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.

项目总结/摘要 严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）是一种在2004年底发现的新型冠状病毒。 2019年，导致了目前的全球大流行。SARS-CoV-2病毒属于Sarbecovirus亚属， β冠状病毒属，两种与SARS-CoV-2密切相关的病毒（SARS-CoV-1和 MERS-CoV）在过去的17年里已经跨越了人类的物种障碍。这些冠状病毒 通过动物宿主的人畜共患病传播进入人类，突出了对人类的潜在威胁。 未来的溢出效应。因此，制定干预战略，可以减轻未来的爆发， 冠状病毒至关重要。为了为未来的冠状病毒（CoV）大流行做准备，期望产生疫苗， 能够引发针对不同CoV的中和抗体（nAb）应答。目前有两大 开发针对冠状病毒的预防性疫苗策略的挑战; 1）CoV刺突的鉴定 用于疫苗靶向的广泛中和抗体（bnAb）位点;以及2）疫苗策略的开发 其可以可重复地诱导针对广泛冠状病毒的持久和保护性bnAb应答。在 在R 01拨款申请中，我们将通过采用基于bnAb表位的 合理的疫苗设计方法，以开发免疫原和免疫策略， 冠状病毒保护性bnAb应答。该项目包括3个目标：目标#1将设计新颖的 使用合理的反向疫苗工程方法，刺入靶向疫苗免疫原的S2茎bnAb位点。 使用CoV刺突S2茎螺旋bnAb和它们的UCA，我们将设计基于CoV S2茎肽的纳米颗粒， 合理工程化的S2 bnAb生殖系靶向S蛋白三聚体免疫原及其多聚化 可以有效地在体内激活靶向保守的S2干细胞区的B细胞前体的纳米颗粒形式 β冠状病毒峰值目标#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，以开发疫苗方案， 针对不同β-CoV的保护性bnAb应答。我们将评估疫苗的体内保护效力- 在适当的病毒攻击模型中诱导bnAb应答。目标#3将生成加标S2茎螺旋bnAb 利用合理的抗体工程方法构建抗β-冠状病毒的“超级抗体”。的 这项R 01拨款提案的总体目标是合理设计新的疫苗免疫原候选物，开发 稳健的疫苗接种策略，可诱导针对广泛β- 冠状病毒和开发“超级抗体”分子有希望为广泛的冠状病毒干预策略 减轻SARS-CoV-2变异的关注和新出现的冠状病毒作为大流行准备的一部分。