From research to phase III: Preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine
From research to phase III: Preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine
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DOI：
10.1016/j.vaccine.2011.06.094
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发表时间：
2011-09-23
期刊：
影响因子：
5.5
通讯作者：
Lang, Jean
中科院分区：
文献类型：
--
作者：
Guy, Bruno;Barrere, Beatrice;Lang, Jean
随着2010年赛诺菲巴斯德CYD四价登革热疫苗（TDV）的第一个III期临床试验的启动，登革热疫苗的开发达到了一个重要的里程碑。CYD TDV候选疫苗由四种重组减毒活疫苗（CYD-1-4）组成，以黄热病疫苗17D （YFV 17D）为骨架，每种疫苗表达四种登革热病毒血清型中的一种的膜前和包膜基因。该疫苗在遗传和表型上稳定，不嗜肝，神经毒性低于YFV 17D，并且不通过口服途径感染蚊子。体外和体内临床前研究表明，CYD TDV诱导人树突状细胞的可控刺激，并在猴子中产生显著的免疫反应。在临床前和临床开发的同时，正在进行规模扩大和工业化，以满足II期/ iii期试验的需要，并在登革热疾病负担使其成为紧急公共卫生重点的国家预测和促进疫苗的供应和获取。目前已向来自登革热流行地区和非流行地区的6000多名儿童和成人接种了该疫苗，在任何已完成或正在进行的试验中均未出现安全问题。在绝大多数接种者中，三剂疫苗方案可诱导针对所有四种血清型的免疫应答。先前存在的黄病毒免疫有利于对CYD TDV产生更快和更高的免疫反应，而不会对临床安全性产生不利影响或增加疫苗病毒血症。观察到的人体细胞免疫反应的水平和性质与该疫苗良好的安全性和免疫原性相符。一项正在泰国儿童中进行的概念有效性验证和大规模安全性研究的初步结果预计将于2012年底出炉。在这里，我们讨论了从研究到工业化发展登革热疫苗的不同步骤和挑战，并总结了成功将登革热疫苗引入免疫规划的一些挑战。(C) 2011 Elsevier Ltd.版权所有。
Dengue vaccine development has reached a major milestone with the initiation, in 2010, of the first phase III clinical trial to investigate the Sanofi Pasteur CYD tetravalent dengue vaccine (TDV). The CYD TDV candidate is composed of four recombinant, live, attenuated vaccines (CYD-1-4) based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the pre-membrane and envelope genes of one of the four dengue virus serotypes. The vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D, and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies showed that CYD TDV induces controlled stimulation of human dendritic cells, and significant immune responses in monkeys. Scale up and industrialization are being conducted in parallel with preclinical and clinical development to fulfill the needs of phase II/Ill trials, and to anticipate and facilitate supply and access to vaccine in the countries where the dengue disease burden makes it an urgent public health priority. The vaccine has now been administered to more than 6000 children and adults from dengue endemic and non-endemic areas and no safety concerns have arisen in any of the completed or ongoing trials. A three-dose vaccination regimen induces an immune response against all four serotypes in the large majority of vaccinees. Preexisting flavivirus immunity favors quicker and higher immune responses to CYD TDV, without adversely effecting clinical safety or increasing vaccine viremia. The observed level and nature of the cellular immune responses in humans are consistent with the good safety and immunogenicity profile of the vaccine. Preliminary results of an ongoing, proof-of-concept efficacy and large scale safety study in Thai children are expected by the end of 2012. Here we discuss the different steps and challenges of developing CYD TDV, from research to industrialization, and summarize some of the challenges to the successful introduction of a dengue vaccine into immunization programs. (C) 2011 Elsevier Ltd. All rights reserved.