登革病毒疫苗组分的开发

摘要

本发明涉及在3'非翻译区（3'‑UTR）中包含突变的登革病毒或嵌合登革病毒，其中所述突变包括除去登革病毒血清型1、2、3和4的每一种中TL‑2同源结构的Δ30突变和除所述Δ30突变外从3'‑UTR中缺失核苷酸，所述缺失以5'方向除去序列最远至登革病毒血清型1、2、3和4的每一种中TL‑3同源结构的5'边界；或用登革病毒第二血清型的3'‑UTR，其任选地含有Δ30突变和除所述Δ30突变外从3'‑UTR中缺失核苷酸，对登革病毒第一血清型的3'‑UTR的替换；并且涉及免疫原性组合物、诱导免疫应答的方法和产生登革病毒或嵌合登革病毒的方法。

主权项

一种编码登革病毒或嵌合登革病毒的核酸，包含被第二登革病毒血清型的第二3’非翻译区取代的第一登革病毒血清型的第一3’非翻译区，所述第二3’非翻译区包含Δ30突变和除所述Δ30突变外从3’非翻译区中缺失核苷酸，并且，所述第一登革病毒血清型和第二登革病毒血清型为登革病毒血清型1、2、3或4，并且第一登革病毒和第二登革病毒为不同的血清型，其中，所述的编码登革病毒或嵌合登革病毒的核酸选自以下所组成的组中：a)rDEN1‑3'D2、rDEN1‑3'D2x、rDEN1‑3'D3、rDEN1‑3'D3x、rDEN1‑3'D4、rDEN1‑3'D4x；rDEN1/2‑3’D1、rDEN1/2‑3'D1x、rDEN1/2‑3'D3、rDEN1/2‑3'D3x、rDEN1/2‑3'D4、rDEN1/2‑3'D4x；rDEN1/3‑3’D1、rDEN1/3‑3'D1x、rDEN1/3‑3'D2、rDEN1/3‑3'D2x、rDEN1/3‑3'D4、rDEN1/3‑3'D4x；rDEN1/4‑3’D1、rDEN1/4‑3’D1x、rDEN1/4‑3'D2、rDEN1/4‑3'D2x、rDEN1/4‑3'D3、rDEN1/4‑3'D3x；b)rDEN2‑3’D1、rDEN2‑3’D1x、rDEN2‑3'D3、rDEN2‑3'D3x、rDEN2‑3'D4、rDEN2‑3'D4x；rDEN2/1‑3'D2、rDEN2/1‑3'D2x、rDEN2/1‑3'D3、rDEN2/1‑3'D3x、rDEN2/1‑3'D4、rDEN2/1‑3'D4x；rDEN2/3‑3D1、rDEN2/3‑3’D1x、rDEN2/3‑3'D2、rDEN2/3‑3’D2x、rDEN2/3‑3'D4、rDEN2/3‑3'D4x；rDEN2/4‑3’D1、rDEN2/4‑3’D1x、rDEN2/4‑3'D2、rDEN2/4‑3'D2x、rDEN2/4‑3'D3、rDEN2/4‑3'D3x；c)rDEN3‑3’D1、rDEN3‑3’D1x、rDEN3‑3'D2、rDEN3‑3'D2x、rDEN3‑3'D4、rDEN3‑3’D4x；rDEN3/1‑3'D2、rDEN3/1‑3'D2x、rDEN3/1‑3’D3、rDEN3/1‑3’D3x、rDEN3/1‑3'D4、rDEN3/1‑3'D4x；rDEN3/2‑3’D1、rDEN3/2‑3’D1x、rDEN3/2‑3'D3、rDEN3/2‑3'D3x、rDEN3/2‑3’D4、rDEN3/2‑3'D4x；rDEN3/4‑3’D1、rDEN3/4‑3’D1x、rDEN3/4‑3'D2、rDEN3/4‑3’D2x、rDEN3/4‑3'D3、rDEN3/4‑3'D3x；和d)rDEN4‑3’D1、rDEN4‑3’D1x、rDEN4‑3’D2、rDEN4‑3'D2x、rDEN4‑3’D3、rDEN4‑3'D3x；rDEN4/1‑3'D2、rDEN4/1‑3'D2x、rDEN4/1‑3'D3、rDEN4/1‑3'D3x、rDEN4/1‑3'D4、rDEN4/1‑3'D4x；rDEN4/2‑3’D1、rDEN4/2‑3’D1x、rDEN4/2‑3'D3、rDEN4/2‑3'D3x、rDEM4/2‑3'D4、rDEN4/2‑3'D4x；rDEN4/3‑3’D1、rDEN4/3‑3’D1x、rDEN4/3‑3'D2、rDEN4/3‑3'D2x、rDEN4/3‑3'D4、rDEN4/3‑3'D4x；其中x是下列的突变，Δ61，对应于DEN3 Sleman/78的3'‑UTR中缺失的核苷酸173‑113，具有缺失接头‑CCGAΔUAAA‑，Δ80，对应于DEN3 Sleman/78的3'‑UTR中缺失的核苷酸192‑113，具有缺失接头‑CACAΔUAAA‑，Δ86，对应于DEN3 Sleman/78的3'‑UTR中缺失的核苷酸228‑143，具有缺失接头‑UAGCΔGACU‑，Δ30/31，对应于DEN3 Sleman/78的3'‑UTR中缺失的核苷酸173‑143/258‑228，具有缺失接头‑CCAAΔGACU‑/‑CUGCΔGACU‑。