Design and Development of a Pan-betacoronavirus Vaccine

泛β冠状病毒疫苗的设计与开发

• 批准号: 10842498
• 负责人: Barton F. Haynes
• 金额: $ 1047.8万
• 依托单位: DUKE UNIVERSITY
• 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/10842498
• 关键词: 2019-nCoV; Address; Alphavirus; Animal Model; Animals; Antibodies; Antigens; B-Lymphocytes; COVID test; COVID-19; Cessation of life; Chiroptera; Cold Chains; Combined Vaccines; Coronavirus; Development; Disease; Disease Outbreaks; Dose; Epidemic; Epitopes; Escape Mutant; Event; Future; Goals; Grant; Human; Immune; Immune response; Immunologic Monitoring; Immunologist; Laboratories; Liquid substance; Macaca; Macaca fascicularis; Macaca mulatta; Measures; Merbecovirus; Messenger RNA; Middle East Respiratory Syndrome; Modeling; Monitor; Mus; Mutate; Mutation; N-terminal; Nucleosides; Population; Program Research Project Grants; Protein Engineering; Proteins; Regimen; Replicon; Resource Sharing; Resources; Rodent; SARS coronavirus; Sarbecovirus; Societies; Structural Biologist; Structure; System; T-Lymphocyte; Testing; Vaccination; Vaccine Design; Vaccines; Virus; Viverridae; Wild Type Mouse; Work; animal coronavirus; betacoronavirus; betacoronavirus vaccine; coronavirus vaccine; cross reactivity; current pandemic; design; future epidemic; future pandemic; human coronavirus; immunogenicity; lipid nanoparticle; molecular modeling; monomer; mouse model; nanoparticle; neutralizing antibody; nonhuman primate; novel; novel coronavirus; pandemic disease; pandemic potential; particle; programs; protective efficacy; receptor binding; respiratory aerosol; social; vaccine candidate; vaccine development; vaccine evaluation; vaccine platform; zoonotic spillover

Abstract - Overall Compared to SARS-CoV-1 and MERS, the current SARS-CoV-2 virus is highly transmissible and to date has caused over 85,000,000cases worldwidewith over 1,800,000 deaths. With an endemic population of multipleother strains of CoVs in bats, rodents with intermediate hosts, civets and pangolins, and because of the ability of CoVs to recombine, it is a certainty that new CoVs with infectious potential for humans will cause future human pandemics. To address this problem in a focused and integrated way, this P01 team of virologists, immunologists, computational biologists, structural biologists, biophysicists, evolutionary biologists, and traditional vacci nologists will develop panbetacoronavirus (panbetaCoV) vaccines, including Merbecoviruses (group 2c), which gave rise to MERS, and Sarbecoviruses (group 2b), which gave rise to SARS CoV-1 and SARS CoV-2, the three most deadly betaCoV human outbreaks. The Significance of this grant is that it will provide for panbetaCoV vaccines for future epidemics that can be immediately available at the onset of a betaCoV pandemic, avoiding much of the human tragedy and social disruption caused by a pandemic. The Overall Specific Aims of the P01 are: Aim 1. Develop and characterize immunogenicity of PanbetaCoV Sarbecovirus (Group 2b) vaccine candidates. Aim 2. Determine Group 2b vaccine candidate protection capacity against group 2b panel of viruses. Aim 3. Develop PanbetaCoVMerbecovirus (group2c) vaccine candidates, determinetheir immunogenicity, cross- reactivity with other betaCoVs and protection capacity against group 2c panel of viruses. This program project grant includes four projects. Project 1 will design vaccines in alphavirus replicon particle (VRP) vaccine system, develop and test P01 vaccines in their unique mouse CoV challenge models. Project 2 will use structure-based molecular modeling and monomer and multimer nanoparticle spike protein designs and test in wild-type mouse models. Project 3 will both design CoV vaccines and test vaccine designs expressed as mRNAs in liquid nanoparticles (LNPs). Project 4 will computationally design B and T cell panbetaCoV vaccines. This P01 proposes three Cores: an Administrative Core, a Biocontainment and Immune Monitoring Core, and a Non-human Primate Core. Work in this P01 will provide panbetaCoV vaccines to protect against escape mutants of SARS-CoV-2 in the current epidemic, and will be available to protect society against new betaCoVs that might emerge to infect humans in the future.

摘要 - 总体 与 SARS-CoV-1 和 MERS 相比，当前的 SARS-CoV-2 病毒具有高度传播性，迄今为止， 全球已造成超过 85,000,000 例病例，超过 1,800,000 人死亡。具有多种其他疾病的流行人群 蝙蝠、具有中间宿主的啮齿类动物、果子狸和穿山甲中存在冠状病毒毒株，并且由于冠状病毒的能力 重组后，可以肯定的是，具有人类感染潜力的新冠状病毒将导致未来人类 流行病。为了以集中和综合的方式解决这个问题，这个由病毒学家、免疫学家组成的 P01 团队， 计算生物学家、结构生物学家、生物物理学家、进化生物学家和传统疫苗学家 将开发泛β冠状病毒（panbetaCoV）疫苗，包括 Merbecoviruses（2c 组），该病毒引起了 MERS 和 Sarbecoviruses（2b 组），产生 SARS CoV-1 和 SARS CoV-2，这三种最致命的病毒 betaCoV 人类爆发。这笔赠款的意义在于，它将为未来提供泛β冠状病毒疫苗 β冠状病毒大流行一开始就可以立即获得流行病，从而避免了人类的大部分接触 流行病造成的悲剧和社会混乱。 P01 的总体具体目标是： 目标 1. 开发 PanbetaCoV Sarbecovirus（2b 组）候选疫苗并对其免疫原性进行表征。 目标 2. 确定 2b 组候选疫苗针对 2b 组病毒的保护能力。 目标 3. 开发 PanbetaCoV Merbecovirus (group2c) 候选疫苗，确定其免疫原性、交叉 与其他 betaCoV 的反应性以及针对 2c 组病毒的保护能力。 该计划项目补助金包括四个项目。项目1将设计甲病毒复制子颗粒疫苗 (VRP) 疫苗系统，在其独特的小鼠 CoV 攻击模型中开发和测试 P01 疫苗。项目2 将使用基于结构的分子建模以及单体和多聚体纳米颗粒刺突蛋白设计 在野生型小鼠模型中进行测试。项目 3 将设计 CoV 疫苗并测试疫苗设计，表达为 液体纳米颗粒 (LNP) 中的 mRNA。项目 4 将通过计算设计 B 细胞和 T 细胞 panbetaCoV 疫苗。 本 P01 提出了三个核心：行政核心、生物遏制和免疫监测核心、 和非人类灵长类动物核心。 P01 的工作将提供 panbetaCoV 疫苗以防止逃逸 当前流行病中 SARS-CoV-2 的突变体，将可用于保护社会免受新的 betaCoV 的侵害 未来可能会感染人类。

项目成果

Non-neutralizing SARS-CoV-2 N-terminal domain antibodies protect mice against severe disease using Fc-mediated effector functions.

非中和性 SARS-CoV-2 N 末端结构域抗体利用 Fc 介导的效应功能保护小鼠免受严重疾病的侵害。

• DOI: 10.1101/2023.07.25.550460
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Pierre,CamilleN;Adams,LilyE;Anasti,Kara;Goodman,Derrick;Stanfield-Oakley,Sherry;Powers,JohnM;Li,Dapeng;Rountree,Wes;Wang,Yunfei;Edwards,RobertJ;MunirAlam,S;Ferrari,Guido;Tomaras,GeorgiaD;Haynes,BartonF;Baric,RalphS;Sa
• 通讯作者: Sa

Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike.

• DOI: 10.1016/j.celrep.2022.111009
• 发表时间: 2022-06-28
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Stalls, Victoria;Lindenberger, Jared;Gobeil, Sophie M. -C.;Henderson, Rory;Parks, Rob;Barr, Maggie;Deyton, Margaret;Martin, Mitchell;Janowska, Katarzyna;Huang, Xiao;May, Aaron;Speakman, Micah;Beaudoin, Esther;Kraft, Bryan;Lu, Xiaozhi;Edwards, Robert J.;Eaton, Amanda;Montefiori, David C.;Williams, Wilton B.;Saunders, Kevin O.;Wiehe, Kevin;Haynes, Barton F.;Acharya, Priyamvada
• 通讯作者: Acharya, Priyamvada

Vaccine-mediated protection against merbecovirus and sarbecovirus challenge in mice.

疫苗介导的针对小鼠 merbecovirus 和 sarbecovirus 攻击的保护。

• DOI: 10.1101/2023.05.22.540829
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Martinez,DavidR;Schafer,Alexandra;Gavitt,TylerD;Mallory,MichaelL;Lee,Esther;Catanzaro,NicholasJ;Chen,Haiyan;Gully,Kendra;Scobey,Trevor;Korategere,Pooja;Brown,Alecia;Smith,Lena;Parks,Rob;Barr,Maggie;Newman,Amanda;Bowman,C
• 通讯作者: Bowman,C