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.

项目总结/摘要 COVID-19大流行是由β-冠状病毒的人畜共患传播引起的第三次爆发 （beta-CoV）在过去的20年里。因此，迫切需要新的疫苗策略来控制正在进行的 大流行和预防未来的CoV爆发。mRNA疫苗已经成为一个理想的平台， 快速反应疫苗的发展，但临床研究表明，中和抗体滴度引起 通过mRNA疫苗诱导的抗体滴度比通过蛋白质纳米颗粒（NP）疫苗诱导的抗体滴度低约10倍。这是一个问题 关于对疫苗不太敏感的SARS-CoV-2变异体的出现- 诱导抗体。此外，全世界只有不到25%的人口接种了疫苗。因此，快速反应 需要用单次注射和/或较低剂量引发有效抗体应答的疫苗技术， 确保持久保护免受VOC侵害，降低成本，并加快全球分销。此外，预防 未来的CoV大流行需要开发一种通用的CoV疫苗， 通过聚焦对保守表位的应答，针对广谱CoV毒株的应答。的范围 拟议的研究是设计和评估新的疫苗策略，以提高基于mRNA的疫苗的效力。 快速反应疫苗和促进通用CoV疫苗的开发。该提案基于EBR NP技术，它修饰膜蛋白，如CoV刺突（S）蛋白，以自组装成病毒- 类似于从细胞表面出芽的NP。NP组装通过插入短氨基酸序列来诱导 进入胞质尾区，目的是从内体分选复合物中募集转运所需的蛋白质 （ESCRT）途径。在小鼠中的初步研究表明，低剂量注射呈现SARS- CoV-2S蛋白引起的中和抗体滴度比可溶性S蛋白和基于蛋白的NP高10倍 显示S蛋白的受体结合域（RBD）。EBR NP技术将应用于 完成三个目标：i）设计编码修饰的SARS-CoV-2 S-EBR构建体的杂交mRNA疫苗 它将在细胞表面表达，并自组装成类似病毒的纳米颗粒， 抗体应答优于获批的辉瑞/Moderna疫苗，同时保留生产特性 和mRNA疫苗的T细胞活化。ii）工程化S-EBR NP以包装和递送S或S-EBR mRNA 疫苗作为脂质NP的替代品。这种递送方法将增强mRNA疫苗的效力，因为S 在S-EBR NP上呈递的蛋白质诱导有效的抗体应答，促进有效的细胞内递送， 将mRNA疫苗靶向SARS-CoV-2自然感染的组织，以诱导局部免疫应答。 iii）设计和评估嵌合的基于S-EBR NP的通用CoV疫苗候选物，其呈现全长CoV 来自多个CoV毒株的膜相关S蛋白，以引发针对 广泛的冠状病毒，并防止未来的爆发。拟议的疫苗战略可能直接 应对COVID-19全球健康危机的影响，并推进我们对下一次大流行的应急准备。