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.

有效四价登革热疫苗的开发策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价，目的是选择合适的候选疫苗纳入四价制剂中。 此前，在总计超过500名人类受试者中评价了单价候选疫苗，以确定安全性、感染性和免疫原性。这些研究鉴定了6种合适的候选疫苗的集合：DEN 1 del 30、DEN 2/4 del 30、DEN 3 del 30/31、DEN 3 - 3D 4 del 30、DEN 4 del 30和DEN 4 del 30 - 200，201。 所选候选疫苗安全且无症状，在超过80%的受试者中引起强烈的抗体应答，并且具有高度传染性（50%感染剂量< 10 PFU）。 四价研究：此前，已经完成了几项I期临床研究，以评估每种候选疫苗的五种不同四价混合物。 从这组数据中，选择了最佳混合物（TV-003：DEN 1 del 30、DEN 2/4 del 30、DEN 3 del 30/31、DEN 4 del 30），并诱导了前所未有的中和抗体水平，该水平在血清型之间平衡，并足以提供针对6个月时第二次给药的无菌免疫力。 这些数据表明，单次剂量的疫苗可能具有足够的免疫原性，这表明LID疫苗与其他减毒活DENV疫苗相比具有显著的优势，其他减毒活DENV疫苗需要两次或三次剂量才能达到类似的结果。 最佳四价混合物的选择使得位于巴西、印度和越南的几家制造商能够进一步开发疫苗。 通过持续的技术和科学支持，这些许可证持有者在疫苗开发方面取得了重大进展，其中一些将很快在其本国进入第二阶段试验。 在LID，目前正在扩大数量的初治受试者（NCT 01436422）和黄病毒血清阳性受试者（NCT 01506570）中进行TV-003的临床评价。如果未来对这种疫苗的研究证明它是有效的，这种疫苗可能是在流行地区控制登革热的一种具有成本效益的手段，也是一种巨大的公共卫生资产。