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表达肠道病毒71型样颗粒的重组腺病毒疫苗用于预防手足口病

Recombinant adeno-vaccine expressing enterovirus 71-like particles against hand, foot, and mouth disease.

作者信息

Tsou Yueh-Liang, Lin Yi-Wen, Shao Hsiao-Yun, Yu Shu-Ling, Wu Shang-Rung, Lin Hsiao-Yu, Liu Chia-Chyi, Huang Chieh, Chong Pele, Chow Yen-Hung

机构信息

Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Zhunan, Taiwan; Graduate Program of Biotechnology in Medicine, Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.

Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Zhunan, Taiwan.

出版信息

PLoS Negl Trop Dis. 2015 Apr 9;9(4):e0003692. doi: 10.1371/journal.pntd.0003692. eCollection 2015 Apr.

DOI:10.1371/journal.pntd.0003692
PMID:25855976
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4391779/
Abstract

Enterovirus 71 (EV71) and coxsackieviruses (CV) are the major causative agents of hand, foot and mouth disease (HFMD). There is not currently a vaccine available against HFMD, even though a newly developed formalin-inactivated EV71 (FI-EV71) vaccine has been tested in clinical trial and has shown efficacy against EV71. We have designed and genetically engineered a recombinant adenovirus Ad-EVVLP with the EV71 P1 and 3CD genes inserted into the E1/E3-deleted adenoviral genome. Ad-EVVLP were produced in HEK-293A cells. In addition to Ad-EVVLP particles, virus-like particles (VLPs) formed from the physical association of EV71 capsid proteins, VP0, VP1, and VP3 expressed from P1 gene products. They were digested by 3CD protease and confirmed to be produced by Ad-EVVLP-producing cells, as determined using transmission electron microscopy and western blotting. Mouse immunogenicity studies showed that Ad-EVVLP-immunized antisera neutralized the EV71 B4 and C2 genotypes. Activation of VLP-specific CD4+ and CD8+/IFN-γ T cells associated with Th1/Th2-balanced IFN-ɣ, IL-17, IL-4, and IL-13 was induced; in contrast, FI-EV71 induced only Th2-mediated neutralizing antibody against EV71 and low VLP-specific CD4+ and CD8+ T cell responses. The antiviral immunity against EV71 was clearly demonstrated in mice vaccinated with Ad-EVVLP in a hSCARB2 transgenic (hSCARB2-Tg) mouse challenge model. Ad-EVVLP-vaccinated mice were 100% protected and demonstrated reduced viral load in both the CNS and muscle tissues. Ad-EVVLP successfully induced anti-CVA16 immunities. Although antisera had no neutralizing activity against CVA16, the 3C-specific CD4+ and CD8+/IFN-γ T cells were identified, which could mediate protection against CVA16 challenge. FI-EV71 did not induce 3C-mediated immunity and had no efficacy against the CVA16 challenge. These results suggest that Ad-EVVLP can enhance neutralizing antibody and protective cellular immune responses to prevent EV71 infection and cellular immune responses against CV infection.

摘要

肠道病毒71型（EV71）和柯萨奇病毒（CV）是手足口病（HFMD）的主要病原体。目前尚无针对手足口病的疫苗，尽管一种新开发的福尔马林灭活EV71（FI-EV71）疫苗已在临床试验中进行了测试，并显示出对EV71的有效性。我们设计并通过基因工程构建了一种重组腺病毒Ad-EVVLP，将EV71的P1和3CD基因插入到缺失E1/E3的腺病毒基因组中。Ad-EVVLP在HEK-293A细胞中产生。除了Ad-EVVLP颗粒外，由P1基因产物表达的EV71衣壳蛋白VP0、VP1和VP3通过物理缔合形成病毒样颗粒（VLP）。它们被3CD蛋白酶消化，并经透射电子显微镜和蛋白质印迹法测定，证实由产生Ad-EVVLP的细胞产生。小鼠免疫原性研究表明，用Ad-EVVLP免疫的抗血清可中和EV71 B4和C2基因型。诱导了与Th1/Th2平衡的IFN-γ、IL-17、IL-4和IL-13相关的VLP特异性CD4+和CD8+/IFN-γ T细胞的活化；相比之下，FI-EV71仅诱导Th2介导的针对EV71的中和抗体以及低水平的VLP特异性CD4+和CD8+ T细胞反应。在hSCARB2转基因（hSCARB2-Tg）小鼠攻毒模型中，用Ad-EVVLP免疫的小鼠对EV71的抗病毒免疫明显得到证实。用Ad-EVVLP免疫的小鼠100%得到保护，并且在中枢神经系统和肌肉组织中的病毒载量均降低。Ad-EVVLP成功诱导了抗CVA16免疫。尽管抗血清对CVA16没有中和活性，但鉴定出了3C特异性CD4+和CD8+/IFN-γ T细胞，它们可介导针对CVA16攻毒的保护作用。FI-EV71未诱导3C介导的免疫，对CVA16攻毒无效。这些结果表明，Ad-EVVLP可增强中和抗体和保护性细胞免疫反应，以预防EV71感染以及针对CV感染的细胞免疫反应。

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