Development of the Next Generation of Conjugate Vaccines

下一代结合疫苗的开发

• 批准号: 9750619
• 负责人: Luc Teyton
• 金额: $ 84.64万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9750619
• 关键词: Address; Adjuvant; Adult; Affinity; Age; Animals; Anniversary; Anti-Bacterial Agents; Antibiotic Resistance; Antibodies; Antibody Affinity; Antibody Formation; Antibody Specificity; Antibody titer measurement; Antifungal Agents; Antigens; B-Lymphocytes; Bacteria; Binding; Biological Models; CD4 Positive T Lymphocytes; Carbohydrates; Carrier Proteins; Cell Maturation; Cells; Communities; Conjugate Vaccines; Coupled; Coupling; Dendritic Cells; Dependence; Development; Disease; Disease Resistance; Elderly; Environment; Eukaryota; Family; Generations; Glycolipids; Glycopeptides; Goals; Haemophilus Influenzae B Vaccine; Haemophilus influenzae; Histocompatibility Antigens Class II; Human; Immune response; Immune system; Immunocompromised Host; Immunoglobulin G; Immunologics; Immunology; Incidence; Individual; Influenza B Virus; Knowledge; Light; Mammals; Memory B-Lymphocyte; Molecular; Mus; Neisseria; Normal Cell; Oligosaccharides; Opsonin; Organism; Pathogenicity; Peptides; Pneumococcal Infections; Pneumococcal vaccine; Polysaccharides; Population; Process; Production; Prokaryotic Cells; Proteins; Publishing; Recombinants; Safety; Series; Serotyping; Severity of illness; Somatic Mutation; Specificity; Streptococcus pneumoniae; Structure; Surface; System; T cell response; T-Lymphocyte; Testing; Therapeutic Agents; Time; Vaccination; Vaccine Design; Vaccines; Water; X-Ray Crystallography; base; capsule; design; enhancing factor; flexibility; fungus; human disease; immunogenic; improved; in vivo; lymph nodes; microbial; mimicry; molecular recognition; nanomolar; neutralizing antibody; next generation; novel diagnostics; novel strategies; novel vaccines; particle; pathogenic bacteria; preclinical study; programs; resistant strain; response; success; sugar; tool

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 第一代共轭疫苗已有效地降低发生率和严重程度 由流感嗜血杆菌B，肺炎链球菌和奈瑟氏菌的疾病引起的疾病 具有拟合免疫系统的个体的细菌。他们在免疫功能低下的患者和长老中的成功，两个 快速增长的人群非常有限。此外，用于开发的方法和 生产不适合对快速出现的新致病菌株反应。下一代 这些靶向聚糖的疫苗必须引入根本不同的概念，以生产针对的疫苗 新兴的细菌和真菌疾病是囊囊是中和的理想目标 抗体。快速选择抗生素抗性菌株使这一需求更加紧迫。 我们使用肺炎链球菌（SP）作为模型系统开始了这项任务 假设当前偶联抗甘油疫苗的限制因素是T细胞帮助的低质量。 我们最近使用SP的两种典型的聚糖发表了一种新方法的例子。反聚糖 具有体细胞突变，精致特异性和低纳米摩尔亲和力的抗体是 生成。 apo和聚糖结构揭示了一种独特的聚糖结合方式。生产 这些抗体完全取决于CD4 T细胞帮助以及NKT细胞辅助的存在，以及 保护动物免受微生物挑战。这些结果表明我们已经开发了一个模块化 能够利用反聚糖反应的系统。促进临床前研究，并了解 聚糖识别的免疫学，我们将执行三个特定的目标，以扩大我们的发展方法 基于合成微生物模拟物的概念的疫苗。目标1：抗原的优化和 显示平台。单一至四糖基序可以定义人类疾病中普遍存在的13种血清型 并包括在有执照的共轭疫苗中。我们将附加所有13种血清型的最小抗原结构 以旨在增强T细胞识别和依赖性的方式到我们的免疫原性平台。抗体 将在聚糖微阵列上检查特异性。 B和T细胞聚糖识别的免疫学规则 将定义。目标2：高亲和抗体和T细胞对聚糖的分子识别。我们将 使用X射线晶体学探索B和T细胞识别聚糖识别的结构规则。这些研究 将告知最佳抗原寡糖的设计。目标3：体内的安全性和效力提高。 我们假设某些增强抗蛋白质免疫反应质量的因素将会 还适用于肽脱离的聚糖，特别是提高向淋巴结的递送效率和 树突状细胞捕获疫苗。这将通过附着已知的opsonins的附着来测试 粒子发展微生物模仿的概念。最后，每个优化平台将在细菌中进行测试 小鼠的挑战。