Integrative Immunogen Design and Testing

综合免疫原设计和测试

• 批准号: 10328121
• 负责人: Erica Ollmann Saphire
• 金额: $ 262.89万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328121
• 关键词: 2019-nCoV; Animal Disease Models; Animal Model; Animals; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Chiroptera; Coronavirus; Coronavirus Infections; Coronavirus spike protein; Detection; Development; Diagnostic; Disease Outbreaks; Dissociation; Engineering; Ensure; Epitopes; Evaluation; Generations; Genetic Variation; Goals; HIV-2; Hamsters; Hand; Health; Human; Immune Targeting; Immune response; Immunity; Infection; Literature; Measures; Mediating; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Modeling; Molecular Conformation; Mus; Mutation; Pathogenicity; Pattern; Polysaccharides; Positioning Attribute; Proteins; Resistance; SARS coronavirus; Severe Acute Respiratory Syndrome; Structure; T-Lymphocyte; Testing; Vaccinated; Vaccines; Variant; Virion; Virus; Zoonoses; cold temperature; combat; coronavirus vaccine; cross reactivity; cross-species transmission; design; efficacy evaluation; glycosylation; human coronavirus; immunogenicity; improved; innovation; neutralizing antibody; novel; novel coronavirus; particle; pressure; programs; receptor binding; response; thermostability; tool; transmission process; vaccine candidate; viral fitness

Project 3 Summary Coronaviruses will likely remain a persistent threat to human health. However, whether the next significant disease outbreak will be caused by a known coronavirus, another novel coronavirus, or continued surges from variant(s) of SARS-CoV-2 is unknown. The goal of this project is to develop novel, improved immunogens to elicit broader anti-coronavirus immunity, to structurally evaluate resulting pan-coronavirus or broad-coronavirus antibodies, and to evaluate efficacy of broad coronavirus vaccines in animal models. We will begin with novel third-generation spikes that better remain in a pre-fusion quaternary assemblies relative to earlier versions of spike that have been described in the literature. These novel spike proteins, termed “VFLIP”, retain a trimeric conformation even in the absence of exogenous trimerization motifs, are resistant to thermal denaturation, feature glycan structures that better reflect those on authentic virions and offer receptor-binding domain positions and conformation that also better reflect those on native virions. These molecules further feature slower “off” rates for a wide panel of anti-coronavirus antibodies. In this program, we will develop novel immunogens from these improved spikes alone and as part of innovative multimeric vaccine particles. Our collaborating projects will evaluate these immunogens for their ability to elicit broad B- and T-cell immune responses. We will then evaluate the efficacy of the best candidate immunogens in mouse and hamster models of infection using multiple relevant coronaviruses. This project represents the beginning and end of the collaborative, iterative circle of immunogen design and evaluation. Cycles of in-depth evaluation and iteration will shepherd vaccine efforts for broad protection against the growing threat posed by coronaviruses.

项目3总结