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: 10041960
• 负责人: George A. Belov
• 金额: $ 18.96万
• 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/10041960
• 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; 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 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.

多种肠病毒与威胁生命和经济上重要的疾病有关，但 许可疫苗仅对脊髓灰质炎病毒和肠病毒71。 肠病毒capsids仅将疫苗的保护作用限制在抗原上非常相似的病毒中。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覆盖。大多数 案件此类有针对性的疫苗开发方法甚至无法实施，要么是因为 生物学约束，例如鼻病毒的抗原多样性，或发展的经济不吸引力 针对病毒的疫苗仅偶发地与严重的病理相关，例如coxsackie病毒 与糖尿病，心肌炎和扩张心肌病的发展有关。因此，尽管有压力 需要对现有和新兴肠病毒威胁的有效疫苗覆盖范围 疫苗开发策略的重点是诱导针对衣壳抗原的中和抗体 本质上无力交付满足这一需求的产品。 然而，与抗原多样性的衣壳不同，这些病毒的非结构性蛋白质具有重要意义 保护程度，以便复制机械的要素基本上可以互换 在各种肠病毒中，导致肠病毒的广泛重组现象 基因组。 在此应用程序中，我们介绍数据以支持，并建议探讨以下假设： 抗原多样性的肠病毒衣壳是免疫主导的抗原，转移了发育 免疫反应远离保守的非结构蛋白。因此，通过删除 可以重新分配帽蛋白的输入，对肠病毒感染的免疫反应的发展。 朝着复制机制的保守膜相关蛋白。可能导致：1。 重新关注保护机制，主要基于中和抗体 由T细胞细胞毒性介导的，2。提供针对范围广泛的肠病毒的保护。