Development of the Next Generation of Conjugate Vaccines

下一代结合疫苗的开发

基本信息

  • 批准号:
    9750619
  • 负责人:
  • 金额:
    $ 84.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-07-25 至 2022-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary Conjugate vaccines of the first generation have been effective at reducing incidence and severity of diseases caused by Haemophilus influenza B, Streptococcus pneumoniae, and Neisseria meningitides bacteria in individuals with fit immune systems. Their success in immunocompromised patients and elders, two fast growing populations, has been very limited. In addition, the approach used for their development and production is inappropriate to respond to rapidly emerging new pathogenic strains. The next generation of these glycan-targeting vaccines must introduce radically different concepts to produce vaccines against emerging bacterial and fungal diseases for which the glycan capsule is an ideal target for neutralizing antibodies. The fast selection of antibiotic-resistant strains makes this need even more urgent. We embarked on this task using Streptococcus pneumoniae (Sp) as a model system, with the working hypothesis that the limiting factor of current conjugate anti-glycan vaccines was the low quality of T cell help. We recently published examples of a new approach using two prototypical glycans from Sp. Anti-glycan antibodies with an accumulation of somatic mutations, exquisite specificity and low-nanomolar affinities were generated. Apo- and glycan bound structures revealed a unique mode of glycan binding. The production of these antibodies was totally dependent on CD4 T cell help and the presence of an NKT cell adjuvant, and protected animals against microbial challenge. These results suggest that we have developed a modular system capable of harnessing the anti-glycan response. To advance to pre-clinical studies, and understand the immunology of glycan recognition we will carry out three specific aims to expand our approach to develop vaccines based on the concept of synthetic microbial mimics. Aim 1: Optimization of the antigen and display platform. Mono- to tetrasaccharide motifs can define the 13 serotypes that prevail in human diseases and are included in licensed conjugate vaccines. We will attach minimal antigenic structures of all 13 serotypes to our immunogenic platform in ways designed to enhance T cell recognition and dependency. Antibody specificity will be examined on glycan micro-arrays. The immunological rules of B and T cell glycan recognition will be defined. Aim 2: Molecular recognition of glycans by high affinity antibodies and T cells. We will explore the structural rules of glycan recognition by B and T cells using x-ray crystallography. These studies will inform the design of optimal antigenic oligosaccharides. Aim 3: Increasing safety and potency in vivo. We hypothesize that some of the same factors that enhance the quality of anti-protein immune response will also apply to peptide-displayed glycans, particularly improved efficiency of delivery to the lymph node and capture of the vaccine by dendritic cells. This will be tested with the attachment of known opsonins to the particle to develop the concept of microbial mimicry. Finally, each optimized platform will be tested in bacterial challenge in mice.
项目摘要 第一代结合疫苗有效地降低了 由流感嗜血杆菌B、肺炎链球菌和脑膜炎奈瑟菌引起的疾病 免疫系统正常的人体内的细菌。他们在免疫功能低下的患者和老年人中的成功, 快速增长的人口,已经非常有限。此外,用于开发的方法和 生产不适合应对迅速出现的新致病菌株。下一代 这些聚糖靶向疫苗必须引入完全不同的概念, 聚糖被膜是理想的中和靶点的新兴细菌和真菌疾病 抗体的快速选择抗真菌菌株使得这一需求更加迫切。 我们开始这项任务使用肺炎链球菌(Sp)作为模型系统, 目前缀合物抗聚糖疫苗的限制因素是T细胞帮助的低质量的假设。 我们最近发表了一个新的方法的例子,使用两个典型的聚糖从SP。 具有累积的体细胞突变、精确的特异性和低纳摩尔亲和力的抗体, 生成的.载脂蛋白和聚糖结合结构揭示了一种独特的聚糖结合模式。生产 这些抗体完全依赖于CD4 T细胞的帮助和NKT细胞佐剂的存在, 保护动物免受微生物的挑战。这些结果表明,我们已经开发了一种模块化的 能够利用抗聚糖反应的系统。推进临床前研究,并了解 聚糖识别的免疫学,我们将进行三个具体的目标,以扩大我们的方法, 基于合成微生物模拟物概念的疫苗。目的1:优化抗原和 展示平台单糖至四糖基序可以定义在人类疾病中流行的13种血清型 并包含在许可的结合疫苗中。我们将所有13种血清型的最小抗原结构 我们的免疫原性平台,旨在增强T细胞识别和依赖性。抗体 将在聚糖微阵列上检查特异性。B和T细胞糖链识别的免疫学规律 将被定义。目的2:高亲和力抗体和T细胞对聚糖的分子识别。我们将 利用X射线晶体学探索B和T细胞对聚糖识别的结构规律。这些研究 将为最佳抗原性寡糖的设计提供信息。目的3:提高体内安全性和效力。 我们假设,一些增强抗蛋白免疫反应质量的相同因素将 也适用于肽展示聚糖,特别是提高了递送至淋巴结的效率, 树突状细胞捕获疫苗。这将通过将已知的调理素连接到细胞上来进行测试。 粒子来发展微生物拟态的概念。最后,每个优化的平台将在细菌中进行测试。 小鼠的挑战

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Luc Teyton其他文献

Luc Teyton的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Luc Teyton', 18)}}的其他基金

Molecular basis of glycan recognition by T and B cells
T 和 B 细胞识别聚糖的分子基础
  • 批准号:
    10549648
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10549641
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
Antibody Core
抗体核心
  • 批准号:
    10549643
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
Leveraging Human iPSC-derived beta-cells to Probe Antigen Specificity of Anti-islet Memory T Cells in T1D
利用人 iPSC 衍生的 β 细胞探测 T1D 中抗胰岛记忆 T 细胞的抗原特异性
  • 批准号:
    10589556
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
Multidimensional development of high-affinity anti-glycan antibodies to fight deadly bacterial infections
多维开发高亲和力抗聚糖抗体以对抗致命细菌感染
  • 批准号:
    10549640
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
Mechanistic Studies of Combination Adjuvants to Target B Cells in Vaccines
疫苗中针对 B 细胞的组合佐剂的机理研究
  • 批准号:
    10599324
  • 财政年份:
    2021
  • 资助金额:
    $ 84.64万
  • 项目类别:
Mechanistic Studies of Combination Adjuvants to Target B Cells in Vaccines
疫苗中针对 B 细胞的组合佐剂的机理研究
  • 批准号:
    10218993
  • 财政年份:
    2021
  • 资助金额:
    $ 84.64万
  • 项目类别:
Mechanistic Studies of Combination Adjuvants to Target B Cells in Vaccines
疫苗中针对 B 细胞的组合佐剂的机理研究
  • 批准号:
    10397167
  • 财政年份:
    2021
  • 资助金额:
    $ 84.64万
  • 项目类别:
Early diagnosis and mechanistic studies of type 1 diabetes using single cell analysis
使用单细胞分析进行 1 型糖尿病的早期诊断和机制研究
  • 批准号:
    10362605
  • 财政年份:
    2019
  • 资助金额:
    $ 84.64万
  • 项目类别:
Early diagnosis and mechanistic studies of type 1 diabetes using single cell analysis
使用单细胞分析进行 1 型糖尿病的早期诊断和机制研究
  • 批准号:
    9884757
  • 财政年份:
    2019
  • 资助金额:
    $ 84.64万
  • 项目类别:

相似海外基金

Metachronous synergistic effects of preoperative viral therapy and postoperative adjuvant immunotherapy via long-term antitumor immunity
术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
  • 批准号:
    23K08213
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Improving the therapeutic immunity of cancer vaccine with multi-adjuvant polymeric nanoparticles
多佐剂聚合物纳米粒子提高癌症疫苗的治疗免疫力
  • 批准号:
    2881726
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
    Studentship
Countering sympathetic vasoconstriction during skeletal muscle exercise as an adjuvant therapy for DMD
骨骼肌运动期间对抗交感血管收缩作为 DMD 的辅助治疗
  • 批准号:
    10735090
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
Evaluation of the Sensitivity to Endocrine Therapy (SET ER/PR) Assay to predict benefit from extended duration of adjuvant endocrine therapy in the NSABP B-42 trial
NSABP B-42 试验中内分泌治疗敏感性 (SET ER/PR) 测定的评估,用于预测延长辅助内分泌治疗持续时间的益处
  • 批准号:
    10722146
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
  • 批准号:
    10933287
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
DEVELOPMENT OF SAS A SYNTHETIC AS01-LIKE ADJUVANT SYSTEM FOR INFLUENZA VACCINES
流感疫苗类 AS01 合成佐剂系统 SAS 的开发
  • 批准号:
    10935776
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
DEVELOPMENT OF SMALL-MOLECULE DUAL ADJUVANT SYSTEM FOR INFLUENZA VIRUS VACCINE
流感病毒疫苗小分子双佐剂体系的研制
  • 批准号:
    10935796
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
A GLYCOLIPID ADJUVANT 7DW8-5 FOR MALARIA VACCINES
用于疟疾疫苗的糖脂佐剂 7DW8-5
  • 批准号:
    10935775
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
Adjuvant Photodynamic Therapy to Reduce Bacterial Bioburden in High-Energy Contaminated Open Fractures
辅助光动力疗法可减少高能污染开放性骨折中的细菌生物负载
  • 批准号:
    10735964
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
Adjuvant strategies for universal and multiseasonal influenza vaccine candidates in the context of pre-existing immunity
在已有免疫力的情况下通用和多季节流感候选疫苗的辅助策略
  • 批准号:
    10649041
  • 财政年份:
    2023
  • 资助金额:
    $ 84.64万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了