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.

多种肠道病毒与危及生命和经济上重要的疾病有关， 现时只有小儿麻痹病毒和肠病毒71型的许可疫苗。的抗原多样性 肠病毒衣壳限制了疫苗的保护效力，仅限于抗原性非常相似的病毒。甚至 对于密切相关的脊髓灰质炎病毒，三种血清型必须由单独的疫苗产品覆盖。在大多数 在某些情况下，这种有针对性的疫苗开发方法甚至无法实施，因为 生物学上的限制，如鼻病毒的抗原多样性，或发展中国家在经济上的不吸引力， 针对仅偶尔与严重病理相关的病毒（如科萨基病毒）的疫苗 与糖尿病、心肌炎和扩张型心肌病的发生有关。尽管有紧迫感， 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 本质上不能提供满足这种需求的产品。 然而，与抗原多样性衣壳不同，这些病毒的非结构蛋白具有显著的 保存程度，因此复制机器的元件基本上可以互换 在多种肠道病毒之间，导致肠道病毒广泛重组的现象 基因组 在本申请中，我们提供数据来支持，并建议探索假设如下： 抗原多样性的肠道病毒衣壳是免疫显性抗原， 免疫反应的关键点。因此，通过移除 输入的衣壳蛋白，肠道病毒感染的免疫反应的发展可以改变路线 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聚焦到 由T细胞细胞毒性介导，和2.提供保护以对抗广泛的肠道病毒。