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/文摘