BACKGROUND Disease 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 four serotypes in phase 3 efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help down select 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. METHODS Two randomized controlled clinical trials were performed. In study 1, 42 subjects received TV005 or placebo (n = 21 each) and six months later all were challenged with dengue 2 virus (DEN2Δ30) at a dose of 103 PFU. In study 2, 23 subjects received TV005, 20 subjects received placebo and six months later all were challenged with 104 PFU dengue 3 virus (DEN3Δ30). Subjects were closely monitored for safety, viremia, and immunologic responses. Infection, measured by post-challenge viremia and by occurrence of rash and neutropenia, were the primary endpoints. Secondary endpoints included safety, immunologic, and virologic profiles following vaccination with TV005 and subsequent DENV2 or DENV3 challenge strains. RESULTS TV005 was well tolerated and protected all vaccinated volunteers from viremia with DENV2 or 3 (none infected in either group). Placebo recipients had viremia post-challenge (100% in study 1, 85% in study 2) and all experienced rash following challenge with either serotype. CONCLUSIONS TV005 is a leading tetravalent dengue vaccine candidate which fully protects against infection with DENV2 and DENV3 in an established controlled human infection model.CLINICAL TRIALS REGISTRATION NUMBERS. NCT02317900 and NCT02873260.

中文翻译：

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TV005 登革热疫苗可预防登革热血清型 2 和 3 控制的人类感染。

背景技术由登革热病毒引起的疾病是日益严重的全球健康威胁，每年造成100-4亿例病例。理想的登革热疫苗应在三期功效试验中证明对所有四种血清型具有持久的保护作用，但缺乏循环血清型可能会导致功效数据不完整。受控人类感染模型有助于选择候选疫苗并提供关键数据来补充功效试验。我们评估了一种领先的减毒四价登革热候选疫苗 TV005 针对新建立的登革热血清型 3 或已建立的血清型 2 攻击病毒感染的功效。方法 进行了两项随机对照临床试验。在研究 1 中，42 名受试者接受 TV005 或安慰剂（每人 n = 21），六个月后，所有受试者均接受 103 PFU 剂量的登革热 2 病毒 (DEN2Δ30) 攻击。在研究 2 中，23 名受试者接受 TV005，20 名受试者接受安慰剂，六个月后全部接受 104 PFU 登革热 3 病毒 (DEN3Δ30) 攻击。密切监测受试者的安全性、病毒血症和免疫反应。主要终点是通过攻击后病毒血症以及皮疹和中性粒细胞减少的发生来测量感染。次要终点包括接种 TV005 和随后的 DENV2 或 DENV3 攻击株疫苗接种后的安全性、免疫学和病毒学特征。结果 TV005 具有良好的耐受性，并保护所有接种疫苗的志愿者免受 DENV2 或 3 病毒血症的影响（两组均未感染）。安慰剂接受者在攻击后出现病毒血症（研究 1 中为 100%，研究 2 中为 85%），并且在任一血清型攻击后均出现皮疹。结论 TV005 是一种领先的四价登革热候选疫苗，在已建立的受控人类感染模型中可充分预防 DENV2 和 DENV3 感染。临床试验注册号。NCT02317900 和 NCT02873260。