Repurposing of Universal and Immunogenic MultiTEP Platform Designed for AD to Develop SARS-CoV-2 Multiepitope Vaccine

项目摘要 在美国首次报告新冠肺炎死亡病例两个月后，死亡率为每百万人228人， 这是全球第十高的比率。45-54岁人群新冠肺炎死亡率为~5%，并呈上升趋势。 到13%的50-60岁的人，不幸的是，美国80%的冠状病毒死亡发生在65岁的人中 年龄在几岁及以上。为了保护人们免受新冠肺炎侵害，世界各地的多个团体已经开始 根据SARS-CoV-2的基因序列开发疫苗。我们不知道细胞和 体液免疫反应对于预防SARS-CoV-2是必要的，但最近的数据显示 新冠肺炎恢复期患者应用疫苗诱导中和 抗体足以预防这种感染。更重要的是，有可能一种疫苗 含有目前未知的SARS-CoV-2 T细胞表位可能会在免疫受试者中诱导一种细胞因子 随后的病毒感染可能导致严重的不良事件，最终导致死亡 尤其是易受影响的老年人。为了避免自身反应性T细胞激活，使用当前的AG060965 计划和其他NIA赠款，我们已经开发出一种通用的、具有极强免疫原性的多重TEP疫苗 针对病理性Aβ、tau和α-syn的AD疫苗平台。利用这一发展，我们 在本行政副刊中提出以专利多TEP为基础研制SARS-CoV-2疫苗 平台技术。我们假设基于多TEP平台的疫苗可以诱导保护性中和 免疫功能低下的老年人，包括MCI/AD患者。这种疫苗可能与许多不同 另一些是因为它可以刺激适应性免疫，提供了广泛的人类MHC基因多态 以及激活原始Th细胞和预先存在的记忆Th细胞两者，这些Th细胞是响应于传统的 在一个人的一生中接种疫苗和/或感染各种病原体而不激活有害病毒- 特定的T细胞。因此，使用我们的基于核酸的疫苗技术，我们将快速产生DNA 通过将20个B细胞表位基因从Spike蛋白连接到MultiTEP构建，(Ii)选择几个B细胞 在小鼠体内诱导病毒中和抗体的表位，(Iii)产生原型重组疫苗CoV2- 2019年同时靶向最多三个与产生中和抗体相关的B细胞表位。 这种多表位CoV2-2019疫苗将在老年非人类灵长类动物(年龄相关模型)中进行测试 免疫衰老)Ana转基因AD/tau病小鼠模型(老年人接种疫苗的季节性模型 以前接种过牛磺酸疫苗的人群和MCI/AD患者(AV-1980)。

Project Summary Two months after the first report of a U.S. death from COVID-19, the death rate is 228 per million people, the tenth highest rate globally. The mortality rate from COVID-19 in those aged 45-54 years is ~5%, and it increased to 13% in people of 50-60 years old, and sadly 80% of all U.S. coronavirus deaths occurred among people 65 years of age and older. To protect people from COVID-19, multiple groups in all over the world have begun developing vaccines based on the genetic sequence of SARS-CoV-2. We do not know whether both cellular and humoral immune responses are necessary for protection against the SARS-CoV-2, but recent data with convalescent plasma administration into the COVID-19 patients indicate that vaccine inducing neutralizing antibodies could be sufficient for the protection against this infection. More of that, it is possible that a vaccine that contains currently unknown T cell epitopes of SARS-CoV-2 may induce in immunized subjects a cytokine storm upon subsequent viral infection that could lead to severe adverse events, culminating in death in particularly susceptible elderly individuals. To avoid autoreactive T cell activation, using the current AG060965 program and other NIA grants, we have developed a universal and extremely immunogenic MultiTEP vaccine platform for A.D. vaccines targeting pathological Aβ, tau, and α-Syn. Taking advantage of this development we propose in this Administrative Supplement to create a SARS-CoV-2 vaccine based on proprietary MultiTEP platform technology. We hypothesize that MultiTEP platform-based vaccine could induce protective neutralizing antibodies in immunocompromised elderly people, including MCI/AD patients. This vaccine may differ from many others because it could stimulate adaptive immunity, providing broad coverage of human MHC polymorphisms and activating both naive Th cells and pre-existing memory Th cells generated in response to conventional vaccines and/or infections with various pathogens during one's lifespan without the activation of harmful virus- specific T cells. Therefore, using our nucleic acid-based vaccine technology we will rapidly generate DNA constructs by attaching twenty B cell epitope genes from the spike protein to MultiTEP, (ii) select several B cell epitopes that induced virus-neutralizing antibodies in mice, (iii) generate prototype recombinant vaccine, CoV2- 2019 targeting simultaneously up to three B cell epitopes associated with production of neutralizing antibodies. This multiepitope CoV2-2019 vaccine will be tested in aged non-human primates (model of age-associated immunosenescence) ana transgenic mouse model of A.D./tauopathy (seasonal model of vaccination of elderly people and MCI/AD patients previously vaccinated with tau-vaccine, AV-1980).