PanCorVac (Center for Pan-Coronavirus Vaccine Development)

PanCorVac（泛冠状病毒疫苗开发中心）

• 批准号: 10841731
• 负责人: YOSHIHIRO KAWAOKA
• 金额: $ 461.82万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 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/10841731
• 关键词: 2019-nCoV; Affinity; Animal Model; Animals; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Bacteriophages; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19 pandemic; COVID-19 vaccine; Capsid Proteins; Cellular Immunity; Cohort Studies; Complement; Coronavirus; Data; Development; Epitopes; Evaluation; Face; Funding; Generations; Genes; Goals; Head; Human; Immune; Immune response; Immunization; Immunize; Immunodominant Epitopes; Immunoglobulins; Immunology; Individual; Infection; Influenza; Institution; Japanese; Knowledge; Longitudinal cohort study; Maintenance; Memory B-Lymphocyte; Mesocricetus auratus; Messenger RNA; Methods; Mission; Modification; Molecular Virology; Monoclonal Antibodies; Mus; Mutate; National Institute of Allergy and Infectious Disease; Persons; Phenotype; Plasma Cells; Population; Prevention; Preventive vaccine; Property; Proteins; Public Health; Reaction; Research; Research Personnel; Research Project Grants; SARS coronavirus; SARS-CoV-2 antigen; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Sampling; Sequence Homology; Serum; Specificity; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Testing; Transgenic Mice; United States National Institutes of Health; Vaccinated; Vaccination; Vaccinee; Vaccines; Viral Proteins; Virus; Virus-like particle; candidate selection; combat; coronavirus receptor; coronavirus vaccine; cross reactivity; design; high throughput analysis; human coronavirus; immunogenic; immunogenicity; innovation; lipid nanoparticle; long term memory; nanobiotechnology; neutralizing antibody; novel; novel strategies; novel vaccines; pandemic coronavirus; pandemic disease; pandemic potential; post SARS-CoV-2 infection; protective efficacy; receptor; response; self assembly; single cell technology; stem; structural biology; universal coronavirus vaccine; vaccine candidate; vaccine development; vaccine platform; viral transmission; zoonotic coronavirus

SUMMARY Most of the vaccines currently approved or in development against the pandemic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus target immunodominant, strain-specific epitopes in the SARS-CoV-2 spike (S) protein and are therefore not expected to confer protection against other coronaviruses. Accordingly, the NIAID announced NOT-AI-21-002, which calls for the “development of prophylactic vaccines to provide broad and durable protection against coronaviruses, especially SARS-CoV-2 and others with pandemic potential”. In response to this call, we assembled the Pan-Coronavirus Vaccine (PanCoVac) consortium to develop and test novel pan-coronavirus vaccines. Research Project 1 (RP1; Design and evaluation of pan- CoV vaccines) uses two strategies to develop broadly protective coronavirus vaccines: (i) Focus immune responses away from the immunodominant epitopes in the head region of S and towards the more conserved, immune-subdominant epitopes in the stem region of S; and (ii) Refocus immune responses from the variable immunodominant epitopes towards more conserved epitopes in the head region of S. For each strategy, several innovative approaches will be used. Novel antigens will be presented by virus-like particles based on a self- assembling bacteriophage coat protein (a highly immunogenic platform). The candidate vaccines will be tested for their immunogenicity and protective efficacy against different coronaviruses in an animal model. Selected candidates will be tested in a second animal model, and with an mRNA lipid nanoparticle platform. Additional studies will test the durability of immune responses and the effect of vaccination on virus transmission. Samples from vaccinated animals will be provided to Research Project 2 (RP2; Immunological responses to pan-CoV vaccines) for a detailed assessment of B- and T-cell responses. First, RP2 will continue its ongoing efforts to generate and characterize panels of SARS-CoV S-specific mAbs, which will be used in RP1 to help characterize and prioritize vaccine candidates. Moreover, “Ig-omics”, which involves single-cell technologies allowing high- throughput analysis of B-cell responses, phenotypes, immunoglobulin (Ig) repertoires and mAbs that react to several coronaviruses (a technology developed by one of the RP2 investigators), will be used to characterize B cell-mediated immunity and mAb specificity induced by the candidate vaccines. RP2 will also test (and compare with data from a human cohort study) the ability of the candidate vaccines to elicit responses to cross-reactive CD4 and CD8 T cell epitopes. In particular, recently developed novel methods will be used to characterize and compare the T-cell repertoires upon infection and vaccination. An Administrative Core will oversee and manage all financial and administrative aspects of the consortium. Our proposed research draws strength from a multi- institutional team of experts in molecular virology, structural biology, nanobiotechnology, and B- and T-cell immunology.

概括 目前已批准或正在开发的大多数针对大流行 SARS-CoV-2（严重急性 呼吸综合征冠状病毒 2) 病毒靶向 SARS-CoV-2 中免疫显性的毒株特异性表位 刺突 (S) 蛋白，因此预计不会提供针对其他冠状病毒的保护作用。因此， NIAID 宣布了 NOT-AI-21-002，呼吁“开发预防性疫苗以提供 针对冠状病毒，特别是 SARS-CoV-2 和其他大流行病提供广泛而持久的保护 潜力”。为了响应这一号召，我们组建了泛冠状病毒疫苗 (PanCoVac) 联盟， 开发和测试新型泛冠状病毒疫苗。研究项目1（RP1；泛- 冠状病毒疫苗）使用两种策略来开发具有广泛保护性的冠状病毒疫苗：（i）焦点免疫 反应远离 S 头部区域的免疫显性表位，转向更保守的表位， S 茎区的免疫亚显性表位； (ii) 重新聚焦变量的免疫反应 免疫显性表位朝向 S 头部区域更保守的表位。对于每种策略，有几个 将采用创新方法。新的抗原将由基于自身的病毒样颗粒呈递。 组装噬菌体外壳蛋白（高度免疫原性平台）。候选疫苗将进行测试 因其在动物模型中对不同冠状病毒的免疫原性和保护功效。已选择 候选者将在第二种动物模型中进行测试，并使用 mRNA 脂质纳米颗粒平台。额外的 研究将测试免疫反应的持久性以及疫苗接种对病毒传播的影响。样品 来自已接种疫苗的动物的样本将提供给研究项目 2（RP2；对泛冠状病毒的免疫反应） 疫苗）以详细评估 B 细胞和 T 细胞反应。首先，RP2将继续不断努力 生成并表征 SARS-CoV S 特异性单克隆抗体组，这些抗体将在 RP1 中用于帮助表征 并优先考虑候选疫苗。此外，“Ig组学”涉及单细胞技术，允许高 B 细胞反应、表型、免疫球蛋白 (Ig) 库和单克隆抗体的通量分析 几种冠状病毒（由 RP2 一名研究人员开发的技术）将用于表征 B 候选疫苗诱导的细胞介导的免疫和单克隆抗体特异性。 RP2 还将测试（并比较 根据人类队列研究的数据）候选疫苗引发交叉反应的能力 CD4 和 CD8 T 细胞表位。特别是，最近开发的新方法将用于表征和 比较感染和接种疫苗后的 T 细胞库。行政核心将监督和管理 财团的所有财务和行政方面。我们提出的研究从多方面汲取力量 分子病毒学、结构生物学、纳米生物技术以及 B 和 T 细胞专家组成的机构团队 免疫学。

项目成果

Recombinant spike protein vaccines coupled with adjuvants that have different modes of action induce protective immunity against SARS-CoV-2.

• DOI: 10.1016/j.vaccine.2023.08.054
• 发表时间: 2023-08
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: S. Chiba;P. Halfmann;S. Iida;Yuichiro Hirata;Yuko Sato;M. Kuroda;T. Armbrust;Sam Spyra;Tadaki Suzuki;Y. Kawaoka

Multivalent S2-based vaccines provide broad protection against SARS-CoV-2 variants of concern and pangolin coronaviruses.

• DOI: 10.1016/j.ebiom.2022.104341
• 发表时间: 2022-12
• 期刊: EBIOMEDICINE
• 影响因子: 11.1
• 作者: Halfmann, Peter J.;Frey, Steven J.;Loef, Kathryn;Kuroda, Makoto;Maemura, Tadashi;Armbrust, Tammy;Yang, Jie E.;Hou, Yixuan J.;Baric, Ralph;Wright, Elizabeth R.;Kawaoka, Yoshihiro;Kane, Ravi S.
• 通讯作者: Kane, Ravi S.