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: 10553634
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553634
• 关键词: 6 year old; Acceleration; 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; Evaluation; Female; Flavivirus; Formulation; Foundations; Generations; Goals; Hand; Hospitalization; Humoral Immunities; Immune response; Immunity; Immunologics; Inactivated Vaccines; Incubated; Insecta; Investigation; K562 Cells; Licensing; Membrane Proteins; Modeling; Mus; Persons; Phase; Phenotype; Production; Proteins; 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; commercial application; cost; epidemic virus; immunogenicity; male; manufacturing scale-up; mindfulness; mouse model; nonhuman primate; novel; pathogen; 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.

发展脊椎动物特异性复制缺陷型登革病毒