Construction, safety, and immunogenicity in nonhuman primates of a chimeric yellow fever-dengue virus tetravalent vaccine
Construction, safety, and immunogenicity in nonhuman primates of a chimeric yellow fever-dengue virus tetravalent vaccine
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DOI：
10.1128/jvi.75.16.7290-7304.2001
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发表时间：
2001-08-01
影响因子：
5.4
通讯作者：
Monath, TP
中科院分区：
文献类型：
--
作者：
Guirakhoo, F;Arroyo, J;Monath, TP
我们之前报道了嵌合黄热病-登革热 2 型病毒 (YF/DEN2) 的构建，并确定了其在恒河猴中的安全性和保护功效 (F. Guirakhoo 等人，J. Virol. 74:5477-5485, 2000)。在本文中，我们描述了使用野生型（WT）临床分离株的前膜（prM）和包膜（E）基因构建三个额外的YF/DEN嵌合体：DEN1（菌株PUO359，1980年在泰国分离）、DEN3（菌株PaH881/88，1988年在泰国分离）和DEN4（菌株1228，1978年在泰国分离）印度尼西亚）。这些嵌合病毒（YF/DEN1、YF/DEN3 和 YF/DEN4）在 Vero 细胞中的复制量约为 7.5 log(10) PFU/ml，在通过脑内途径接种的 3 至 4 周龄 ICR 小鼠中不具有神经毒性，并且在猴子中具有免疫原性。所有皮下接种一剂这些嵌合病毒（作为单价或四价制剂）的恒河猴均出现病毒血症，其程度与 YF 17D 疫苗株（YF-VAX）相似，但显着低于其亲本 WT 病毒。接种单价 YF/DEN1 -3 或 -4 疫苗的 9 只猴子中的 8 只和接种四价 YF/DEN1-4 疫苗的 6 只猴子中的 6 只在单剂量后出现血清转化。 6 个月后，当猴子接受四价 YF/DENI-4 剂量加强时，单价 YF/DEN 组中的 9 只猴子中有 4 只出现了低水平的病毒血症，而在之前接种 YF/DEN1-4 疫苗或 WT DEN 病毒的任何动物中均未检测到病毒血症。在第二次给药后，所有猴子都观察到了记忆反应。在接受四价 YF/DENI-4 疫苗的 YF 病毒免疫猴和未免疫猴之间或在接受 YF-VAX 的四价 YF/DEN1-4 免疫猴和非免疫猴之间，没有观察到中和抗体水平的统计学显着差异。然而，免疫前的猴子要么没有检测到病毒血症，要么病毒血症水平低于非免疫对照。这是第一个在非人类灵长类动物中成功评估的重组四价登革热疫苗。
We previously reported construction of a chimeric yellow fever-dengue type 2 virus (YF/DEN2) and determined its safety and protective efficacy in rhesus monkeys (F. Guirakhoo et al., J. Virol. 74:5477-5485, 2000). In this paper, we describe construction of three additional YF/DEN chimeras using premembrane (prM) and envelope (E) genes of wild-type (WT) clinical isolates: DEN1 (strain PUO359, isolated in 1980 in Thailand), DEN3 (strain PaH881/88, isolated in 1988 in Thailand), and DEN4 (strain 1228, isolated in 1978 in Indonesia). These chimeric viruses (YF/DEN1, YF/DEN3, and YF/DEN4) replicated to similar to7.5 log(10) PFU/ml in Vero cells, were not neurovirulent in 3- to 4-week-old ICR mice inoculated by the intracerebral route, and were immunogenic in monkeys. All rhesus monkeys inoculated subcutaneously with one dose of these chimeric viruses (as monovalent or tetravalent formulation) developed viremia with magnitudes similar to that of the YF 17D vaccine strain (YF-VAX) but significantly lower than those of their parent WT viruses. Eight of nine monkeys inoculated with monovalent YF/DEN1 -3, or -4 vaccine and six of six monkeys inoculated with tetravalent YF/DEN1-4 vaccine seroconverted after a single dose. When monkeys were boosted with a tetravalent YF/DENI-4 dose 6 months later, four of nine monkeys in the monovalent YF/DEN groups developed low levels of viremia, whereas no viremia was detected in any animals previously inoculated with either YF/DEN1-4 vaccine or WT DEN virus. An anamnestic response was observed in all monkeys after the second dose. No statistically significant difference in levels of neutralizing antibodies was observed between YF virus-immune and nonimmune monkeys which received the tetravalent YF/DENI-4 vaccine or between tetravalent YF/DEN1-4-immune and nonimmune monkeys which received the YF-VAX. However, preimmune monkeys developed either no detectable viremia or a level of viremia lower than that in nonimmune controls. This is the first recombinant tetravalent dengue vaccine successfully evaluated in nonhuman primates.