Developing a Multi-epitope Pan-Coronavirus Vaccine

开发多表位泛冠状病毒疫苗

• 批准号: 10171239
• 负责人: Lbachir BenMohamed
• 金额: $ 74.54万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-07 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171239
• 关键词: 2019-nCoV; Adult Respiratory Distress Syndrome; Antibodies; Antigens; B-Lymphocytes; Blood; Body Weight decreased; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; CXCL10 gene; CXCL11 gene; CXCL9 gene; Cells; Cessation of life; China; Chiroptera; Coronavirus; Coronavirus Infections; Country; Data; Development; Disease; Disease Outbreaks; Elderly; Epithelial; Epithelium; Epitopes; Future; Genome; Goals; HLA A*0201 antigen; HLA-DR Antigens; Health; Histopathology; Human; Immune response; Immune system; Immunization; Individual; Infection; Inflammatory; Inflammatory Response; Intervention; Lead; Legal patent; Lung; Medical; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Minority; Mucous Membrane; Outcome; Phase I Clinical Trials; Phenotype; Pneumonia; Preclinical Testing; Preparation; Proteins; Province; Route; SARS coronavirus; Safety; Severe Acute Respiratory Syndrome; Severity of illness; Specificity; Structure of parenchyma of lung; Symptoms; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Tissues; Transgenes; Transgenic Mice; United States; Vaccines; Virus Diseases; authority; base; brain tissue; chemokine; coronavirus disease; cytokine release syndrome; design; fighting; human coronavirus; immunogenicity; immunopathology; in vitro testing; in vivo evaluation; innovation; mouse model; nanoparticle; neurotropic; neutralizing antibody; novel; pandemic disease; pre-clinical; prevent; promoter; prophylactic; protective efficacy; prototype; public health emergency; vaccine candidate; vaccine delivery; vaccine evaluation; vector

SUMMARY Humanity is confronting a pandemic caused by the new Corona Virus 2 (SARS-CoV-2) infection. Our long- term goal is to develop a potent prophylactic pan-Coronavirus vaccine to stop/reduce past, current and future Coronavirus infections and/or diseases. While SARS-CoV-2-induced antibody and CD4+ and CD8+ T cell responses are critical to reducing viral infection in the majority of asymptomatic individuals, an excessive proinflammatory cytokine storm appears to lead to acute respiratory distress syndrome in many symptomatic individuals. Major gaps: Identifying the epitope specificities, the phenotype and function of B cells, CD4+ T cells and CD8+ T cells associated with “natural protection seen in asymptomatic individuals (those who are infected, but never develop any major symptoms) should guide the development of a future coronavirus vaccine. Preliminary Results: We have made significant progress in: (A) Identifying a priori potential human B-cell, CD4+ and CD8+ T cell target epitopes from the whole SARS-CoV-2 genome; (B) Identifying “universal” epitopes conserved and common between: (1) previous SARS and MERS coronavirus outbreaks, (2) current 4388 SARS-CoV-2 strains that now circulate in the United States and 184 other countries; and (3) SARS-like coronavirus strains currently found in bats that have the potential to produce future human outbreaks; (C) Applying our scalable self-assembling protein nanoparticles (SAPNs) antigen delivery platform to produce prototype multi-epitope pan-Coronavirus vaccine candidates, that incorporate conserved protective epitopes from human and bats Coronaviruses, and demonstrated their B- and T-cell immunogenicity in HLA transgenic mice; and (D) Generating a novel “humanized” susceptible HLA-DR/HLA-A*0201/hACE2 triple transgenic mouse model in which to test these vaccine candidates. Our hypothesis is that one of our pan-Coronavirus vaccine candidates, containing conserved “asymptomatic” SARS-CoV-2 B- and T-cell epitopes that are mainly recognized by the immune system of “protected,” asymptomatic individuals would protect from SARS-CoV-2 infection and disease, upon intranasal delivery. To test this hypothesis our Specific Aims are: Aim 1: To test in vitro the antigenicity of conserved Coronavirus epitopes, we recently identified from the whole SARS-CoV-2 genome, using blood-derived antibodies, CD4+ T-cells and CD8+ T-cells from SARS-CoV-2-infected symptomatic vs. asymptomatic individuals. The immunodominant conserved “asymptomatic” epitopes will be identified and used in our multi-epitope pan-Coronavirus vaccine candidates. Aim 2: To test in vivo the safety, immunogenicity, and protective efficacy of highly conserved multi-epitope pan-Coronavirus vaccine candidates, delivered mucosally, to our novel “humanized” susceptible triple transgenic mouse model. Successful completion of this preclinical vaccine project is expected to identify a broadly protective pan- Coronavirus vaccine candidate that could quickly proceed into an FDA Phase 1 clinical trial.

概括 人类正在面对由新的电晕病毒2（SARS-COV-2）感染引起的大流行。我们的长期 术语目标是开发一种有效的预防性泛环病毒疫苗，以停止/减少过去，当前和 未来的冠状病毒感染和/或疾病。而SARS-COV-2诱导的抗体以及CD4+和CD8+ T细胞反应对于减少大多数无症状个体的病毒感染至关重要， 过多的促炎细胞因子风暴似乎导致许多​​急性呼吸窘迫综合征 有症状的人。主要差距：识别发作规范，B的表型和功能 细胞，CD4+ T细胞和CD8+ T细胞与“无症状的个体中看到的自然保护相关的细胞 （被感染但从未出现任何主要症状的人）应该指导未来的发展 冠状病毒疫苗。初步结果：我们在以下方面取得了重大进展：（a）确定先验 来自整个SARS-COV-2基因组的潜在人B细胞，CD4+和CD8+ T细胞靶位表位； （b） 识别构成和共同的“通用”表位：（1）先前的SARS和MERS 冠状病毒爆发，（2）当前的4388 SARS-COV-2菌株现在在美国流通 184个其他国家； （3）目前在具有潜力的蝙蝠中发现的类似SARS的冠状病毒菌株 产生未来的人类暴发； （c）应用我们的可扩展的自组装蛋白纳米颗粒 （SAPNS）抗原输送平台以生产原型多肠盘泛病毒疫苗 候选人，纳入人类和蝙蝠冠状病毒的受保护表位，以及 在HLA转基因小鼠中证明了它们的B和T细胞免疫原性； （d）产生小说 “人性化”易感HLA-DR/HLA-A*0201/HACE2三重转基因小鼠模型在其中进行测试 这些疫苗候选物。我们的假设是，我们的泛氧化病毒疫苗之一， 包含构成的“无症状” SARS-COV-2 B和T细胞表位，主要由 “受保护”的免疫系统无症状的个体将免受SARS-COV-2感染和 疾病，鼻内分娩。为了检验这一假设，我们的具体目的是：目标1：在体外测试 组成的冠状病毒表位的抗原性，我们最近从整个SARS-COV-2中确定 基因组，使用血液衍生的抗体，CD4+ T细胞和来自SARS-COV-2感染的CD8+ T细胞 有症状与无症状的个体。免疫主导构成的“无症状”表位将 可以识别并在我们的多肠病毒疫苗候选物中使用。目标2：在体内测试 高度保守的多肠病毒疫苗的安全性，免疫原性和受保护的效率 候选者以粘液递送给我们新颖的“人性化”易感三重转基因小鼠模型。 预计该临床前疫苗项目的成功完成将确定广泛保护的泛池 可以快速进入FDA 1期临床试验的冠状病毒疫苗候选者。