Elucidating the Structural Requirements for Next-Gen Glycoconjugate Vaccines

阐明下一代糖复合疫苗的结构要求

• 批准号: 10533764
• 负责人: Dennis L. Kasper
• 金额: $ 61.31万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533764
• 关键词: Affinity; Antibodies; Antibody Affinity; Antibody Avidity; Antibody Response; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attention; Avidity; CD4 Positive T Lymphocytes; Carbohydrates; Carrier Proteins; Cell Communication; Cells; Characteristics; Dendritic Cells; Disease; Egg Proteins; Elderly; Epitopes; Evaluation; Genetic Transcription; Glycoconjugates; Glycopeptides; Health Benefit; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immunity; Immunization; Immunoglobulin G; Immunologics; Infection; Link; Mediating; Memory B-Lymphocyte; Modeling; Peptide Vaccines; Peptides; Polysaccharides; Population; Proteins; Proteomics; Recombinants; Role; Site; Streptococcus Group B; Surface; T-Cell Receptor; T-Lymphocyte; TCR Activation; Tularemia; Vaccines; Work; high risk; microbial; mouse model; pathogen; public health relevance; response; sugar

Modified Project Summary/Abstract Section Glycoconjugate vaccines provide enormous health benefits globally, although they have been less successful in some populations at high risk for developing disease, such as the elderly. In most cases, conjugation of the sugar antigen to the carrier protein has been done empirically with little attention paid to variables critical for the immune response. Recent findings from our lab offer a new and rational explanation for how conjugates work. The new model suggests that carbohydrate presentation to T cells by antigen-presenting cells may strongly enhance the efficacy of antibody responses. Application of this principle in mouse models of group B streptococcal disease and Francisella tularensis infection by using a carrier peptide rather than a protein, resulted in vaccines more protective than standard glycoconjugate vaccines. We have also demonstrated the critical role of the peptide linker and the conjugation site in enhancing both the conjugation efficiency and the immune response to vaccines. The results support the notion that peptide glycoconjugate vaccines provide superior protection against bacterial challenges. Remarkably, the use of a peptide instead of a protein as a carrier confers better protection at much lower levels of carbohydrate specific IgG. This observation challenges the paradigm of a direct correlation between the amount of IgG induced by a glycoconjugate and protection. A comprehensive evaluation of antibodies and immune cells generated by protein vs. peptide glycoconjugates will clarify the features that make peptide vaccines extremely potent. We will evaluate the antibody response to glycopeptide vaccines in terms of IgG subtypes, affinity, avidity and functional activity, and elucidate the costimulatory/coinhibitory molecules being expressed on memory B cells and relate this to the functionality of the antibodies being made. Finally, we will define the interactions between the MHCII antigen presentation molecule and the helper T cell receptor using a proteomic approach. Recombinant TCRs will be used to structurally define the interactions with glycopeptide epitopes. Our approach will identify the characteristics that make glycopeptide-induced antibodies so potent. We will apply our studies of these peptide/polysaccharide conjugates to create more efficacious and longer lasting immunity to glycoconjugate vaccines.

修改项目摘要/摘要部分 糖缀合物疫苗在全球范围内提供了巨大的健康益处，尽管它们在某些疾病高风险人群（如老年人）中不太成功。在大多数情况下，糖抗原与载体蛋白的缀合是凭经验进行的，很少注意对免疫应答至关重要的变量。我们实验室最近的发现为共轭物的工作原理提供了一个新的合理解释。新模型表明，抗原呈递细胞向T细胞呈递碳水化合物可能会强烈增强抗体应答的功效。在B组链球菌病和土拉弗朗西斯菌感染的小鼠模型中，通过使用载体肽而不是蛋白质来应用该原理，导致疫苗比标准糖缀合物疫苗更具保护性。我们还证明了肽接头和缀合位点在增强缀合效率和对疫苗的免疫反应方面的关键作用。结果支持肽糖缀合物疫苗提供针对细菌攻击的上级保护的观点。值得注意的是，使用肽代替蛋白质作为载体在低得多的碳水化合物特异性IgG水平下赋予更好的保护。该观察结果挑战了由糖缀合物诱导的IgG的量与保护之间的直接相关性的范例。对蛋白质与肽糖缀合物产生的抗体和免疫细胞的综合评价将阐明使肽疫苗极其有效的特征。我们将根据IgG亚型、亲和力、亲合力和功能活性来评估对糖肽疫苗的抗体应答，并阐明在记忆B细胞上表达的共刺激/共抑制分子，并将其与所制备的抗体的功能性相关联。最后，我们将使用蛋白质组学方法来定义MHCII抗原呈递分子和辅助性T细胞受体之间的相互作用。重组TCR将用于在结构上定义与糖肽表位的相互作用。我们的方法将确定使糖肽诱导的抗体如此有效的特征。我们将应用我们对这些肽/多糖缀合物的研究来产生对糖缀合物疫苗更有效和更持久的免疫力。