Genetically modified, live attenuated dengue virus type 3 vaccine candidates
Genetically modified, live attenuated dengue virus type 3 vaccine candidates
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DOI：
10.4269/ajtmh.2004.71.811
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发表时间：
2004-12-01
影响因子：
3.3
通讯作者：
Whitehead, SS
中科院分区：
文献类型：
--
作者：
Blaney, JE;Hanson, CT;Whitehead, SS
从1978年印度尼西亚爪哇中部Sleman地区轻微爆发的登革热中分离出的DEN3病毒，已经产生了三种新的重组登革3型(DEN3)病毒候选疫苗。重组DEN4(RDEN4)病毒的膜前体和包膜(ME)蛋白在存在(rDEN3/4Delta30(ME))和不存在030突变(rDEN3/4(ME))的情况下用DEN3Sleman/78的膜前体和包膜蛋白(ME)替换，从而获得抗原性嵌合病毒。此外，从DEN3分离株中获得了一个全长的感染性cDNA克隆，用于生产rDEN3病毒和候选疫苗rDEN3Delta30。嵌合病毒rDEN3/4(ME)和rDEN3/4Delta30(ME)似乎是可接受的候选疫苗，因为它们在移植人肝癌细胞的严重联合免疫缺陷小鼠、恒河猴、伊蚊和弓形虫蚊子中的复制受到限制，并且它们在恒河猴身上对DEN3病毒的攻击具有保护作用。RDEN3/4(ME)和rDEN3/4Delta30(ME)病毒在评价的所有参数中都具有可比性，表明抗原嵌合导致了观察到的高水平的衰减。令人惊讶的是，与野生型rDEN3相比，rDEN3Delta30在任何测试模型中都没有减弱，因此目前不是候选疫苗。因此，rDEN3/4(ME)和rDEN3/4Delta30(ME)抗原嵌合病毒可以考虑在人类身上进行评估，并包括在四价登革热疫苗中。
Three novel recombinant dengue type 3 (DEN3) virus vaccine candidates have been generated from a DEN3 virus isolated from a mild outbreak of dengue fever in the Sleman area of central Java in Indonesia in 1978. Antigenic chimeric viruses were prepared by replacing the membrane precursor and envelope (ME) proteins of recombinant DEN4 (rDEN4) virus with those from DEN3 Sleman/78 in the presence (rDEN3/4Delta30(ME)) and the absence (rDEN3/4(ME)) of the 030 mutation, a previously described 30-nucleotide deletion in the 3' untranslated region. In addition, a full-length infectious cDNA clone was generated from the DEN3 isolate and used to produce rDEN3 virus and the vaccine candidate rDEN3Delta30. The chimeric viruses rDEN3/4(ME) and rDEN3/4Delta30(ME) appear to be acceptable vaccine candidates since they were restricted in replication in severe combined immune deficiency mice transplanted with human hepatoma cells, in rhesus monkeys, and in Aedes and Toxorynchites mosquitoes, and each was protective in rhesus monkeys against DEN3 virus challenge. The rDEN3/4(ME) and rDEN3/4Delta30(ME) viruses were comparable in all parameters evaluated, indicating that antigenic chimerization resulted in the observed high level of attenuation. Surprisingly, rDEN3Delta30 was not attenuated in any model tested when compared with wild-type rDEN3 and therefore, is not a vaccine candidate at present. Thus, the rDEN3/4(ME) and rDEN3/4Delta30(ME) antigenic chimeric viruses can be considered for evaluation in humans and for inclusion in a tetravalent dengue vaccine.