Clinical Trials of Biodefense Vaccines (Dengue)

生物防御疫苗（登革热）的临床试验

• 批准号: 8745441
• 负责人: Kanta Subbarao
• 金额: $ 248.97万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745441
• 关键词: Admixture; Antibody Formation; Area; Attenuated; Brazil; Clinical Research; Clinical Trials; Collection; Country; Data; Data Set; Dengue; Dengue Virus; Development; Dose; Drug Formulations; Equilibrium; Flavivirus; Future; Goals; Immunity; India; Infection; Life; Manufacturer Name; Phase; Phase II Clinical Trials; Public Health; Safety; Serotyping; Sterility; Vaccines; Vietnam; Virus; biodefense; cost effective; human subject; immunogenic; immunogenicity; neutralizing antibody; research clinical testing; vaccine candidate; vaccine development

The development strategy for an effective tetravalent dengue vaccine has consisted of the clinical evaluation of monovalent vaccine candidates for each of the four serotypes with the goal of selecting suitable candidates for inclusion in a tetravalent formulation. Previously, monovalent vaccine candidates were evaluated in a combined total of over 500 human subjects to determine safety, infectivity, and immunogenicity. These studies identified a collection of 6 suitable vaccine candidates: DEN1del30, DEN2/4del30, DEN3del30/31, DEN3-3D4del30, DEN4del30, and DEN4del30-200,201. The selected vaccine candidates were safe and asymptomatic, elicited a robust antibody response in more than 80% of subjects, and were highly infectious (50% infection dose < 10 PFU). Tetravalent studies: Previously, several Phase I clinical studies were completed to evaluate five different tetravalent admixtures of each vaccine candidate. From this set of data, an optimal admixture (TV-003: DEN1del30, DEN2/4del30, DEN3del30/31, DEN4del30) was selected and induces an unprecedented level of neutralizing antibody that is both balanced among the serotypes and sufficient to provide sterile immunity against a second dose administered at six months. These data suggest that a single dose of vaccine may be sufficiently immunogenic, which points to a significant advantage of the LID vaccine compared to other live attenuated DENV vaccines which require two or three doses to achieve a similar result. The selection of an optimal tetravalent admixture has enabled the further development of the vaccine by several manufacturers located in Brazil, India, and Vietnam. Through on-going technological and scientific support, these licensees are making significant progress in the development of the vaccine and some will soon enter Phase 2 trials in their own countries. At LID, clinical evaluation of TV-003 in an expanded number of both naive subjects (NCT01436422) and flavivirus sero-positive subjects (NCT01506570) is currently underway. Should future studies of this vaccine prove it to be efficacious, the vaccine could be a cost-effective means of controlling dengue in endemic areas and a tremendous public health asset.

有效的四价登革热疫苗的开发战略包括对四种血清型中每一种的单价候选疫苗进行临床评估，目的是选择合适的候选疫苗纳入四价疫苗配方。此前，单价疫苗候选疫苗在总共500多名人类受试者中进行评估，以确定安全性、传染性和免疫原性。这些研究确定了6个合适的候选疫苗：DEN1del30、DEN2/4del30、DEN3del30/31、DEN3-3D4del30、DEN4del30和DEN4del30-200,201。选定的候选疫苗是安全的和无症状的，在超过80%的受试者中引起了强烈的抗体反应，并且具有高度的传染性(50%的感染量和10pfu)。 四价研究：之前，已经完成了几项I期临床研究，以评估每个候选疫苗的五种不同的四价混合物。从这组数据中，选择了一种最佳的混合物(TV-003：DEN1del30，DEN2/4del30，DEN3del30/31，DEN4del30)，并诱导出前所未有的中和抗体水平，该抗体既在血清型之间平衡，又足以提供对6个月第二次接种的无菌免疫力。这些数据表明，单剂疫苗可能具有足够的免疫原性，这表明与其他需要两剂或三剂才能达到类似结果的减毒活疫苗相比，LID疫苗具有显著的优势。对最佳四价混合物的选择使巴西、印度和越南的几家制造商能够进一步开发疫苗。通过持续不断的技术和科学支持，这些许可证获得者在疫苗开发方面取得了重大进展，其中一些将很快在自己的国家进入第二阶段试验。在LID，TV-003在更多的幼稚受试者(NCT01436422)和黄病毒血清阳性受试者(NCT01506570)中的临床评估目前正在进行中。如果未来对这种疫苗的研究证明它是有效的，这种疫苗可能是在登革热流行地区控制登革热的一种具有成本效益的手段，并是一笔巨大的公共卫生资产。