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).

项目摘要 在美国首次报告COVID-19死亡两个月后，死亡率为每百万人228人， 全球排名第十。45-54岁人群的COVID-19死亡率约为5%， 在50-60岁的人群中，这一比例为13%，可悲的是，美国80%的冠状病毒死亡病例发生在65岁以上的人群中。 年龄和年龄更大。为了保护人们免受COVID-19的影响，世界各地的多个团体已经开始 根据SARS-CoV-2的基因序列研制疫苗。我们不知道细胞和 体液免疫应答对于预防SARS-CoV-2是必要的，但最近的数据显示， 对COVID-19患者的恢复期血浆给药表明，疫苗诱导中和 抗体可能足以防止这种感染。更重要的是，疫苗有可能 含有目前未知的SARS-CoV-2的T细胞表位的疫苗可以在免疫受试者中诱导细胞因子 随后的病毒感染可能导致严重的不良事件，最终导致死亡， 尤其是老年人。为了避免自身反应性T细胞活化，使用当前AG 060965 计划和其他NIA赠款，我们已经开发了一种通用的和极免疫原性的MultiTEP疫苗 靶向病理性Aβ、tau和α-Syn的AD疫苗平台。利用这一发展，我们 在本行政补充文件中，我建议根据专利MultiTEP创建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患者的抗体。这种疫苗可能不同于许多 另一些是因为它可以刺激适应性免疫，提供了人类MHC多态性的广泛覆盖 以及激活初始Th细胞和预先存在的记忆Th细胞两者，所述记忆Th细胞响应于常规免疫应答而产生。 疫苗和/或在人的一生中感染各种病原体，而不会激活有害病毒- 特异性T细胞因此，利用我们的核酸疫苗技术， 通过将来自刺突蛋白的20个B细胞表位基因连接到MultiTEP构建体，（ii）选择几个B细胞表位基因， 在小鼠中诱导病毒中和抗体的表位，（iii）产生原型重组疫苗，CoV 2- 2019同时靶向与中和抗体产生相关的多达三个B细胞表位。 这种多表位CoV 2 -2019疫苗将在老年非人灵长类动物中进行测试（与年龄相关的模型）。 A.D./A.D.转基因小鼠模型tau病（老年人疫苗接种的季节性模型 人和先前用tau疫苗AV-1980接种的MCI/AD患者）。