Refocusing the immune response from structural to conserved non-structural proteins as a novel vaccination approach for inducing broad anti-enterovirus protection

多种肠道病毒与危及生命和经济上重要的疾病有关，但 获得许可的疫苗仅针对脊髓灰质炎病毒和肠道病毒71型。沙门氏菌的抗原性多样性 肠道病毒衣壳病毒将疫苗的保护效力限制在抗原性非常相似的病毒上。连 对于密切相关的脊髓灰质炎病毒，三种血清型必须由不同的疫苗产品覆盖。在大多数 在一些情况下，这种有针对性的疫苗开发方法甚至无法实施，要么是因为 生物限制，如鼻病毒的抗原性多样性，或发展的经济吸引力 针对仅偶尔与严重病理有关的病毒的疫苗，如柯萨奇病毒 与糖尿病、心肌炎和扩张型心肌病的发展有关。因此，尽管迫在眉睫 需要有效的疫苗覆盖现有的和新出现的肠道病毒威胁，目前 着眼于诱导针对衣壳抗原的中和抗体的疫苗开发策略 本质上无法提供满足这一需求的产品。 然而，与抗原性不同的衣壳不同，这些病毒的非结构蛋白具有显著的 保护程度，以便复制机器的元件基本上是可互换的 在种类繁多的肠道病毒中，导致肠道病毒广泛重组的现象 基因组。 在本应用程序中，我们提供数据来支持，并建议探索假设以下假设： 抗原性不同的肠道病毒衣壳是免疫显性抗原，它改变了发育。 远离保守的非结构蛋白的免疫反应。因此，通过删除 衣壳蛋白的输入，可以改变对肠道病毒感染的免疫反应的发展 朝向复制机制中保守的膜相关蛋白。可能导致：1. 将保护机制从主要基于中和抗体的保护机制重新集中到 由T细胞细胞毒性介导，以及2.提供对广谱肠道病毒的保护。

Multiple enteroviruses are associated with life-threatening and economically important diseases, yet the licensed vaccines are only available against poliovirus and enterovirus 71. The antigenic diversity of enterovirus capsids restricts the protective efficacy of vaccines only to antigenically very similar viruses. Even for closely related polioviruses, the three serotypes must be covered by separate vaccine products. In most cases such targeted vaccine development approach cannot even be implemented, either because of the biological constraints, such as antigenic diversity of rhinoviruses, or economic unattractiveness of developing vaccines against viruses only sporadically associated with severe pathologies, such as Coxsackie viruses linked to the development of diabetes, myocarditis and dilated cardiomyopathy. Thus, in spite of a pressing need for an effective vaccine coverage of existing and emerging enterovirus threats, the current vaccine development strategies focused on inducing neutralizing antibodies against capsid antigens are intrinsically incapable of delivering products meeting this demand. Yet, unlike the antigenically diverse capsids, the non-structural proteins of these viruses feature a significant degree of conservation, so that the elements of the replication machinery are essentially interchangeable among diverse enteroviruses, resulting in the phenomenon of extensive recombination of enterovirus genomes. In this application we present data to support, and propose to explore the hypothesis that posits the following: Antigenically diverse enteroviral capsids are immuno-dominant antigens which divert the development of immune response away from the conserved non-structural proteins. Consequently, by removing the input of the capsid proteins, the development of the immune response to enterovirus infection can be rerouted towards the conserved membrane-associated proteins of the replication machinery. likely resulting in: 1. Refocusing the protection mechanism from that based mostly on neutralizing antibodies to the one mediated by T-cell cytotoxicity, and 2. Providing protection against broad spectrum of enteroviruses.