Development of an Enterovirus 71 Vaccine Efficacy Test Using Human Scavenger Receptor B2 Transgenic Mice
Development of an Enterovirus 71 Vaccine Efficacy Test Using Human Scavenger Receptor B2 Transgenic Mice
复制标题
DOI：
10.1128/jvi.01921-19
复制
发表时间：
2020-03-01
影响因子：
5.4
通讯作者：
Koike，Satoshi
中科院分区：
文献类型：
--
作者：
Imura，Ayumi;Sudaka，Yui;Koike，Satoshi
肠道病毒71型（EV71）是手足口病的病原体，有时会导致严重的神经系统疾病。需要开发有效的疫苗和动物模型来评估候选疫苗。然而，目前用于疫苗效力测试的动物模型，即猴子和新生小鼠，具有经济、伦理和实践上的缺陷。此外，制备用于致死性攻击的EV71菌株在细胞培养物中繁殖期间常常发展出降低的毒力。为了克服这些问题，我们使用了表达人清道夫受体B2（hSCARB 2）的小鼠模型，该模型显示出对EV71的终身易感性。我们选择了属于亚基因组B4、B5、C1、C2和C4的EV71毒株，并使用EV71的培养方法对其进行繁殖，而毒力没有明显降低。在这里，我们描述了一种新的EV71疫苗效力测试的基础上，这些hSCARB 2转基因（Tg）小鼠和这些强毒病毒。用福尔马林灭活的EV 71皮下免疫成年Tg小鼠。疫苗在免疫小鼠中引发足够水平的中和抗体。小鼠通过静脉注射用强毒病毒进行致死性攻击。观察2周的存活率、临床体征和体重变化。大多数免疫小鼠存活，无临床体征或组织病理学病变。免疫小鼠体内病毒复制量明显低于未免疫小鼠。用EV71疫苗免疫的小鼠仅部分地保护免于柯萨奇病毒A16的致死攻击。这些结果表明，这种新的模型是有用的在vivoEV71疫苗的效力testing.IMPORTANCEThe新疫苗的EV71依赖于小动物模型的可用性适合在vivoEV71效力测试的发展。已经使用了猴子和新生小鼠，但使用这些动物有几个缺点，包括成本高，敏感性有限，实验重现性差。此外，相关的道德问题也相当多。基于hSCARB 2 Tg小鼠和在本文中提出的遗传修饰细胞系中繁殖的EV71强毒株的新效力测试可以克服这些缺点，并且有望加速新EV71疫苗的开发。
Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease, and it sometimes causes severe neurological disease. Development of effective vaccines and animal models to evaluate vaccine candidates are needed. However, the animal models currently used for vaccine efficacy testing, monkeys and neonatal mice, have economic, ethical, and practical drawbacks. In addition, EV71 strains prepared for lethal challenge often develop decreased virulence during propagation in cell culture. To overcome these problems, we used a mouse model expressing human scavenger receptor B2 (hSCARB2) that showed lifelong susceptibility to EV71. We selected virulent EV71 strains belonging to the subgenogroups B4, B5, C1, C2, and C4 and propagated them using a culture method for EV71 without an apparent reduction in virulence. Here, we describe a novel EV71 vaccine efficacy test based on these hSCARB2 transgenic (Tg) mice and these virulent viruses. Adult Tg mice were immunized subcutaneously with formalin-inactivated EV71. The vaccine elicited sufficient levels of neutralizing antibodies in the immunized mice. The mice were subjected to lethal challenge with virulent viruses via intravenous injection. Survival, clinical signs, and body weight changes were observed for 2 weeks. Most immunized mice survived without clinical signs or histopathological lesions. The viral replication in immunized mice was much lower than that in nonimmunized mice. Mice immunized with the EV71 vaccine were only partially protected against lethal challenge with coxsackievirus A16. These results indicate that this new model is useful forin vivoEV71 vaccine efficacy testing.IMPORTANCEThe development of new vaccines for EV71 relies on the availability of small animal models suitable forin vivoefficacy testing. Monkeys and neonatal mice have been used, but the use of these animals has several drawbacks, including high costs, limited susceptibility, and poor experimental reproducibility. In addition, the related ethical issues are considerable. The new efficacy test based on hSCARB2 Tg mice and virulent EV71 strains propagated in genetically modified cell lines presented here can overcome these disadvantages and is expected to accelerate the development of new EV71 vaccines.