A Novel Multi-Epitope-Based Universal Vaccine Against Multiple Coronavirus Variants of Concern

一种针对多种冠状病毒变体的新型多表位通用疫苗

• 批准号: 10603075
• 负责人: Hawa Vahed
• 金额: $ 30万
• 依托单位: TECHIMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603075
• 关键词: 2019-nCoV; Affect; Amino Acid Sequence; Antigen Targeting; Antigens; Authorization documentation; B-Lymphocytes; Brain; CD8B1 gene; COVID-19; COVID-19 outbreak; COVID-19 pandemic; COVID-19 patient; COVID-19 vaccine; Cells; Cessation of life; China; Coronavirus; Country; DNA Sequence Alteration; Disease; Disease Outbreaks; Epitopes; Future; Generations; Genome; Goals; HLA A*0201 antigen; HLA-DR Antigens; Human; Humanities; Immune system; Immunity; Infection; Lead; Lung; Messenger RNA; Mutate; Mutation; Outcome; Pathogenicity; Phase I Clinical Trials; Preclinical Testing; Predisposition; Proteins; Province; Reporting; Risk; SARS-CoV-2 B.1.1.529; SARS-CoV-2 genome; SARS-CoV-2 infection; SARS-CoV-2 variant; Safety; Seasons; South Africa; Speed; Subunit Vaccines; System; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Transgenic Mice; Vaccines; Viral Antigens; Virus; asymptomatic COVID-19; authority; cell mediated immune response; coronavirus disease; design; design and construction; humanized mouse; immunogenic; immunogenicity; innovation; mRNA delivery; mouse model; neutralizing antibody; novel; novel coronavirus; pandemic disease; pre-clinical; protective efficacy; prototype; public health emergency; universal coronavirus vaccine; universal vaccine; vaccine access; vaccine candidate; vaccine platform; variants of concern

SUMMARY Over the last 2 years humanity has been confronting COVID-19 pandemic caused by the new Corona Virus 2 (SARS-CoV-2) infection. Major gaps: Mutations and deletions often occur in the genome of SARS-CoV-2 (predominantly in the Spike protein) resulting in more transmissible and pathogenic “variants of concern” (VOCs) that can escape immunity conferred by first generation COVID-19 vaccines. Because most mutations and deletions that produced the 20 known VOCs are concentrated on the Spike protein, there is a risk that current COVID-19 sub-unit vaccines based on the Spike protein will fail to protect against future VOCs despite inducing strong virus-specific neutralizing antibodies against the original virus strain. Among the 80 mutations/deletions present in OMICRON variant, 32 mutations/deletions are concentrated in the sequence Spike protein alone. This emphasizes two major limitations of currently available vaccines: The need for second-generation universal coronavirus vaccines that (1) target antigens (Ags) other than the highly variable Spike protein; and (2) incorporate both B- and T-cell epitopes from Spike and non-Spike Ags that are highly conserved in all 20 VOCs and that will induce strong humoral and cell-mediated immune responses. Our long-term goal is to develop a potent second generation universal CoV vaccine to stop/reduce SARS-CoV-2 infections and disease caused by multiple VOCs. Preliminary Results: We: (1) Identified highly immunogenic human B and T cell target epitopes from the whole SARS-CoV-2 genome; (2) Characterized human T cell epitopes from the whole SARS-CoV-2 genome that are selectively targeted by the “protective” immune system from asymptomatic COVID-19 patients; and (3) Produced a first prototype multi-epitope universal CoV vaccine candidate using the validated mRNA delivery system platform, and (4) Created novel “humanized” susceptible HLA-DR/HLA-A*0201/hACE2 triple transgenic mouse model with which to test 7 additional multi-epitope universal CoV vaccine candidates that bear different highly conserved human B and T cell epitopes spanning the entire CoV genome. We hypothesize that one or more of our 7 universal vaccine candidates will protect “humanized” mice from infection and disease caused by intranasal inoculation with SARS-CoV-2 a, b, g, d and Omicron VOCs. Our Specific Aims are: Aim 1: To design and construct 7 additional mRNA-based universal vaccine candidates that will incorporate highly conserved B and T cell epitopes selected from 20 VOCs. Aim 2: To determine the safety, immunogenicity, and protective efficacy against SARS-CoV-2 a, b, g, d or Omicron VOCs of 7 multi-epitope universal CoV vaccine candidates delivered intranasally in the “humanized” HLA-DR/HLA-A*0201/hACE2 mouse model. The durability of protection and its correlation with blocking/neutralizing antibodies and the number and function of CoV-specific CD4+ and CD8+ TRM cells that reside in the lungs and brains will be determined. If successful, the lead universal CoV vaccine that protects against most of the 5 VOCs could proceed quickly into an FDA Phase 1 clinical trial

概括 在过去的两年中 （SARS-COV-2）感染。主要差距：突变和缺失通常发生在SARS-COV-2的基因组中 （主要是在峰值蛋白中），导致更多可传播和致病的“关注变体”（VOC） 可以避免第一代Covid-19疫苗赋予的免疫力。因为大多数突变和 产生20个已知VOT的缺失集中在峰值蛋白上，存在风险。 基于峰值蛋白的COVID-19-19子单位疫苗将无法防止诱导未来的VOC目的地 针对原始病毒菌株的强病毒特异性中和抗体。在80个突变/删除中 存在于Omicron变体中，仅在序列尖峰蛋白中集中了32个突变/缺失。这 强调当前可用疫苗的两个主要局限性：第二代环球的需求 冠状病毒疫苗（1）靶向抗原（AG），而不是高度可变的峰值蛋白； （2） 在所有20个VOC中都高度保守的尖峰和非尖峰AG的B-和T细胞表位 这将引起强烈的体液和细胞介导的免疫复杂。我们的长期目标是开发 潜在的第二代通用COV疫苗，以停止/减少SARS-COV-2感染和疾病 多个VOC。初步结果：WE：（1）鉴定出高度免疫原性的人B和T细胞靶标 来自整个SARS-COV-2基因组； （2）表征了整个SARS-COV-2的人类T细胞表位 基因组由非对称COVID患者的“保护性”免疫系统有选择地靶向； （3）使用经过验证的mRNA产生了第一个原型多质蛋白COV疫苗候选者 交付系统平台，（4）创建了新颖的“人性化”敏感HLA-DR/HLA-A*0201/HACE2三重 转基因小鼠模型可以测试7个其他多质蛋白COV疫苗的候选者 不同的高度组成的人B和T细胞表位跨越整个COV基因组。我们假设这一点 我们7种通用疫苗候选者中的一个或多个将保护“人性化”小鼠免受感染和疾病的影响 由SARS-COV-2 A，B，G，D和OMICRON VOC的鼻内接种引起。我们的具体目标是：目标 1：设计和构建7个基于mRNA的额外的通用疫苗候选物，这些疫苗将高度合并 从20个VOC中选择了保守的B和T细胞表位。目标2：确定安全性，免疫原性和 针对7个多蛋白质通用COV疫苗的SARS-COV-2 A，B，G，D或OMICRON VOC的保护效率 候选人在“人性化的” HLA-DR/HLA-A*0201/HACE2小鼠模型中进行了鼻内交付。耐用性 保护及其与阻塞/中和抗体的相关性以及COV特异性的数量和功能 将确定存在于肺和大脑中的CD4+和CD8+ TRM细胞。如果成功，则是普遍的领导 预防5个VOC中大多数的COV疫苗可以迅速进入FDA 1阶段临床试验