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

总结 在过去的2年里，人类一直面临由新冠状病毒2引起的COVID-19大流行 （SARS-CoV-2）感染。主要空白：突变和缺失经常发生在SARS-CoV-2的基因组中 （主要存在于刺突蛋白中），导致更多的传染性和致病性“关注变体”（VOC） 可以逃避第一代COVID-19疫苗所赋予的免疫力。因为大多数突变和 产生20种已知VOC的缺失集中在刺突蛋白上，因此存在当前VOC缺失的风险。 基于刺突蛋白的COVID-19亚单位疫苗尽管诱导了新冠病毒的产生， 针对原始病毒株的强病毒特异性中和抗体。在80个突变/缺失中， 在OMICRON变体中，32个突变/缺失仅集中在刺突蛋白序列中。这 强调了目前可用疫苗的两个主要局限性：需要第二代普及疫苗， 冠状病毒疫苗，（1）靶向抗原（Ag）而不是高度可变的刺突蛋白;和（2） 掺入来自刺突和非刺突Ag的B-和T-细胞表位，所述刺突和非刺突Ag在所有20种VOC中高度保守 并且将诱导强烈的体液和细胞介导的免疫应答。我们的长期目标是发展一个 有效的第二代通用冠状病毒疫苗，以阻止/减少SARS-CoV-2感染和疾病引起的 多种VOC。初步结果：（1）鉴定了高免疫原性的人B和T细胞靶表位 从SARS-CoV-2全基因组中获得的人T细胞表位 无症状COVID-19患者的“保护性”免疫系统选择性靶向的基因组; 以及（3）使用经验证的mRNA产生第一原型多表位通用CoV疫苗候选物 （4）创造了新的“人源化”易感HLA-DR/HLA-A*0201/hACE 2三联体 转基因小鼠模型，用于测试7种额外的多表位通用CoV疫苗候选物， 跨越整个CoV基因组的不同的高度保守的人B和T细胞表位。我们假设 我们的7种通用候选疫苗中的一种或多种将保护“人源化”小鼠免受感染和疾病 鼻内接种SARS-CoV-2 a、B、g、d和Omicron VOCs引起。我们的目标是：目标 1：设计和构建7种额外的基于mRNA的通用候选疫苗， 选自20种VOC的保守B和T细胞表位。目的2：确定安全性，免疫原性， 7种多表位通用冠状病毒疫苗对SARS-CoV-2 a、B、g、d或Omicron VOCs的保护效力 在“人源化”HLA-DR/HLA-A*0201/hACE 2小鼠模型中鼻内递送的候选物。耐久性 保护作用及其与阻断/中和抗体的相关性，以及CoV特异性抗体的数量和功能。 将测定肺和脑中的CD 4+和CD 8 + TRM细胞。如果成功的话， 保护5种挥发性有机化合物中的大多数的CoV疫苗可以迅速进入FDA的1期临床试验