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.

项目摘要 - 总体：基于结构的冠状病毒疫苗的设计 我们提出了一项高度协同的研究计划，旨在开发两个广泛保护的冠状病毒 候选疫苗：第二年末的泛 - 萨尔贝病毒疫苗，以及一个末端的泛贝曲霉病毒 5年级。我们的计划汇集了六个具有完整和协同专业知识的研究小组 基于结构的疫苗设计，冠状病毒结构生物学和免疫学，疫苗的免疫学， 动物模型的发展和病毒进化。该团队响应SARS-COV-2大流行而出现 快速开发目前正在I/II期临床试验中的超能力蛋白纳米粒子疫苗 第三阶段的资金。我们的计划包括由四个科学核心支持的三个科学项目 和行政核心。这种结构将允许我们的小组之间的最大协同作用，以追求这三个 我们计划的中心输出：工具，抗体和疫苗。工具：我们将开发反向遗传平台 用于生产野生型和指标病毒的面板以及人类冠状病毒疾病的新动物模型 可以用来评估中和和保护广度。我们还将为深度开发平台 跨越BETACORONAVIRUS系统发育的尖峰蛋白的突变扫描，以告知抗原设计和 模拟疫苗吸引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目标的贝塔克罗纳梭菌峰蛋白中保守的表位 抗体，并表征高分辨率的广泛神经化和保护的结构基础。这 信息将用于迭代地为基于结构的抗原和疫苗设计提供信息，并将产生 抗体疗法可能会钝化未来人畜共患溢出的影响。疫苗：我们最近表明 在同一自组装蛋白纳米粒子上共同播种多种血凝素抗原，一种方法 称为镶嵌纳米颗粒的显示，诱导了对影响力的广泛保护的体液免疫。我们将 将此方法与稳定糖蛋白抗原和 设计量身定制的纳米颗粒支架，以显示最佳几何形状的冠状病毒尖峰。我们期望 由此产生的纳米颗粒疫苗候选者会引起对抗体反应的有效和广泛保护的抗体反应 Betacoronavirus峰值中保守的表位。我们将在机械和功能上评估性能 在相关动物模型中，这些候选疫苗的候选者，包括 非人类私人。为了促进成功转移给行业合作伙伴，我们将准备技术转移 我们计划将生产的两种铅疫苗的包装：一种泛 - 萨伯病毒疫苗 在第二年底，在第五年底进行了一种泛贝曲霉病毒疫苗。

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