Human enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the two major causative agents of hand-foot-and-mouth disease (HFMD). To investigate novel combined vaccines to prevent EV71 and CA16 infection, we constructed chimeric virus-like particles (tHBc/SPA or tHBc/SP VLPs) displaying conserved epitopes of EV71 (aa 208-222 of VP1 and aa 248-263 of VP2) and CA16 (aa271-285 of VP1) using a truncated hepatitis B virus core carrier (tHBc). Immunization with the chimeric VLPs induced epitope- or virus-specific IgG and neutralization antibodies against EV71 and CA16 in the mice. Compared with inactivated EV71, the chimeric VLPs induced significantly increased Th1 cytokine (IFN-γ, IL-2) production and decreased Th2 cytokine (IL-4, IL-10) responses. Neonatal mice born to dams immunized with the recombinant particles were completely protected from lethal EV71 and partially protected from CA16 infection. Co-expression of the conserved human MHC class I CD4+ T cell epitope (aa248-263 of VP2) did not improve the antiviral immunity of the chimeric VLP vaccine in mice. Our results demonstrate that experimental combination vaccines comprised of EV71 and CA16 epitopes induce both humoral and cellular immune responses and therefore support further preclinical and clinical development of a bivalent VLP vaccine targeting both CA16 and EV71.

中文翻译：

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包含多个表位的乙型肝炎病毒核心颗粒赋予小鼠抗肠道病毒71和柯萨奇病毒A16感染的保护作用。

人肠道病毒71（EV71）和柯萨奇病毒A16（CA16）是手足口病（HFMD）的两种主要病原体。为了研究预防EV71和CA16感染的新型联合疫苗，我们构建了嵌合病毒样颗粒（tHBc / SPA或tHBc / SP VLP），这些颗粒表现出EV71的保守表位（VP1的aa 208-222和VP2的aa 248-263）和使用截短的乙型肝炎病毒核心载体（tHBc）的CA16（VP1的aa271-285）。嵌合VLP免疫后在小鼠中诱导了针对EV71和CA16的表位或病毒特异性IgG和中和抗体。与灭活的EV71相比，嵌合VLP诱导的Th1细胞因子（IFN-γ，IL-2）产生显着增加，而Th2细胞因子（IL-4，IL-10）应答则降低。用重组颗粒免疫的水坝出生的新生小鼠受到了致命性EV71的完全保护，而免受CA16感染的部分保护。保守的人类MHC I类CD4 + T细胞表位（VP2的aa248-263）的共表达不能改善嵌合VLP疫苗在小鼠中的抗病毒免疫性。我们的结果表明，由EV71和CA16表位组成的实验性组合疫苗可诱导体液和细胞免疫反应，因此支持针对CA16和EV71的二价VLP疫苗的进一步临床前和临床开发。