Hand-foot-and-mouth disease (HFMD) is an infectious disease of infants and young children frequently caused by the enterovirus A species, mainly enterovirus 71 (EV71) and coxsackievirus A16 (CA16). In this study, we prepared the EV71 virus-like particle (EV71-VLP) and its chimeras using recombinant baculovirus (Bac-P1-3CD) co-expressing EV71 P1 (under polyhedrin promoter) and 3CD (under CMV-IE promoter) proteins in Sf9 cells. EV71-VLP chimera ChiEV71(1E)-VLP or ChiEV71(4E)-VLP displayed single CA16 PEP71 epitope in VP1 or four conserved CA16 neutralizing epitopes (PEP71 in VP1, aa136-150 in VP2, aa176-190 in VP3 and aa48-62 in VP4) by substitution of the corresponding regions of EV71 structure proteins, respectively. In mice, EV71-VLP and its chimeras elicited similar EV71-specific IgG and neutralizing antibody (NAb) titers compared to inactivated EV71. Expectedly, vaccination of ChiEV71(1E)-VLP or ChiEV71(4E)-VLP resulted in significantly increased CA16-specific IgG and NAb production and improved cross-protection against CA16 infection compared to EV71-VLP. Interestingly, the VLPs induced potent cellular immune responses and significantly decreased Th2 type (IL-4 and IL-10) cytokines secretion in the splenocytes of immunized mice compared to inactivated EV71 or inactivated CA16. Neonatal mice born to dams immunized with the chimeric VLPs or neonatal mice passively transferred with sera of immunized mice were completely protected from lethal EV71 challenge and partially protected from lethal CA16 infection. Our study provides a novel bivalent or multivalent vaccine strategy to prevent EV71 and related-enterovirus infections.

中文翻译：

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展示保守的柯萨奇病毒 A16 表位的嵌合肠道病毒 71 病毒样颗粒可引发有效的免疫反应并保护小鼠免受致命的 EV71 和 CA16 感染

手足口病（HFMD）是一种常见的婴幼儿传染病，由肠道病毒A种引起，主要是肠道病毒71型（EV71）和柯萨奇病毒A16型（CA16）。在本研究中，我们利用重组杆状病毒（Bac-P1-3CD）共表达EV71 P1（在多角体启动子下）和3CD（在CMV-IE启动子下）蛋白制备了EV71病毒样颗粒（EV71-VLP）及其嵌合体。在Sf9细胞中。 EV71-VLP 嵌合体 ChiEV71(1E)-VLP 或 ChiEV71(4E)-VLP 在 VP1 中显示单个 CA16 PEP71 表位或四个保守的 CA16 中和表位（VP1 中的 PEP71、VP2 中的 aa136-150、VP3 中的 aa176-190 和 aa48-62在VP4中）通过分别替换EV71结构蛋白的相应区域。在小鼠中，与灭活的 EV71 相比，EV71-VLP 及其嵌合体引发了相似的 EV71 特异性 IgG 和中和抗体 (NAb) 滴度。预计，与 EV71-VLP 相比，接种 ChiEV71(1E)-VLP 或 ChiEV71(4E)-VLP 会显着增加 CA16 特异性 IgG 和 NAb 的产生，并改善针对 CA16 感染的交叉保护。有趣的是，与灭活的 EV71 或灭活的 CA16 相比，VLP 诱导了有效的细胞免疫反应，并显着降低了免疫小鼠脾细胞中 Th2 型（IL-4 和 IL-10）细胞因子的分泌。用嵌合VLP免疫的母鼠所生的新生小鼠或被动转移免疫小鼠血清的新生小鼠完全免受致命性EV71攻击，并部分免受致命性CA16感染。我们的研究提供了一种新的二价或多价疫苗策略来预防 EV71 和相关肠道病毒感染。