Widman Douglas G, Frolov Ilya, Mason Peter W
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Adv Virus Res. 2008;72:77-126. doi: 10.1016/S0065-3527(08)00402-8.
Flaviviruses are arthropod-borne pathogens that cause significant disease on all continents of the world except Antarctica. Flavivirus diseases are particularly important in tropical regions where arthropod vectors are abundant. Live-attenuated virus vaccines (LAVs) and inactivated virus vaccines (INVs) exist for some of these diseases. LAVs are economical to produce and potent, but are not suitable for use in the immunocompromised. INVs are safer, but are more expensive to produce and less potent. Despite the success of both classes of these first-generation flavivirus vaccines, problems associated with their use indicate a need for improved products. Furthermore, there are no suitable vaccines available for important emerging flavivirus diseases, notably dengue and West Nile encephalitis (WNE). To address these needs, new products, including LAVs, INVs, viral-vectored, genetically engineered LAVs, naked DNA, and subunit vaccines are in various stages of development. Here we describe the current state of these first- and second-generation vaccine candidates, and compare these products to our recently described single-cycle, encapsidation defective flavivirus vaccine: RepliVAX. RepliVAX can be propagated in C-expressing cells (or as a unique two-component virus) using methods similar to those used to produce today's economical and potent LAVs. However, due to deletion of most of the gene for the C protein, RepliVAX cannot spread between normal cells, and is unable to cause disease in vaccinated animals. Nevertheless, RepliVAX is potent and efficacious in animal models for WNE and Japanese encephalitis, demonstrating its utility as a third-generation flavivirus vaccine that should be potent, economical to produce, and safe in the immunocompromised.
黄病毒是节肢动物传播的病原体，在除南极洲以外的世界各大洲都会引发严重疾病。黄病毒疾病在节肢动物媒介丰富的热带地区尤为重要。针对其中一些疾病，有减毒活病毒疫苗（LAV）和灭活病毒疫苗（INV）。减毒活病毒疫苗生产成本低且效力强，但不适用于免疫功能低下者。灭活病毒疫苗更安全，但生产成本更高且效力较弱。尽管这两类第一代黄病毒疫苗都取得了成功，但与其使用相关的问题表明需要改进产品。此外，对于重要的新兴黄病毒疾病，尤其是登革热和西尼罗河脑炎（WNE），尚无合适的疫苗。为满足这些需求，包括减毒活病毒疫苗、灭活病毒疫苗、病毒载体疫苗、基因工程减毒活病毒疫苗、裸DNA疫苗和亚单位疫苗在内的新产品正处于不同的研发阶段。在此，我们描述这些第一代和第二代候选疫苗的当前状态，并将这些产品与我们最近描述的单周期、衣壳缺陷黄病毒疫苗：RepliVAX进行比较。RepliVAX可以使用与生产当今经济高效的减毒活病毒疫苗类似的方法在表达C蛋白的细胞中（或作为独特的双组分病毒）进行繁殖。然而，由于C蛋白的大部分基因被删除，RepliVAX无法在正常细胞之间传播，也无法在接种疫苗的动物中引发疾病。尽管如此，RepliVAX在西尼罗河脑炎和日本脑炎的动物模型中效力强且有效，证明了其作为第三代黄病毒疫苗的效用，该疫苗应效力强、生产成本低且对免疫功能低下者安全。
