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MER相比，当前的SARS-COV-2病毒是高度传播的，迄今为止 在全球造成超过85,000,000次造成的死亡人数超过1,800,000人死亡。有一个多个人的地方性人口 蝙蝠中的COV菌株，具有中间宿主的啮齿动物，Civets和Pangolins的菌株，以及COV的能力 重新组合，可以肯定的是，具有感染力人类潜力的新COV将导致未来的人类 大流行。为了以一种集中和综合的方式解决这个问题，这支P01病毒学家，免疫学家， 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科学家 将开发PANBETACORONAVIRUS（PANBETACOV）疫苗，包括Merbecovires（2C组），该疫苗引起 MERS和SARBECOVIRASE（第2B组），这引起了SARS COV-1和SARS COV-2，这三个最致命的 贝塔科夫人爆发。这笔赠款的意义在于，它将为未来提供Panbetacov疫苗 在贝塔科夫大流行病开始时可以立即可用的流行病，避免了许多人 由于大流行造成的悲剧和社会破坏。 P01的总体具体目标是： AIM 1。发展并表征Panbetacov Sarbecovirus（第2B组）疫苗的免疫原性。 AIM 2。确定2B组候选候选病毒面板的候选疫苗保护能力。 AIM 3。发展Panbetacovmerbecovirus（Group2c）候选疫苗，确定性免疫原性，交叉 对其他Betacovs的反应性和针对2C组病毒组的保护能力。 该计划项目赠款包括四个项目。项目1将在α病毒复制子粒子中设计疫苗 （VRP）疫苗系统，在其独特的小鼠COV挑战模型中开发和测试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纳米粒子尖峰蛋白设计以及 在野生型小鼠模型中进行测试。项目3将同时设计COV疫苗和测试疫苗设计，称为 液体纳米颗粒（LNP）中的mRNA。项目4将在计算设计B和T细胞Panbetacov疫苗。 该p01提出了三个核心：行政核心，生物膜维护和免疫监测核心， 和非人类灵长类动物核心。在此P01中的工作将提供Panbetacov疫苗以防止逃脱 当前流行病中SARS-COV-2的突变体，可以保护社会免受新的Betacovs 这可能会在未来感染人类。

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

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

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