上海巴斯德所双价手足口病疫苗研究取得新进展

rentianyixu

　8月19日，国际学术期刊Vaccine在线发表了中科院上海巴斯德研究所抗感染免疫与疫苗研究课题组的研究论文“Hexon-modified recombinant E1-deleted adenoviral vectors as bivalent vaccine carriers for Coxsackievirus A16 and Enterovirus 71”。  

　　手足口病是五岁以下儿童中常见的病毒性疾病，具有很强的传染性，已经成为我国及东南亚地区严重的公共卫生问题，但目前尚无治疗手足口病合适的疫苗。手足口病主要由肠道病毒71型（EV71）和柯萨奇病毒A16型（CA16）感染所致，研发同时针对EV71和CA16的双价疫苗对于手足口病的防控具有重要意义。

　　腺病毒载体是目前最有应用前景的病毒载体之一，被广泛应用于疫苗研发、基因治疗等各种基础研究和临床试验。由于人群中普遍存在常见的人血清型腺病毒的中和抗体，会影响相应的腺病毒载体诱导的免疫反应，研究人员采用稀有人血清型或其它种属来源（如黑猩猩型腺病毒载体AdC68）的腺病毒作为疫苗载体。经过人工改装的腺病毒载体不仅可以插入外源基因，高效表达外源蛋白，而且腺病毒表面的结构蛋白（如Hexon、Fiber等）也可以经过改造后插入外源抗原表位，诱导免疫反应。

　　上海巴斯德研究所抗感染免疫与疫苗研究课题组博士研究生张超等在周东明研究员和黄忠研究员的共同指导下，将CA16的中和表位PEP71和截短的EV71中和表位sSP70分别嵌入E1缺失的非复制型黑猩猩腺病毒载体AdC68 Hexon的HVR1 和HVR2区，同时将EV71的VP1基因序列克隆至E1缺失区以增强免疫效果。研究结果表明，PEP71和sSP70表位都能较好地展示于AdC68的病毒外壳，使EV71-VP1高效表达，并且实验组重组腺病毒免疫小鼠后可诱导理想的免疫反应。被动保护实验显示，注射实验组血清的小鼠比注射对照组血清的小鼠在攻毒试验后具有更高的存活率。此外,Hexon改造的腺病毒不能被抗野生型腺病毒的中和抗体所中和，表明腺病毒经Hexon适当改造后，与野生型腺病毒有不同的免疫原性，可以为“初免-加强” 的免疫策略提供更多的选择。该研究表明，基于黑猩猩型腺病毒AdC68载体的双价手足口病疫苗具有良好的发展潜力。  

    此项研究得到了中科院百人计划和上海巴斯德健康研究基金会等项目的支持。

文章链接：http://www.sciencedirect.com/science/article/pii/S0264410X15011305

图1.重组腺病毒的构建及结构模拟 a:分子克隆流程； b: Hexon结构模拟，红色为PEP71，洋红为sSP70  

rentianyixu

Hexon-modified recombinant E1-deleted adenoviral vectors as bivalent vaccine carriers for Coxsackievirus A16 and Enterovirus 71
Chao Zhang,
Yong Yang,
Yudan Chi,
Jieyun Yin,
Lijun Yan,
Zhiqiang Ku,
Qingwei Liu,
Zhong Huang, ,
Dongming Zhou,

Abstract

Hand, foot and mouth disease (HFMD) is a major public health concern in Asia; more efficient vaccines against HFMD are urgently required. Adenoviral (Ad) capsids have been used widely for the presentation of foreign antigens to induce specific immune responses in the host. Here, we describe a novel bivalent vaccine for HFMD based on the hexon-modified, E1-deleted chimpanzee adenovirus serotype 68 (AdC68). The novel vaccine candidate was generated by incorporating the neutralising epitope of Coxsackievirus A16 (CA16), PEP71, into hypervariable region 1 (HVR1), and a shortened neutralising epitope of Enterovirus 71 (EV71), sSP70, into HVR2 of the AdC68 hexon. In order to enhance the immunogenicity of EV71, VP1 of EV71 was cloned into the E1-region of the AdC68 vectors. The results demonstrated that these two epitopes were well presented on the virion surface and had high affinity towards specific antibodies, and VP1 of EV71 was also significantly expressed. In pre-clinical mouse models, the hexon-modified AdC68 elicited neutralising antibodies against both CA16 and EV71, which conferred protection to suckling mice against a lethal challenge of CA16 and EV71. In summary, this study demonstrates that the hexon-modified AdC68 may represent a promising bivalent vaccine carrier against EV71 and CA16 and an epitope-display platform for other pathogens.