Guy Bruno, Saville Melanie, Lang Jean
Research and Discovery Departments, sanofi Pasteur, Marcy l'Etoile, France.
Hum Vaccin. 2010 Sep 16;6(9). doi: 10.4161.hv.6.9.12739.
The Sanofi Pasteur tetravalent dengue vaccine candidate is composed of 4 recombinant live attenuated vaccines based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes. Pre-clinical studies have demonstrated that the TV dengue 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 also showed that the TV dengue vaccine induced controlled stimulation in human dendritic cells and significant immune responses in monkeys. TV dengue vaccine reactogenicity, viraemia induction and antibody responses were investigated in three Phase I trials in the USA, the Philippines and Mexico, in a two or three-dose regimen over a 12 month period. Results showed that the majority of adverse events were mild to moderate and transient in nature. Viraemia was transient and low, and was not increased after initial dengue TV administration, even in the case of incomplete responses. ϕSeropositivity [≥10 in a PRNT 50 assay] was 100% for all four serotypes in flavivirus-naive adults injected with 3 doses of TV dengue vaccine in the USA. Similarly, seropositivity was 88-100% following three administrations in flavivirus-naive Mexican children aged 2-5 years. Furthermore, the proportion of seropositive subjects increased with each dengue TV injection in the Philippines where baseline flavivirus immunity was high. Responses were also monitored at the cellular level in humans, and their level and nature were in good agreement with the observed safety and the immunogenicity of the vaccine. Finally, the challenges inherent to the development of such TV dengue vaccines will also be discussed in the last part of this review. In conclusion, preclinical and clinical results support the favorable immunogenicity and short-term safety of the dengue TV vaccine. An extensive clinical development program for dengue TV is underway including completion of the enrollment of 4,000 4-11 years old children in an efficacy trial in Thailand, in an area of high dengue incidence. Assuming continued successful outcomes, initial submissions to regulatory authorities are envisaged within a 5-year period.
赛诺菲巴斯德四价登革热候选疫苗由4种基于黄热病疫苗17D（YFV 17D）骨架的重组减毒活疫苗组成，每种疫苗表达四种登革热病毒血清型之一的prM和包膜基因。临床前研究表明，四价登革热疫苗在基因和表型上稳定，无嗜肝性，神经毒性低于YFV 17D，且不会通过口服途径感染蚊子。体外和体内临床前研究还表明，四价登革热疫苗在人树突状细胞中诱导可控刺激，并在猴子中引发显著的免疫反应。在美国、菲律宾和墨西哥进行的三项I期试验中，采用两剂或三剂方案，在12个月内对四价登革热疫苗的反应原性、病毒血症诱导和抗体反应进行了研究。结果表明，大多数不良事件性质为轻至中度且短暂。病毒血症短暂且程度低，即使在反应不完全的情况下，初次接种四价登革热疫苗后病毒血症也未增加。在美国，接种3剂四价登革热疫苗的未感染黄病毒的成年人中，所有四种血清型的血清阳性率[PRNT 50试验中≥10]均为100%。同样，在墨西哥2至5岁未感染黄病毒的儿童中，三次接种后血清阳性率为88 - 100%。此外，在菲律宾，由于基线黄病毒免疫力较高，血清阳性受试者的比例随每次四价登革热疫苗注射而增加。还在人体细胞水平监测了反应，其水平和性质与观察到的疫苗安全性和免疫原性高度一致。最后，本综述的最后一部分还将讨论此类四价登革热疫苗开发所固有的挑战。总之，临床前和临床结果支持四价登革热疫苗良好的免疫原性和短期安全性。一项针对四价登革热疫苗的广泛临床开发计划正在进行中，包括在泰国登革热高发地区完成一项针对4000名4至11岁儿童的疗效试验的入组工作。假设继续取得成功结果，预计将在5年内首次向监管机构提交申请。
