Novel chikungunya vaccine candidate with an IRES-based attenuation and host range alteration mechanism.
Novel chikungunya vaccine candidate with an IRES-based attenuation and host range alteration mechanism.
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DOI：
10.1371/journal.ppat.1002142
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发表时间：
2011-07
期刊：
影响因子：
6.7
通讯作者：
Weaver SC
中科院分区：
文献类型：
--
作者：
Plante K;Wang E;Partidos CD;Weger J;Gorchakov R;Tsetsarkin K;Borland EM;Powers AM;Seymour R;Stinchcomb DT;Osorio JE;Frolov I;Weaver SC
基孔肯雅病毒 (CHIKV) 是一种重新出现的蚊媒病原体，最近引起了毁灭性的城市流行病，包括严重的、有时是慢性的关节痛。与大多数其他蚊媒病毒性疾病一样，控制措施依赖于减少蚊子数量及其与人类的接触，但这在大多数地方都是无效的。因此，疫苗仍然是预防大多数媒介传播疾病的最佳策略。理想情况下，针对资源有限国家的疾病的疫苗应结合低成本和单剂量功效，同时诱导快速和长期的免疫力，并且严重不良反应的风险可以忽略不计。为了开发这种疫苗来预防基孔肯雅热，我们采用了合理的减毒机制，该机制也可以防止蚊媒感染。脑心肌炎病毒的内部核糖体进入位点 (IRES) 取代了 cDNA CHIKV 克隆中的亚基因组启动子，从而改变了结构蛋白基因表达的水平和宿主特异性机制。在正常近交系和干扰素反应缺陷小鼠中进行的测试表明，这种新的候选疫苗在单剂量后具有高度减毒、免疫原性和有效性。此外，它无法在蚊子细胞中复制或在体内感染蚊子。这种基于 IRES 的减毒平台技术可用于任何甲病毒的可预测减毒。基孔肯雅病毒 (CHIKV) 是一种由蚊子传播的甲病毒，自 2004 年以来重新出现，导致数百万例严重且往往持续的关节痛。由于没有获得许可的疫苗可以预防这种疾病，因此我们采用减毒方法来生产活的 CHIKV 候选疫苗，该候选疫苗可引发强大的保护性免疫反应，但不会在小鼠中引起可检测到的疾病。它也无法感染蚊媒，这是活病毒疫苗的一个重要安全特征，可用于非流行地区对旅行者或实验室人员进行免疫。这种疫苗方法利用了小核糖核酸病毒 IRES 改变甲病毒结构蛋白表达的减毒作用，可广泛适用于引起重要发热性疾病和脑炎的其他甲病毒。
Chikungunya virus (CHIKV) is a reemerging mosquito-borne pathogen that has recently caused devastating urban epidemics of severe and sometimes chronic arthralgia. As with most other mosquito-borne viral diseases, control relies on reducing mosquito populations and their contact with people, which has been ineffective in most locations. Therefore, vaccines remain the best strategy to prevent most vector-borne diseases. Ideally, vaccines for diseases of resource-limited countries should combine low cost and single dose efficacy, yet induce rapid and long-lived immunity with negligible risk of serious adverse reactions. To develop such a vaccine to protect against chikungunya fever, we employed a rational attenuation mechanism that also prevents the infection of mosquito vectors. The internal ribosome entry site (IRES) from encephalomyocarditis virus replaced the subgenomic promoter in a cDNA CHIKV clone, thus altering the levels and host-specific mechanism of structural protein gene expression. Testing in both normal outbred and interferon response-defective mice indicated that the new vaccine candidate is highly attenuated, immunogenic and efficacious after a single dose. Furthermore, it is incapable of replicating in mosquito cells or infecting mosquitoes in vivo. This IRES-based attenuation platform technology may be useful for the predictable attenuation of any alphavirus. Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged since 2004 to cause millions of cases of severe and often persistent arthralgia. Because no licensed vaccine exists to prevent this disease, we utilized an attenuation approach to produce a live CHIKV vaccine candidate that elicits a robust, protective immune response yet causes no detectable disease in mice. It is also incapable of infecting mosquito vectors, an important safety feature for a live virus vaccine that may be used in nonendemic locations to immunize travelers or laboratory personnel. This vaccine approach, which exploits the attenuating effect of altering the expression of the alphavirus structural proteins with a picornavirus IRES, may be broadly applicable to other alphaviruses that cause important febrile diseases as well as encephalitis.
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