Self-Assembling Spike-EBR Nanoparticles as a Vaccine Platform Technology Against SARS-CoV-2 and Future Pandemic Coronaviruses.

自组装 Spike-EBR 纳米颗粒作为针对 SARS-CoV-2 和未来大流行冠状病毒的疫苗平台技术。

• 批准号: 10705078
• 负责人: Magnus Adrian Gero Hoffmann
• 金额: $ 42.1万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705078
• 关键词: 2019-nCoV; Acceleration; Amino Acid Sequence; Antibody Response; Antibody titer measurement; Applications Grants; Award; B-Cell Activation; Binding Proteins; COVID-19 pandemic; Cell surface; Cells; Clinical; Clinical Research; Collaborations; Combined Vaccines; Complex; Coronavirus; Coronavirus spike protein; Cytoplasmic Tail; Development; Disease Outbreaks; Dose; Educational process of instructing; Encapsulated; Endosomes; Engineering; Ensure; Epitopes; Faculty; Financial Support; Funding; Future; Goals; HIV-1; Health; Human; Hybrids; Immune; Immune response; Immunity; Individual; Infection; Injections; Institution; Job Application; Laboratories; Length; Liquid substance; Membrane; Membrane Proteins; Mentors; Messenger RNA; Monoclonal Antibodies; Mus; Pathway interactions; Persons; Population; Prevention; Production; Property; Protein Binding Domain; Proteins; RNA vaccine; RNA-Protein Interaction; Readiness; Research; Research Personnel; Robot; SARS-CoV-2 spike protein; SARS-CoV-2 variant; Sorting; System; T-Cell Activation; Technology; Therapeutic; Tissues; Translational Research; Vaccinated; Vaccines; Virus; Zoonoses; betacoronavirus; coronavirus pandemic; cost; cost effective; cross reactivity; design; emergency preparedness; future outbreak; future pandemic; graduate student; in vivo; industry partner; invention; lipid nanoparticle; low income country; mRNA delivery; manufacture; member; mosaic; nanoparticle; neutralizing antibody; novel vaccines; pandemic coronavirus; pandemic disease; preclinical development; preclinical study; prevent; programs; receptor binding; recruit; response; self assembly; student mentoring; technology platform; transmission process; universal coronavirus vaccine; vaccine candidate; vaccine delivery; vaccine development; vaccine platform; vaccine response; vaccine strategy; vaccine-induced antibodies; variants of concern

Project Summary/Abstract The COVID-19 pandemic represents the 3rd outbreak caused by zoonotic transmission of a beta-coronavirus (beta-CoV) in the last 20 years. Hence there is an urgent need for new vaccine strategies to control the ongoing pandemic and prevent future CoV outbreaks. mRNA vaccines have emerged as an ideal platform for the development of rapid-response vaccines, but clinical studies have shown that neutralizing antibody titers elicited by mRNA vaccines are ~10-fold lower than titers elicited by protein nanoparticle (NP) vaccines. This is a concern with regards to the emergence of SARS-CoV-2 variants of concern (VOCs) that are less sensitive to vaccine- induced antibodies. In addition, less than 25% of the world population is fully vaccinated. Thus, rapid-response vaccine technologies are needed that elicit potent antibody responses with a single injection and/or lower doses, to ensure lasting protection against VOCs, reduce costs, and accelerate global distribution. Moreover, prevention of future CoV pandemics requires the development of a universal CoV vaccine that elicits cross-reactive immune responses against a broad spectrum of CoV strains by focusing responses to conserved epitopes. The scope of the proposed research is to design and evaluate new vaccine strategies to enhance the potency of mRNA-based rapid-response vaccines and facilitate universal CoV vaccine development. The proposal is based on the EBR NP technology, which modifies membrane proteins such as CoV spike (S) proteins to self-assemble into virus- resembling NPs that bud from the cell surface. NP assembly is induced by inserting a short amino acid sequence into the cytoplasmic tail designed to recruit proteins from the endosomal sorting complex required for transport (ESCRT) pathway. Initial studies in mice showed that low-dose injections of EBR NPs presenting the SARS- CoV-2 S protein elicited 10-fold higher neutralizing antibody titers than soluble S protein and protein-based NPs that displayed the receptor-binding domain (RBD) of the S protein. The EBR NP technology will be applied to accomplish three goals: i) Design a hybrid mRNA vaccine encoding the modified SARS-CoV-2 S-EBR construct that would be expressed at the cell surface and self-assemble into virus-resembling NPs to elicit more potent antibody responses than the approved Pfizer/Moderna vaccines, while retaining the manufacturing properties and T-cell activation of mRNA vaccines. ii) Engineer S-EBR NPs to package and deliver S or S-EBR mRNA vaccines as an alternative to lipid NPs. This delivery approach would enhance mRNA vaccine potency as S proteins presented on S-EBR NPs induce potent antibody responses, facilitate efficient intracellular delivery, and target mRNA vaccines to tissues that are naturally infected by SARS-CoV-2 to induce local immune responses. iii) Design and evaluate mosaic S-EBR NP-based universal CoV vaccine candidates that present full-length membrane-associated S proteins from multiple CoV strains to elicit cross-reactive immune responses against a broad spectrum of CoVs and protect against future outbreaks. The proposed vaccine strategies could have direct impact on the COVID-19 global health crisis and advance our emergency preparedness for the next pandemic.

项目摘要/摘要 COVID-19大流行代表了由β-核可纳病毒的人畜共动性传播引起的第三次爆发 （beta-cov）在过去20年中。因此，迫切需要新的疫苗策略来控制正在进行的 大流行并防止未来的COV暴发。 mRNA疫苗已成为理想的平台 快速反应疫苗的开发，但临床研究表明，中和抗体滴度引起了。 由mRNA疫苗比蛋白质纳米颗粒（NP）疫苗引起的滴度低约10倍。这是一个问题 关于关注的SARS-COV-2变体的出现（VOC），这些变体对疫苗不太敏感 诱导抗体。此外，不到25％的世界人口已完全接种疫苗。因此，快速响应 需要进行疫苗技术，以单个注射和/或较低剂量引起有效的抗体反应， 为了确保对VOC的持久保护，降低成本并加速全球分配。此外，预防 未来的COV大流行需要开发一种通用COV疫苗，该疫苗会引起交叉反应性免疫 通过将响应集中在保守的表位上，对广泛的COV菌株的反应。范围 拟议的研究是设计和评估新的疫苗策略，以增强基于mRNA的效力 快速反应疫苗并促进普遍的COV疫苗开发。该提议基于EBR NP技术，它改变了膜蛋白（例如COV峰值蛋白）以自我组装为病毒 - 类似于从细胞表面芽的NP。通过插入短氨基酸序列来诱导NP组件 进入细胞质尾巴，旨在从运输所需的内体分类复合物中募集蛋白质 （escrt）途径。对小鼠的初步研究表明，呈现SARS-的EBR NP的低剂量注射 COV-2 S蛋白比可溶性S蛋白和基于蛋白质的NP引起10倍中和抗体滴度高10倍 这显示了S蛋白的受体结合结构域（RBD）。 EBR NP技术将用于 完成三个目标：i）设计编码修改后的SARS-COV-2 S-EBR构建体的混合mRNA疫苗 这将在细胞表面表达，并自组装成与病毒相称的NP，以引起更有效的 抗体反应比批准的辉瑞/现代疫苗，同时保留制造特性 和mRNA疫苗的T细胞激活。 ii）工程师s-ebr nps包装并提供S或S-EBR mRNA 疫苗作为脂质NP的替代品。这种输送方法将提高mRNA疫苗效力 S-EBR NP上呈现的蛋白质诱导有效的抗体反应，促进有效的细胞内递送和 将mRNA疫苗靶向自然感染SARS-COV-2的组织，以诱导局部免疫反应。 iii）设计和评估基于MosaiC S-EBR NP的通用COV疫苗候选物 膜相关的S蛋白从多个COV菌株引起交叉反应性免疫反应针对A 广泛的COV并防止未来的爆发。拟议的疫苗策略可以直接 对COVID-19的全球健康危机的影响，并促进我们为下一个大流行的紧急准备。