Knowledge-based Vaccines Built on Paradigm Changes in Antigen Presentation

描述(由申请人提供)：目前的糖结合疫苗是经验性合成的，没有基于科学基础的抗原呈递优化。我们建议建立新一代以知识为基础的、靶标特定的、结构设计的、高度免疫原性和保护性的疫苗，这些疫苗可以以低得多的成本生产，从而允许在全球范围内更广泛地使用。我们预计，从我们提出的关于抗原处理和提呈、T细胞反应和糖结合疫苗设计的机制研究中获得的新见解将重新定义疫苗设计影响T细胞激活的机制，而T细胞激活反过来提供B细胞帮助。作为我们研究的模式抗原，我们将使用B群链球菌糖结合疫苗。我们的初步数据显示，与传统的模式相反，复杂的糖共轭分子并不像以前认为的那样由内体间隔处理。因此，目前由疫苗制造商和设计者进行的糖结合疫苗的经验构建未能优化免疫原性潜力。更具体地说，目前的糖结合疫苗的设计没有考虑哪些表位应该呈递给T细胞以获得最佳的免疫反应。我们的数据显示，糖结合疫苗的糖肽表位，而不仅仅是表位，实际上是以抗原提呈细胞(APC)表面的主要组织相容性复合体II类(MHCII)的形式呈现给T细胞的。在拟议的研究中，我们将确定CD4T细胞是否能够区分糖肽和多肽，以及糖肽表位是否可以诱导从IgM到IgG的转换。有了这些信息，我们可以在最佳频率和密度下合成最佳表位，通过APC的高效处理和呈递以及高度特异性的T细胞识别来增强疫苗的免疫原性和保护性。根据我们的数据，我们认为，就T细胞帮助而言，这些免疫原性表位是糖肽。通过优化使用最具免疫原性的成分，我们将生产出免疫原性更强、免疫寿命更长、剂量要求更低(因此更安全)的疫苗，并极有可能提高老年人和儿童的免疫原性和保护能力。

DESCRIPTION (provided by applicant): Current glycoconjugate vaccines are synthesized empirically, without scientifically based optimization of antigen presentation. We propose to establish a new generation of knowledge- based, target-specific, structurally designed, highly immunogenic and protective vaccines that can be produced at much lower cost, allowing for much wider use on a global scale. We anticipate that novel insights obtained from our proposed mechanistic studies on antigen processing and presentation, T cell responses, and glycoconjugate vaccine design will redefine the mechanisms by which vaccine design influences T cell activation, which in turn provides B cell help. As the model antigens for our studies, we will use group B streptococcal glycoconjugate vaccines. Our preliminary data show that, contrary to the traditional paradigm, complex glycoconjugate molecules are not handled by the endosomal compartment as previously believed. Consequently, the empirical construction of glycoconjugate vaccines, as presently undertaken by vaccine manufacturers and designers, fails to optimize immunogenic potential. More specifically, current glycoconjugate vaccines are designed without consideration of which epitopes should be presented to T cells for optimal immune responses. Our data show that glycopeptide epitopes of glycoconjugate vaccines, rather than peptide epitopes alone, are actually presented to T cells in the context of major histocompatibility complex class II (MHCII) on the surface of antigen-presenting cells (APCs). In the proposed studies, we will determine whether CD4+ T cells can differentiate glycopeptides from peptides and whether glycopeptide epitopes can induce IgM-to-IgG switching. With this information in hand, we can synthetically mimic optimal epitopes at optimal frequency and density, enhancing vaccine immunogenicity and protection through efficient processing and presentation by APCs and highly specific T cell recognition. On the basis of our data, we believe that, in terms of T cell help, these immunogenic epitopes are glycopeptides. By optimizing the use of the most immunogenic components, we will produce vaccines with greater immunogenicity; longer-lived immunity; lower dosage requirements (and therefore greater safety); and, in all probability, greater immunogenicity and protective capacity in elderly individuals and in children.