Department of Medicine and.
Department of Microbiology and Molecular Genetics, The University of Vermont Larner College of Medicine, Vaccine Testing Center, Burlington, Vermont, USA.
J Clin Invest. 2024 Feb 1;134(3):e173328. doi: 10.1172/JCI173328.
BACKGROUNDDisease due to dengue viruses is a growing global health threat, causing 100-400 million cases annually. An ideal dengue vaccine should demonstrate durable protection against all 4 serotypes in phase III efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help downselect vaccine candidates and supply critical data to supplement efficacy trials. We evaluated the efficacy of a leading live-attenuated tetravalent dengue vaccine candidate, TV005, against infection with a newly established dengue serotype 3 or an established serotype 2 challenge virus.METHODSTwo randomized, controlled clinical trials were performed. In study 1, a total of 42 participants received TV005 or placebo (n = 21 each), and 6 months later, all were challenged with dengue 2 virus (rDEN2Δ30) at a dose of 103 PFU. In study 2, a total of 23 participants received TV005 and 20 received placebo, and 6 months later, all were challenged with 104 PFU dengue 3 virus (rDEN3Δ30). The study participants were closely monitored for safety, viremia, and immunologic responses. Infection, measured by post-challenge viremia, and the occurrence of rash and neutropenia were the primary endpoints. Secondary endpoints included safety, immunologic, and virologic profiles following vaccination with TV005 and subsequent challenge with the rDEN2Δ30 or rDEN3Δ30 strain.RESULTSTV005 was well tolerated and protected all vaccinated volunteers from viremia with DENV2 or DENV3 (none infected in either group). Placebo recipients had post-challenge viremia (100% in study 1, 85% in study 2), and all experienced rash following challenge with either serotype.CONCLUSIONSTV005 is a leading tetravalent dengue vaccine candidate that fully protected against infection with DENV2 and DENV3 in an established controlled human infection model.TRIAL REGISTRATIONClinicalTrials.gov NCT02317900 and NCT02873260.FUNDINGIntramural Research Program, NIH (contract HHSN272200900010C).
背景
登革热病毒引起的疾病是一个日益严重的全球健康威胁，每年导致 1 亿至 4 亿例病例。理想的登革热疫苗应在 III 期疗效试验中对所有 4 种血清型均具有持久的保护作用，但由于缺乏循环血清型，可能导致疗效数据不完整。人体感染控制模型有助于选择候选疫苗，并提供补充疗效试验的关键数据。我们评估了一种领先的减毒活四价登革热候选疫苗 TV005 对新建立的登革热 3 型或已建立的 2 型挑战病毒感染的疗效。
方法
进行了两项随机、对照临床试验。在研究 1 中，共有 42 名参与者接受 TV005 或安慰剂（每组 21 名），6 个月后，所有人均以 103 PFU 的剂量接受登革热 2 型病毒（rDEN2Δ30）的攻击。在研究 2 中，共有 23 名参与者接受 TV005，20 名接受安慰剂，6 个月后，所有人均以 104 PFU 的登革热 3 型病毒（rDEN3Δ30）接受攻击。研究参与者被密切监测安全性、病毒血症和免疫反应。感染，通过攻击后病毒血症测量，以及皮疹和中性粒细胞减少的发生是主要终点。次要终点包括接种 TV005 后的安全性、免疫学和病毒学特征，以及随后用 rDEN2Δ30 或 rDEN3Δ30 株进行的攻击。
结果
TV005 耐受性良好，可完全保护所有接种疫苗的志愿者免受 DENV2 或 DENV3 的病毒血症（两组均无人感染）。安慰剂组在接受挑战后出现病毒血症（研究 1 中为 100%，研究 2 中为 85%），所有参与者在接受任一血清型的攻击后均出现皮疹。
结论
TV005 是一种领先的四价登革热候选疫苗，在已建立的人体感染控制模型中可完全预防 DENV2 和 DENV3 的感染。
试验注册
ClinicalTrials.gov NCT02317900 和 NCT02873260。
资金来源
美国国立卫生研究院内部研究计划（HHSN272200900010C 合同）。
