Development of pan-betacoronavirus vaccines

泛β冠状病毒疫苗的研制

• 批准号: 10660881
• 负责人: Raiees Ahmad Andrabi
• 金额: $ 80.56万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-03 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10660881
• 关键词: 2019-nCoV; Address; Affinity; Animal Model; Animals; Antibodies; Antibody Response; Antigens; Applications Grants; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Binding; COVID-19; Coronavirus; Coronavirus Infections; Coronavirus spike protein; Development; Directed Molecular Evolution; Elements; Engineering; Epitopes; Future; Genetic; Germ Cells; Goals; Health; Human; Immune response; In Vitro; Intervention; Knowledge; Methods; Middle East Respiratory Syndrome Coronavirus; Modeling; Molecular; Peptides; Preventive vaccine; Property; Protein Engineering; Proteins; Reproducibility; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 variant; Sarbecovirus; Site; Testing; Translating; Vaccination; Vaccine Design; Vaccines; Virus; Work; Zoonoses; antibody engineering; betacoronavirus; betacoronavirus vaccine; coronavirus pandemic; coronavirus vaccine; current pandemic; design; future outbreak; human coronavirus; in vivo; nanoparticle; neutralizing antibody; novel; novel coronavirus; novel vaccines; outbreak control; pandemic coronavirus; pandemic disease; pandemic potential; pandemic preparedness; pre-clinical; protective efficacy; prototype; rational design; research clinical testing; respiratory; stem; therapy development; tool; transmission process; universal coronavirus vaccine; vaccination protocol; vaccination strategy; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine platform; vaccine strategy; vaccine trial; vaccine-induced antibodies; variants of concern; welfare

PROJECT SUMMARY/ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus identified at the end of 2019, has led to the current global pandemic. The SARS-CoV-2 virus belongs to the subgenus sarbecovirus of the genus betacoronavirus, the genus from which two SARS-CoV-2 closely related viruses (SARS-CoV-1 and MERS-CoV) have crossed the species barrier to humans in the past 17 years. These coronaviruses have crossed into humans through zoonotic transmissions from animal reservoirs highlighting a potential threat for future spillovers. Therefore, development of intervention strategies that can mitigate outbreaks of future coronaviruses is critical. To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting neutralizing antibody (nAb) responses against diverse CoVs. Currently there are two major challenges to develop prophylactic vaccine-based strategies against coronaviruses; 1) identification of CoV spike broadly neutralizing antibody (bnAb) sites for vaccine targeting; and 2) the development of vaccine strategies that can reproducibly induce durable and protective bnAb responses against a broad range of coronaviruses. In this R01 grant application, we will squarely address these knowledge gaps by employing a bnAb epitope based rational vaccine design approach to develop immunogens and immunization strategies that can induce coronavirus protective bnAb responses by vaccination. The project consists of 3 aims: Aim #1 will design novel spike S2 stem bnAb site targeting vaccine immunogens using a rational reverse vaccine engineering approach. Using CoV spike S2 stem helix bnAbs and their UCAs we will design, CoV S2 stem peptide-based nanoparticles, rationally engineered S2 bnAb germline-targeting S-protein trimer immunogens and their multimerized nanoparticle versions that can efficiently in vivo activate B cell precursors targeting the S2 stem region conserved across β-CoV spikes. Aim #2 will iteratively evaluate and optimize prime boost immunization strategies in appropriate pre-clinical animal models to develop vaccine protocols that can reproducibly induce durable and protective bnAb responses against diverse β-CoVs. We will assess the in vivo protective efficacy of the vaccine- induced bnAb responses in appropriate virus challenge models. Aim #3 will generate spike S2 stem helix bnAb based “super antibodies” against β-coronaviruses by utilizing rational antibody engineering approaches. The overall goal of this R01 grant proposal is to rationally design novel vaccine immunogen candidates, develop robust vaccination strategies that can induce durable protective bnAb responses against a broad range of β- coronaviruses and develop “super antibody” molecules promising for broad coronaviruses intervention strategies to mitigate SARS-CoV-2 variants of concern and emerging coronaviruses as part of pandemic preparedness.

项目概要/摘要 严重急性呼吸综合征冠状病毒 2（SARS-CoV-2），一种于 2019 年年底鉴定出的新型冠状病毒 2019 年，导致了当前全球大流行的 SARS-CoV-2 病毒属于 sarbecovirus 亚属。 β冠状病毒属，该属中有两种与 SARS-CoV-2 密切相关的病毒（SARS-CoV-1 和 在过去的 17 年里，中东呼吸综合征冠状病毒 (MERS-CoV) 已经跨越了物种障碍，传染给了人类。 通过动物宿主的人畜共患传播传染给人类，这凸显了对人类的潜在威胁 因此，制定可以减轻未来爆发的干预策略。 冠状病毒至关重要，为了应对未来的冠状病毒（CoV）大流行，需要生产疫苗。 能够引发针对多种冠状病毒的中和抗体（nAb）反应，目前主要有两种。 开发针对冠状病毒的预防性疫苗策略面临的挑战；1) 冠状病毒尖峰的识别； 用于疫苗靶向的广泛中和抗体（bnAb）位点；2）制定疫苗策略； 可以重复地诱导针对多种冠状病毒的持久和保护性 bnAb 反应。 在这个 R01 拨款申请中，我们将通过采用基于 bnAb 表位的方法来直接解决这些知识差距 合理的疫苗设计方法来开发可诱导的免疫原和免疫策略 通过疫苗接种产生冠状病毒保护性 bnAb 反应 该项目包含 3 个目标： 目标 1 将设计新颖的产品。 使用合理的反向疫苗工程方法，将 S2 干 bnAb 位点靶向疫苗免疫原。 使用 CoV 刺突 S2 茎螺旋 bnAb 及其 UCA，我们将设计基于 CoV S2 茎肽的纳米颗粒， 合理设计的 S2 bnAb 种系靶向 S 蛋白三聚体免疫原及其多聚化 纳米颗粒版本可在体内有效激活针对保守的 S2 干区的 B 细胞前体 目标 #2 将迭代评估和优化初免加强免疫策略。 适当的临床前动物模型来开发疫苗方案，可以重复地诱导持久和 我们将评估疫苗的体内保护功效。 在适当的病毒攻击模型中诱导 bnAb 反应，目标#3 将产生尖峰 S2 茎螺旋 bnAb。 利用合理的抗体工程方法，开发出针对β冠状病毒的“超级抗体”。 这项 R01 拨款提案的总体目标是合理设计新型候选疫苗免疫原，开发 强有力的疫苗接种策略，可以诱导针对多种 β- 的持久保护性 bnAb 反应 冠状病毒并开发“超级抗体”分子，有望用于广泛的冠状病毒干预策略 作为大流行防范的一部分，减轻人们关注的 SARS-CoV-2 变种和新出现的冠状病毒的影响。