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Developing a Multi-epitope Pan-Coronavirus Vaccine

开发多表位泛冠状病毒疫苗

基本信息

批准号：
10231272
负责人：
Lbachir BenMohamed
金额：
$ 71.8万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
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/10231272
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 COVID-19 outbreak COVID-19 severity COVID-19 susceptibility CXCL10 gene CXCL11 gene CXCL9 gene Cells Cessation of life China Chiroptera Coronavirus Coronavirus Infections Country Data Development Disease Disease Outbreaks Elderly Epithelial Epitopes Future 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 SARS-CoV-2 genome SARS-CoV-2 infection Safety Severe Acute Respiratory Syndrome 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 coronavirus vaccine cytokine release syndrome design fighting human coronavirus immunogenicity immunopathology in vitro testing in vivo evaluation innovation mouse model nanoparticle neurotropic neutralizing antibody novel novel coronavirus pandemic disease pre-clinical prevent promoter prophylactic protective efficacy prototype public health emergency universal coronavirus vaccine vaccine candidate vaccine delivery vaccine evaluation vector

项目摘要

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.

概括人类正面临由新型冠状病毒 2 (SARS-CoV-2) 感染引起的大流行。我们的长期短期目标是开发一种有效的预防性泛冠状病毒疫苗，以阻止/减少过去、现在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，过度的促炎细胞因子风暴似乎会导致许多人出现急性呼吸窘迫综合征有症状的个体。主要差距：确定 B 的表位特异性、表型和功能细胞、CD4+ T 细胞和 CD8+ T 细胞与“无症状个体中观察到的自然保护”相关（那些被感染但从未出现任何重大症状的人）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) 确定先验潜在的人类 B 细胞、CD4+ 和 CD8+ T 细胞靶向来自整个 SARS-CoV-2 基因组的表位； (二) 识别以下之间保守且共有的“通用”表位：(1) 以前的 SARS 和 MERS 冠状病毒爆发，(2) 目前在美国流行的 4388 种 SARS-CoV-2 毒株，以及其他 184 个国家； (3) 目前在蝙蝠中发现的具有潜在潜力的 SARS 样冠状病毒株造成未来的人类疫情爆发； (C) 应用我们的可扩展自组装蛋白质纳米粒子 (SAPNs) 抗原递送平台，生产原型多表位泛冠状病毒疫苗候选者，包含人类和蝙蝠冠状病毒的保守保护表位，以及在 HLA 转基因小鼠中证明了它们的 B 细胞和 T 细胞免疫原性； (D) 创作一部小说用于测试的“人源化”易感 HLA-DR/HLA-A*0201/hACE2 三重转基因小鼠模型这些候选疫苗。我们的假设是我们的一种泛冠状病毒候选疫苗，含有保守的“无症状”SARS-CoV-2 B 和 T 细胞表位，这些表位主要被 “受保护”的无症状个体的免疫系统将防止 SARS-CoV-2 感染，并且鼻内给药后发生的疾病。为了检验这一假设，我们的具体目标是：目标 1：在体外测试我们最近从整个 SARS-CoV-2 中鉴定出保守的冠状病毒表位的抗原性基因组，使用来自 SARS-CoV-2 感染的血源性抗体、CD4+ T 细胞和 CD8+ T 细胞有症状与无症状的个体。免疫显性保守的“无症状”表位将被识别并用于我们的多表位泛冠状病毒候选疫苗。目标 2：体内测试高度保守的多表位泛冠状病毒疫苗的安全性、免疫原性和保护功效候选者，经粘膜递送至我们新型的“人源化”易感三重转基因小鼠模型。该临床前疫苗项目的成功完成预计将确定一种具有广泛保护性的泛冠状病毒候选疫苗可能会很快进入 FDA 一期临床试验。