Rationally designed platform for enhanced glycoconjugate vaccines

合理设计的增强糖复合物疫苗平台

• 批准号: 8791873
• 负责人: Dennis L. Kasper
• 金额: $ 61.94万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8791873
• 关键词: Animal Model; Antibodies; B-Lymphocytes; Brucella abortus; Burkholderia mallei; Burkholderia pseudomallei; CD4 Positive T Lymphocytes; Carbohydrates; Coupling; Disease; Epitopes; Event; Family; Francisella tularensis; Generations; Glycoconjugates; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Immune response; Immunity; Immunization; Immunologics; Learning; Length; Mediating; Peptides; Polysaccharides; Production; Publishing; Receptor Cell; Site; T-Lymphocyte; Testing; Time; Translating; Vaccines; adaptive immunity; antimicrobial; base; design; immunogenic; immunogenicity; improved; innovation; knowledge base; microbial; novel vaccines; pathogen; protective efficacy; prototype; therapy development; vaccine development; vaccine evaluation

We have uncovered new cellular mechanisms for adaptive immune responses mediated by glycoconjugate immunization. Following immunization, glycoconjugates undergo enzymatic and oxidative changes resulting in relatively small glycan-peptides being mounted onto MHCII, with the peptide serving as the MHCII anchor and the carbohydrate presented to and recognized by the CD4+T cell (Tcarb). Importantly, the peptide is not recognized by the Tcarb, only the glycan. Presentation of the carbohydrate is the key event required for very robust T cell help in order for the B cell to make very high-titered anti-glycan antibodies. Demystifying the Tcell activation mechanisms of glycoconjugate vaccines was a key step towards designing new-generation vaccines as outlined in this proposal. We learned from our mechanistic studies that the most important feature of an ideal glycoconjugate vaccine is enrichment for these glycan-peptide epitopes. We synthesized a prototype new-generation glycoconjugate vaccine and tested it for immunogenicity and protective capacity in comparison to a traditionally made glycoconjugate vaccine. Our results showed that the new-generation vaccine was 50-100x more immunogenic and protective than the traditional vaccine. In this proposal, we build on our mechanistic studies and develop a translational platform for optimizing carbohydrate-based vaccines to produce a new generation of vaccines applicable to many microbial glycans. There are two Specific Aims: 1) Optimization of the platform construct for glycoconjugate vaccines. In this Specific Aim, we will optimize the carrier peptide, the glycan chain length, and the glycoconjugate construction to establish parameters for a new vaccine platform that can be applied to new vaccines; 2) We will translate our basic discoveries and use our vaccine platform to make new vaccines against important pathogens such as Francisella tularensis, Burkholderia mallei and pseudomallei, and Brucella abortus. The approach offers a knowledge-based design that will serve as a platform for a wide variety of glycoconjugate vaccines for diseases where vaccines have not been created and to greatly improve current glycoconjugate vaccines.

我们发现了新的细胞机制，用于由糖缀合物免疫介导的适应性免疫反应。免疫后，糖缀合物发生酶促和氧化变化，导致将相对较小的糖肽安装在MHCII上，肽用作MHCII锚固剂，并被CD4+T细胞（TCARB）呈现给并识别为碳水化合物。重要的是，肽不被TCARB识别，只有聚糖。碳水化合物的表示是非常健壮的T细胞帮助所需的关键事件，以使B细胞生产非常高的抗聚糖抗体。脱神经偶联疫苗的TCELL激活机制是设计新一代疫苗的关键一步，如本提案中所述。我们从机械研究中学到，理想的糖缀合物疫苗的最重要特征是这些糖肽表位的富集。我们合成了新一代糖缀合物疫苗的原型，并与传统制作的糖缀合物疫苗相比，对其进行了免疫原性和保护能力。我们的结果表明，与传统疫苗相比，新一代疫苗的免疫原性和保护性高50-100倍。在此提案中，我们以机械研究为基础，并开发了一种转化平台，以优化基于碳水化合物的疫苗，以生产适用于许多微生物聚糖的新一代疫苗。有两个具体的目的：1）对糖缀合疫苗的平台构建体的优化。在这个具体目的中，我们将优化载体肽，聚糖链长度和糖缀合物结构，以建立可以应用于新疫苗的新疫苗平台的参数； 2）我们将翻译我们的基本发现，并使用我们的疫苗平台对重要病原体（例如Francisella Tularensis，Burkholderia Mallei和Pseudomallei和Brucella Abortus）进行新的疫苗。该方法提供了一种基于知识的设计，该设计将作为用于尚未创建疫苗并大大改善当前糖缀合物疫苗的疾病的多种糖结疫苗的平台。