Structure-based design of broadly protective coronavirus vaccines

基于结构的广泛保护性冠状病毒疫苗的设计

• 批准号: 10425024
• 负责人: Neil King
• 金额: $ 906.54万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425024
• 关键词: Adjuvant; Animal Model; Animals; Antibodies; Antibody Response; Antigens; COVID-19 pandemic; Communities; Computing Methodologies; Coronavirus; Development; Epitopes; Evolution; Funding; Future; Geometry; Glycoproteins; Goals; HIV-1; Hemagglutinin; Human; Humoral Immunities; Immunity; Immunology; Influenza; Influenza Hemagglutinin; Intervention; Knowledge; Lead; Mosaicism; Output; Performance; Phase; Phase I/II Clinical Trial; Phylogeny; Proteins; Public Health; Research; Resolution; Sarbecovirus; Science; Secure; Structure; Technology; Technology Transfer; Therapeutic antibodies; Vaccine Design; Vaccines; Viral; Virus; Work; Zoonoses; animal model development; base; betacoronavirus; betacoronavirus vaccine; clinically relevant; coronavirus disease; coronavirus vaccine; cross reactivity; design; human model; industry partner; model development; mortality; multidisciplinary; mutation screening; nanoparticle; neutralizing antibody; nonhuman primate; novel; pandemic coronavirus; pandemic disease; programs; public health priorities; resistance mutation; response; reverse genetics; scaffold; structural biology; support tools; synergism; tool; tool development; vaccine candidate; vaccine development; virology; zoonotic spillover

PROJECT SUMMARY – OVERALL: Structure-based design of broadly protective coronavirus vaccines We propose a highly synergistic research Program focused on developing two broadly protective coronavirus vaccine candidates: a pan-sarbecovirus vaccine at the end of Year 2, and a pan-betacoronavirus at the end of Year 5. Our Program brings together six research groups with complementary and synergistic expertise in structure-based vaccine design, coronavirus structural biology and immunity, the immunology of vaccines, animal model development, and viral evolution. This team emerged in response to the SARS-CoV-2 pandemic to rapidly develop an ultrapotent protein nanoparticle vaccine that is currently in Phase I/II clinical trials, with funding secured for Phase III. Our Program comprises three Scientific Projects supported by four Scientific Cores and an Administrative Core. This structure will allow maximal synergy between our groups in pursuit of the three central outputs of our Program: Tools, Antibodies, and Vaccines. Tools: we will develop reverse genetic platforms for producing panels of wild-type and indicator viruses and new animal models of human coronavirus disease that can be used to assess neutralizing and protective breadth. We will also develop platforms for deep mutational scanning of spike proteins spanning the betacoronavirus phylogeny to inform antigen design and model development and assess the breadth and mutational resistance of vaccine-elicited antibodies. Antibodies: our Program will identify conserved epitopes in betacoronavirus spike proteins targeted by cross-reactive antibodies, and characterize the structural basis for broad neutralization and protection at high resolution. This information will be used to iteratively inform structure-based antigen and vaccine design and will generate antibody therapeutics that could blunt the effects of future zoonotic spillovers. Vaccines: we recently showed that co-displaying multiple hemagglutinin antigens on the same self-assembling protein nanoparticle, an approach termed mosaic nanoparticle display, induced broadly protective humoral immunity against influenza. We will combine this approach with cutting-edge computational methods for stabilizing glycoprotein antigens and designing nanoparticle scaffolds tailored to display coronavirus spikes in optimal geometries. We expect the resultant nanoparticle vaccine candidates to elicit potent and broadly protective antibody responses against conserved epitopes in betacoronavirus spikes. We will mechanistically and functionally evaluate the performance of these vaccine candidates formulated with clinically relevant adjuvants in relevant animal models, including nonhuman primates. To facilitate successful transfer to industry partners, we will prepare technology transfer packages for the two lead vaccine candidates that will be produced by our Program: a pan-sarbecovirus vaccine at the end of Year 2, and a pan-betacoronavirus vaccine at the end of Year 5.

项目总结-总体：基于结构的广泛保护性冠状病毒疫苗设计 我们提出了一个高度协同的研究计划，专注于开发两种广泛保护的冠状病毒 候选疫苗：第二年年底接种泛肉瘤病毒疫苗，第二年年底接种泛贝塔冠状病毒 第五年。我们的计划汇集了六个研究小组，他们在以下领域具有互补和协同的专业知识 基于结构的疫苗设计，冠状病毒结构生物学与免疫学，疫苗免疫学， 动物模型的发展和病毒的进化。这个团队是为应对SARS-CoV-2大流行而成立的 快速开发目前处于I/II阶段临床试验的超强蛋白纳米疫苗， 我们的计划包括三个由四个科学核心支持的科学项目 和一个管理核心。这一结构将使我们的团队在追求三个目标的过程中实现最大程度的协同 我们项目的中心成果：工具、抗体和疫苗。工具：我们将开发反向遗传平台 用于制作野生型和指示性病毒面板以及人类冠状病毒病的新动物模型 这可以用来评估中和和保护的广度。我们还将为深度开发平台 对跨越贝塔冠状病毒系统发育的刺突蛋白的突变扫描，以告知抗原设计和 模型开发和评估疫苗引发抗体的广度和突变抗性。抗体： 我们的计划将确定以交叉反应为靶点的贝塔冠状病毒刺突蛋白中的保守表位 抗体，并表征了高分辨率的广泛中和和保护的结构基础。这 信息将被用于迭代地告知基于结构的抗原和疫苗设计，并将生成 抗体疗法可能会削弱未来人畜共患病的溢出效应。疫苗：我们最近展示了 一种在同一自组装蛋白纳米颗粒上共展示多个血凝素抗原的方法 被称为镶嵌纳米颗粒展示，诱导对流感的广泛保护性体液免疫。我们会 将这种方法与稳定糖蛋白抗原的尖端计算方法相结合 设计定制的纳米颗粒支架，以最佳几何形状显示冠状病毒尖峰。我们期待着 由此产生的纳米颗粒候选疫苗可诱导有效和广泛的保护性抗体反应 贝塔冠状病毒尖峰中的保守表位。我们将从机械和功能上对性能进行评估 在相关动物模型中，使用临床相关佐剂配制的候选疫苗包括 非人灵长类动物。为了促进向行业伙伴的成功转移，我们将准备技术转移 我们计划将生产的两种主要候选疫苗的包装：泛肉瘤病毒疫苗 在第二年年底，并在第五年年底接种泛贝塔冠状病毒疫苗。

项目成果

Persistent immune imprinting after XBB.1.5 COVID vaccination in humans.

人类接种 XBB.1.5 COVID 疫苗后出现持续免疫印记。

• DOI: 10.1101/2023.11.28.569129
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Tortorici,MAlejandra;Addetia,Amin;Seo,AlbertJ;Brown,Jack;Sprouse,KaitlinR;Logue,Jenni;Clark,Erica;Franko,Nicholas;Chu,Helen;Veesler,David
• 通讯作者: Veesler,David

Neutralization, effector function and immune imprinting of Omicron variants.

• DOI: 10.1038/s41586-023-06487-6
• 发表时间: 2023-09
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Addetia, Amin;Piccoli, Luca;Case, James Brett;Park, Young-Jun;Beltramello, Martina;Guarino, Barbara;Dang, Ha;de Melo, Guilherme Dias;Pinto, Dora;Sprouse, Kaitlin;Scheaffer, Suzanne M.;Bassi, Jessica;Silacci-Fregni, Chiara;Muoio, Francesco;Dini, Marco;Vincenzetti, Lucia;Acosta, Rima;Johnson, Daisy;Subramanian, Sambhavi;Saliba, Christian;Giurdanella, Martina;Lombardo, Gloria;Leoni, Giada;Culap, Katja;Mcalister, Carley;Rajesh, Anushka;Dellota, Exequiel;Zhou, Jiayi;Farhat, Nisar;Bohan, Dana;Noack, Julia;Chen, Alex;Lempp, Florian A.;Quispe, Joel;Kergoat, Lauriane;Larrous, Florence;Cameroni, Elisabetta;Whitener, Bradley;Giannini, Olivier;Cippa, Pietro;Ceschi, Alessandro;Ferrari, Paolo;Franzetti-Pellanda, Alessandra;Biggiogero, Maira;Garzoni, Christian;Zappi, Stephanie;Bernasconi, Luca;Kim, Min Jeong;Rosen, Laura E.;Schnell, Gretja;Czudnochowski, Nadine;Benigni, Fabio;Franko, Nicholas;Logue, Jennifer K.;Yoshiyama, Courtney;Stewart, Cameron;Chu, Helen;Bourhy, Herve;Schmid, Michael A.;Purcell, Lisa A.;Snell, Gyorgy;Lanzavecchia, Antonio;Diamond, Michael S.;Corti, Davide;Veesler, David
• 通讯作者: Veesler, David

A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines.

一种广泛适用的 sarbecovirus 融合机器疫苗的稳定策略。

• DOI: 10.1101/2023.12.12.571160
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Lee,Jimin;Stewart,Cameron;Schaefer,Alexandra;Leaf,ElizabethM;Park,Young-Jun;Asarnow,Daniel;Powers,JohnM;Treichel,Catherine;Corti,Davide;Baric,Ralph;King,NeilP;Veesler,David
• 通讯作者: Veesler,David