入非人类灵长类动物测试并建立开发其他重要黄病毒疫苗的平台。