Pletnev Alexander G, Claire Marisa St, Elkins Randy, Speicher Jim, Murphy Brian R, Chanock Robert M
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Virology. 2003 Sep 15;314(1):190-5. doi: 10.1016/s0042-6822(03)00450-1.
Two molecularly engineered, live-attenuated West Nile virus (WN) vaccine candidates were highly attenuated and protective in rhesus monkeys. The vaccine candidates are chimeric viruses (designated WN/DEN4) bearing the membrane precursor and envelope protein genes of WN on a backbone of dengue 4 virus (DEN4) with or without a deletion of 30 nucleotides (Delta 30) in the 3' noncoding region of DEN4. Viremia in WN/DEN4- infected monkeys was reduced 100-fold compared to that in WN- or DEN4-infected monkeys. WN/DEN4-3'Delta 30 did not cause detectable viremia, indicating that it is even more attenuated for monkeys. These findings indicate that chimerization itself and the presence of the Delta 30 mutation independently contribute to the attenuation phenotype for nonhuman primates. Despite their high level of attenuation in monkeys, the chimeras induced a moderate-to-high titer of neutralizing antibodies and prevented viremia in monkeys challenged with WN. The more attenuated vaccine candidate, WN/DEN4-3'Delta 30, will be evaluated first in our initial clinical studies.
两种经过分子工程改造的西尼罗河病毒（WN）减毒活疫苗候选株在恒河猴中高度减毒且具有保护作用。这些疫苗候选株是嵌合病毒（命名为WN/DEN4），其在登革热4型病毒（DEN4）的骨架上携带WN的膜前体蛋白和包膜蛋白基因，DEN4的3'非编码区有或没有30个核苷酸的缺失（Δ30）。与WN或DEN4感染的猴子相比，WN/DEN4感染的猴子的病毒血症降低了100倍。WN/DEN4-3'Δ30未引起可检测到的病毒血症，表明它对猴子的减毒作用更强。这些发现表明，嵌合化本身和Δ30突变的存在独立地导致了非人灵长类动物的减毒表型。尽管这些嵌合病毒在猴子中高度减毒，但它们诱导了中到高滴度的中和抗体，并在WN攻击的猴子中预防了病毒血症。减毒作用更强的疫苗候选株WN/DEN4-3'Δ30将在我们最初的临床研究中首先进行评估。
