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

将免疫反应从结构蛋白重新聚焦到保守的非结构蛋白，作为诱导广泛抗肠道病毒保护的新型疫苗接种方法

• 批准号: 10254302
• 负责人: George A. Belov
• 金额: $ 22.82万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254302
• 关键词: Amino Acid Sequence; Antibodies; Antigenic Diversity; Antigens; Asthma; Attenuated Vaccines; Biological; CD8B1 gene; Capsid; Capsid Proteins; Cells; China; Code; Coxsackie Viruses; Cytotoxic T-Lymphocytes; Data; Development; Diabetes Mellitus; Dilated Cardiomyopathy; Disease; Disease Outbreaks; Economic Burden; Economics; Elements; Encephalomyelitis; Enterovirus; Enterovirus 68; Enterovirus 71; Enterovirus Infections; Epidemiology; Family Picornaviridae; Flavivirus; Gene Pool; Genetic Recombination; Genome; Health Resources; Human poliovirus; Immune response; Immunity; Immunization; Immunize; Immunodominant Antigens; In Vitro; Inactivated Vaccines; Individual; Infection; Insulin-Dependent Diabetes Mellitus; Life; Link; Mediating; Membrane Proteins; Mus; Myocarditis; Nonstructural Protein; Oral; Oral Poliovirus Vaccine; Paralysed; Pathology; Phase; Poliomyelitis; Poliovirus Vaccines; Primates; Property; Proteins; Public Health; RNA; RNA Viruses; Replicon; Rhinovirus; Role; Scheme; Serotyping; Specificity; Stretching; Structure; System; T cell response; T-Lymphocyte; Time; Vaccination; Vaccines; Viral; Viral Proteins; Virion; Virus; Virus-like particle; antigen-specific T cells; base; cytotoxic; cytotoxicity; human pathogen; in vivo; meetings; mouse model; neutralizing antibody; novel; pathogen; prevent; product development; protective efficacy; response; vaccine access; vaccine development; vaccine efficacy

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.

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。 肠道病毒衣壳将疫苗的保护功效限制为仅针对抗原非常相似的病毒。甚至 对于密切相关的脊髓灰质炎病毒，这三种血清型必须由单独的疫苗产品涵盖。在大多数 在这种情况下，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，例如鼻病毒的抗原多样性，或发展中国家的经济吸引力 针对仅偶尔与严重病症相关的病毒（例如柯萨奇病毒）的疫苗 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和新出现的肠道病毒威胁，目前 疫苗开发策略侧重于诱导针对衣壳抗原的中和抗体 本质上无法提供满足这种需求的产品。 然而，与抗原多样化的衣壳不同，这些病毒的非结构蛋白具有显着的特征 保守程度，使得复制机器的元件本质上是可以互换的 多种肠道病毒之间相互交叉，造成肠道病毒广泛重组的现象 基因组。 在此应用程序中，我们提供数据来支持，并建议探索提出以下假设的假设： 抗原多样化的肠道病毒衣壳是免疫显性抗原，可改变其发育 免疫反应远离保守的非结构蛋白。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 朝向复制机器的保守膜相关蛋白。可能导致：1. 将保护机制从主要基于中和抗体重新调整为基于中和抗体的保护机制 由 T 细胞的细胞毒性介导，以及 2. 提供针对广谱肠道病毒的保护。