Vaccine candidates for dengue virus type 1 (DEN1) generated by replacement of the structural genes of rDEN4 and rDEN4Delta30 with those of DEN1.
Vaccine candidates for dengue virus type 1 (DEN1) generated by replacement of the structural genes of rDEN4 and rDEN4Delta30 with those of DEN1.
复制标题
通过用DEN1替换RDEN4和RDEN4DELTA30的结构基因而产生的1型登革热病毒（DEN1）的疫苗候选物。
DOI：
10.1186/1743-422x-4-23
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发表时间：
2007-02-28
期刊：
影响因子：
4.8
通讯作者：
Whitehead SS
中科院分区：
文献类型：
--
作者：
Blaney JE Jr;Sathe NS;Hanson CT;Firestone CY;Murphy BR;Whitehead SS
以前已经产生了抗原性嵌合病毒，其中重组登革4型病毒(RDEN4)的结构基因已经被来自DEN2或DEN3的基因所取代。确定了两个候选疫苗，rDEN4Δ30(ME)和rDEN3/4Δ30(ME)，它们分别含有DEN2膜(M)前体和包膜(E)基因，以及DEN4主干3‘非翻译区的30个核苷酸缺失(Δ30)。基于这些病毒有希望的临床前表型和Δ30(ME)在人类中的安全性和免疫原性，我们现在描述了用DEN1波多黎各/94株的衣壳(C)、M和E(CME)或ME结构基因产生一组抗原性嵌合DEN4病毒。4株抗原嵌合病毒rDEN1/4(CME)、rDEN1/4Δ30(CME)、rDEN1/4(ME)和rDEN1/4Δ30(ME)在Vero细胞中高效复制。除rDEN1/4(ME)外，在SCID-HUN-7小鼠异种移植模型中，每个嵌合病毒都显著减弱，与野生型DEN1相比，复制减少了25倍或更多。在恒河猴中，根据病毒血症的持续时间和程度，似乎只有带有Δ30突变的嵌合病毒才会减弱。RDEN1/4CME 30(Δ30)由于不能诱导可检测到的中和抗体，对野生型DEN1攻击没有保护作用，出现了过度减毒现象。相反，rDEN1/4Δ30(ME)可诱导66%的血清转化率，并对DEN1攻击有保护作用。Δ30突变的存在显着限制了蚊虫对Δ30(ME)的感染性，而ME对埃及伊蚊来说是非传染性的。在SCID-HUN-7小鼠、恒河猴和蚊子中观察到的减毒表型和在恒河猴中观察到的保护性免疫表明，rDEN1/4Δ30(ME)应该被考虑用于临床试验的评估。
Antigenic chimeric viruses have previously been generated in which the structural genes of recombinant dengue virus type 4 (rDEN4) have been replaced with those derived from DEN2 or DEN3. Two vaccine candidates were identified, rDEN2/4Δ30(ME) and rDEN3/4Δ30(ME), which contain the membrane (M) precursor and envelope (E) genes of DEN2 and DEN3, respectively, and a 30 nucleotide deletion (Δ30) in the 3' untranslated region of the DEN4 backbone. Based on the promising preclinical phenotypes of these viruses and the safety and immunogenicity of rDEN2/4Δ30(ME) in humans, we now describe the generation of a panel of four antigenic chimeric DEN4 viruses using either the capsid (C), M, and E (CME) or ME structural genes of DEN1 Puerto Rico/94 strain. Four antigenic chimeric viruses were generated and found to replicate efficiently in Vero cells: rDEN1/4(CME), rDEN1/4Δ30(CME), rDEN1/4(ME), and rDEN1/4Δ30(ME). With the exception of rDEN1/4(ME), each chimeric virus was significantly attenuated in a SCID-HuH-7 mouse xenograft model with a 25-fold or greater reduction in replication compared to wild type DEN1. In rhesus monkeys, only chimeric viruses with the Δ30 mutation appeared to be attenuated as measured by duration and magnitude of viremia. rDEN1/4Δ30(CME) appeared over-attenuated since it failed to induce detectable neutralizing antibody and did not confer protection from wild type DEN1 challenge. In contrast, rDEN1/4Δ30(ME) induced 66% seroconversion and protection from DEN1 challenge. Presence of the Δ30 mutation conferred a significant restriction in mosquito infectivity upon rDEN1/4Δ30(ME) which was shown to be non-infectious for Aedes aegypti fed an infectious bloodmeal. The attenuation phenotype in SCID-HuH-7 mice, rhesus monkeys, and mosquitoes and the protective immunity observed in rhesus monkeys suggest that rDEN1/4Δ30(ME) should be considered for evaluation in a clinical trial.