IRES-driven expression of the capsid protein of the Venezuelan equine encephalitis virus TC-83 vaccine strain increases its attenuation and safety.
IRES-driven expression of the capsid protein of the Venezuelan equine encephalitis virus TC-83 vaccine strain increases its attenuation and safety.
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DOI：
10.1371/journal.pntd.0002197
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发表时间：
2013
影响因子：
3.8
通讯作者：
Weaver SC
中科院分区：
文献类型：
--
作者：
Guerbois M;Volkova E;Forrester NL;Rossi SL;Frolov I;Weaver SC
TC-83减毒活疫苗株是唯一获得许可的兽用疫苗，可用于保护马免受委内瑞拉马脑炎病毒（VEEV）感染，并通过防止马扩增间接保护人类。然而，TC-83是反应原性的，因为它只依赖于两个减毒点突变，并且在马接种疫苗后感染了蚊子。为了提高其稳定性和安全性，先前通过将病毒结构蛋白的表达置于脑心肌炎病毒（EMCV）的内部核糖体进入位点（IRES）的控制下来工程化重组TC-83，该位点在昆虫细胞中驱动低效的翻译。然而，该候选疫苗的免疫原性差。在这里，我们描述了第二代的重组TC-83，其中的亚基因组启动子被保留，只有衣壳蛋白基因是从IRES翻译。这种VEEV/IRES/C候选疫苗不感染蚊子，在连续的小鼠传代后其减毒表型稳定，并且在新生小鼠中更减毒，但仍然与TC-83一样对VEEV攻击具有保护性。因此，通过使用IRES来调节TC-83衣壳蛋白表达，我们产生了一种候选疫苗，其结合了有效的免疫原性和功效以及较低的毒力和降低的在自然界中传播的潜力。委内瑞拉马脑炎病毒（VEEV）由蚊子传播，在中美洲和南美洲广泛分布，在马和人类中引起定期爆发。人类VEEV感染经常被误诊为登革热，可导致终身神经系统后遗症，在高达80%的马病例中是致命的，这对拉丁美洲的发展中国家来说是一个重大的社会经济负担和持续的公共卫生威胁。唯一可用的疫苗是减毒活TC-83菌株，由于其在人类中的高反应原性和毒力返强的风险，仅限于兽医使用，这可能引发流行病。通过使用允许调节病毒衣壳蛋白表达的减毒方法，我们产生了TC-83的新版本，其更加减毒，但仍然在小鼠中诱导保护性免疫应答。此外，这种新疫苗不会感染蚊子，从而防止了在自然界传播的风险。我们描述的减毒方法可以应用于许多其他甲病毒，以开发针对经常出现并威胁发展中国家的疾病的疫苗。
The live-attenuated TC-83 strain is the only licensed veterinary vaccine available to protect equids against Venezuelan equine encephalitis virus (VEEV) and to protect humans indirectly by preventing equine amplification. However, TC-83 is reactogenic due to its reliance on only two attenuating point mutations and has infected mosquitoes following equine vaccination. To increase its stability and safety, a recombinant TC-83 was previously engineered by placing the expression of the viral structural proteins under the control of the Internal Ribosome Entry Site (IRES) of encephalomyocarditis virus (EMCV), which drives translation inefficiently in insect cells. However, this vaccine candidate was poorly immunogenic. Here we describe a second generation of the recombinant TC-83 in which the subgenomic promoter is maintained and only the capsid protein gene is translated from the IRES. This VEEV/IRES/C vaccine candidate did not infect mosquitoes, was stable in its attenuation phenotype after serial murine passages, and was more attenuated in newborn mice but still as protective as TC-83 against VEEV challenge. Thus, by using the IRES to modulate TC-83 capsid protein expression, we generated a vaccine candidate that combines efficient immunogenicity and efficacy with lower virulence and a reduced potential for spread in nature. Venezuelan equine encephalitis virus (VEEV) is transmitted by mosquitoes and widely distributed in Central and South America, causing regular outbreaks in horses and humans. Often misdiagnosed as dengue, VEEV infection in humans can lead to lifelong neurological sequelae and is fatal in up to >80% of equine cases, representing a significant socio-economic burden and constant public health threats for developing countries of Latin America. The only available vaccine, the live-attenuated TC-83 strain, is restricted to veterinary use due to its high reactogenicity in humans and risk for reversion to virulence, which could initiate an epidemic. By using an attenuation approach that allows the modulation of the virus capsid protein expression, we generated a new version of TC-83 that is more attenuated but still induces a protective immune response in mice. Additionally, this new vaccine cannot infect mosquitoes, which prevents the risk of spreading in nature. The attenuation approach we describe can be applied to a lot of other alphaviruses to develop vaccines against diseases regularly emerging and threatening developing countries.
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影响因子：
3.8
作者：
Hunt, Ann R.;Frederickson, Shana;Blair, Carol D.
通讯作者：
Blair, Carol D.
影响因子：
5.4
作者：
KINNEY, RM;CHANG, GJ;TRENT, DW
通讯作者：
TRENT, DW
影响因子：
6.4
作者：
BURKE, DS;RAMSBURG, HH;EDELMAN, R
通讯作者：
EDELMAN, R
影响因子：
7.7
作者：
LEON, CA;JARAMILLO, R;DEGUZMAN, R
通讯作者：
DEGUZMAN, R
DOI：
10.1126/science.1183021
发表时间：
2010-01-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iwasaki A;Medzhitov R
通讯作者：
Medzhitov R