Blaney Joseph E, Durbin Anna P, Murphy Brian R, Whitehead Stephen S
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, LID, Bethesda, Maryland 20892-8133, USA.
Viral Immunol. 2006 Spring;19(1):10-32. doi: 10.1089/vim.2006.19.10.
There are four serotypes of dengue (DEN1-DEN4) virus that are endemic in most areas of Southeast Asia, Central and South America, and other subtropical regions. The number of cases of severe disease associated with DEN virus infection is growing because of the continued spread of the mosquito vector, Aedes aegypti, which transmits the virus to humans. Infection with DEN virus can result in an asymptomatic infection, a febrile illness called dengue fever (DF), and the very severe disease called dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Currently, a licensed vaccine is not available. However, a tetravalent vaccine is urgently needed to prevent DF and DHF/DSS, the latter of which occurs predominantly in partially immune individuals. A live attenuated, tetravalent DEN virus vaccine candidate has been generated using reverse genetics that is able to provide immunity to each of the four serotypes of DEN. Attenuation has been achieved by generating recombinant DEN (rDEN) viruses which are modified by deletion or, alternatively, by antigenic chimerization between two related DEN viruses using the following two strategies: 1) introduction of an attenuating 30 nucleotide deletion (Delta30) mutation into the 3' untranslated region of DEN1 and DEN4; and 2) replacement of structural proteins of the attenuated rDEN4Delta30 vaccine candidate with those from DEN2 or DEN3. Attenuation of the four monovalent vaccine candidates has been achieved for rhesus monkeys or humans and an immunogenic tetravalent vaccine candidate has been formulated. The level of attenuation of each dengue vaccine component can be increased, if needed, by introduction of additional attenuating mutations that have been well characterized.
登革热病毒有四种血清型（DEN1 - DEN4），在东南亚大部分地区、中美洲和南美洲以及其他亚热带地区呈地方性流行。由于传播病毒给人类的蚊媒埃及伊蚊持续扩散，与登革热病毒感染相关的严重疾病病例数正在增加。感染登革热病毒可导致无症状感染、一种称为登革热（DF）的发热性疾病，以及一种非常严重的疾病，即登革出血热/登革休克综合征（DHF/DSS）。目前尚无已获许可的疫苗。然而，迫切需要一种四价疫苗来预防登革热和登革出血热/登革休克综合征，后者主要发生在部分免疫个体中。一种使用反向遗传学方法构建的减毒活四价登革热病毒候选疫苗，能够对四种登革热血清型中的每一种提供免疫力。通过以下两种策略生成重组登革热（rDEN）病毒实现了减毒，这些病毒通过缺失进行修饰，或者通过两种相关登革热病毒之间的抗原嵌合进行修饰：1）在DEN1和DEN4的3'非翻译区引入一个减毒的30个核苷酸缺失（Delta30）突变；2）用DEN2或DEN3的结构蛋白替换减毒的rDEN4Delta30候选疫苗的结构蛋白。恒河猴或人类的四种单价候选疫苗已实现减毒，并且已配制出一种具有免疫原性的四价候选疫苗。如果需要，可以通过引入已充分表征的额外减毒突变来提高每种登革热疫苗成分的减毒水平。
