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

重新利用专为 AD 设计的通用和免疫原性 MultiTEP 平台来开发 SARS-CoV-2 多表位疫苗

• 批准号: 10162389
• 负责人: Michael G Agadjanyan
• 金额: $ 38.91万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162389
• 关键词: 2019-nCoV; AN-1792; Administrative Supplement; Age; Age-Years; Alzheimer' s disease model; Amyloid beta-42; Amyloid beta-Protein; Antibodies; Antibody titer measurement; Antiviral Agents; B-Lymphocyte Epitopes; B-Lymphocytes; Biological Assay; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 pandemic; Cell Culture Techniques; Cells; Cessation of life; Coronavirus; Critical Illness; DNA; DNA Vaccines; Data; Death Rate; Development; Disease Outbreaks; Ebola virus; Elderly; Engineering; Epitopes; Future; Gene Proteins; Generations; Genes; Genetic; Genetic Polymorphism; Glycoproteins; Goals; Grant; Human; Humoral Immunities; Immune Sera; Immune response; Immunization; Immunize; Immunocompromised Host; Immunoglobulin G; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Interferon Type II; Interleukin-10; Interleukin-6; Lead; Longevity; Lung; Lymphopenia; Macaca fascicularis; Memory; Meningoencephalitis; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Modeling; Monkeys; Mus; Nucleic Acids; Pathologic; Patients; Peptides; Plasma; Play; Production; Proteins; QS21; Recombinant Vaccines; Reporting; Rest; Role; SARS coronavirus; Safety; Series; Serious Adverse Event; Severity of illness; Splenocyte; Suggestion; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Epitopes; TNF gene; Tauopathies; Technology; Testing; Time; Transgenic Mice; Transgenic Organisms; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Vaccines; Virus; Virus Diseases; Vulnerable Populations; adaptive immunity; aged; alpha synuclein; autoreactive T cell; base; cytokine; cytokine release syndrome; design; efficacy testing; immunogenic; immunogenicity; immunopathology; immunosenescence; mortality; mouse model; neutralizing antibody; nonhuman primate; novel coronavirus; pathogen; phase I trial; prevent; programs; prototype; response; tau Proteins; vaccine evaluation

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).

项目概要 在美国首次报告因 COVID-19 死亡的两个月后，死亡率为每百万人 228 人， 全球第十高的比率。 45-54 岁人群中 COVID-19 死亡率约为 5%，并且还在上升 50-60 岁人群中的死亡率高达 13%，遗憾的是，美国所有冠状病毒死亡病例中有 80% 发生在 65 岁人群中 岁及以上。为了保护人们免受 COVID-19 的侵害，世界各地的多个团体已经开始 开发基于 SARS-CoV-2 基因序列的疫苗。我们不知道蜂窝和 体液免疫反应对于预防 SARS-CoV-2 是必要的，但最近的数据 对 COVID-19 患者进行恢复期血浆注射表明疫苗可诱导中和 抗体足以预防这种感染。更重要的是，疫苗有可能 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细胞因子 随后的病毒感染风暴可能会导致严重的不良事件，最终导致死亡 尤其是老年人易受影响。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 拨款，我们开发了一种通用且极具免疫原性的 MultiTEP 疫苗 针对病理性 Aβ、tau 和 α-Syn 的 A.D. 疫苗平台。利用这一发展优势，我们 在本行政补充文件中提议创建基于专有 MultiTEP 的 SARS-CoV-2 疫苗 平台技术。我们假设基于 MultiTEP 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）中存在抗体。这种疫苗可能与许多疫苗不同 其他原因是它可以刺激适应性免疫，提供人类 MHC 多态性的广泛覆盖 并激活幼稚 Th 细胞和响应传统方法而产生的预先存在的记忆 Th 细胞 在一个人的一生中接种疫苗和/或感染各种病原体，但没有激活有害病毒- 特异性T细胞。因此，利用我们基于核酸的疫苗技术，我们将快速生成DNA 通过将刺突蛋白中的 20 个 B 细胞表位基因连接到 MultiTEP 来构建，(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) 生成原型重组疫苗 CoV2- 2019 同时靶向多达三个与中和抗体产生相关的 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）AD/tau蛋白病转基因小鼠模型（老年人疫苗接种的季节性模型） 人和 MCI/AD 患者之前接种过 tau 疫苗，AV-1980）。