Substitution of the structural genes of dengue virus type 4 with those of type 2 results in chimeric vaccine candidates which are attenuated for mosquitoes, mice, and rhesus monkeys
Substitution of the structural genes of dengue virus type 4 with those of type 2 results in chimeric vaccine candidates which are attenuated for mosquitoes, mice, and rhesus monkeys
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DOI：
10.1016/s0264-410x(03)00488-2
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发表时间：
2003-10-01
期刊：
影响因子：
5.5
通讯作者：
Murphy, BR
中科院分区：
文献类型：
--
作者：
Whitehead, SS;Hanley, KA;Murphy, BR
作为产生活的减毒四价登革热病毒疫苗的第一步，已经产生并评价了抗原嵌合病毒，其中4型登革热病毒（DEN 4）的结构基因已经被来自2型登革热病毒（DEN 2）的结构基因替换。具体地，DEN 2的衣壳、膜前体和包膜（CME）或膜前体和包膜（ME）基因区被野生型rDEN 4或疫苗候选物rDEN 4Delta 30的相应基因取代，所述疫苗候选物rDEN 4Delta 30在3'非翻译区中含有30个核苷酸缺失。缺乏Delta 30突变的两种DEN 2/4嵌合病毒在携带肿瘤的SCID-HuH-7小鼠、蚊子和恒河猴中高度减毒，表明与CME或ME区域的嵌合导致减毒。在蚊子和SCID-HuH-7小鼠中，向嵌合病毒中添加Delta 30突变导致相当或仅略微增加的减毒水平。在恒河猴中，添加Delta 30突变使得CME嵌合病毒不具有感染性，表明嵌合和Delta 30突变导致的减毒对这些动物是累加的。相比之下，ME嵌合病毒在恒河猴中的减毒没有通过添加Delta 30突变而显著改变。通过含ME的DEN 2/4Delta 30嵌合病毒实现的令人满意的减毒和免疫原性水平，以及其对蚊子的极低感染性，使其成为适合于在I期临床试验中评估的疫苗候选物。出版社：Elsevier Ltd
Antigenic chimeric viruses in which the structural genes of dengue virus type 4 (DEN4) have been replaced with those derived from dengue virus type 2 (DEN2) have been created and evaluated as a first step in generating a live attenuated tetravalent dengue virus vaccine. Specifically, the capsid, membrane precursor, and envelope (CME) or the membrane precursor and envelope (ME) gene regions of DEN2 were substituted for the corresponding genes of wild-type rDEN4 or vaccine candidate rDEN4Delta30 which contains a 30 nucleotide deletion in the 3' untranslated region. The two DEN2/4 chimeric viruses lacking the Delta30 mutation were highly attenuated in tumor-bearing SCID-HuH-7 mice, mosquitoes, and rhesus monkeys, indicating chimerization with either the CME or ME regions lead to attenuation. In mosquitoes and SCID-HuH-7 mice, addition of the Delta30 mutation to the chimeric viruses resulted in comparable or only slightly increased levels of attenuation. In rhesus monkeys, addition of the Delta30 mutation rendered the CME chimeric virus non-infectious, indicating that the attenuation resulting from chimerization and the Delta30 mutation were additive for these animals. In contrast, the attenuation in rhesus monkeys of ME chimeric virus was not significantly modified by the addition of the Delta30 mutation. The satisfactory level of attenuation and immunogenicity achieved by the ME containing DEN2/4Delta30 chimeric virus, as well as its very low infectivity for mosquitoes, make it a vaccine candidate suitable for evaluation in phase I clinical trials. Published by Elsevier Ltd.