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合成的，没有基于科学的抗原呈递优化。我们建议建立新一代以知识为基础的、针对特定目标的、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，从而在全球范围内更广泛地使用。我们预计，从我们提出的抗原加工和呈递、T细胞反应和糖缀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细胞活化的机制，从而为B细胞提供帮助。作为我们研究的模型抗原，我们将使用B组链球菌糖结合疫苗。我们的初步数据表明，与传统范式相反，复杂的糖缀合分子并不像以前认为的那样由内体室处理。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现给T细胞以获得最佳免疫反应。我们的数据表明，糖结合疫苗的糖肽表位，而不是单独的肽表位，实际上是在抗原呈递细胞（APCs）表面的主要组织相容性复合体II类（MHCII）的背景下呈递给T细胞的。在拟议的研究中，我们将确定CD4+ T细胞是否可以从多肽中分化糖肽，以及糖肽表位是否可以诱导igm到igg的转换。有了这些信息，我们可以以最佳频率和密度合成模拟最佳表位，通过apc的有效加工和呈递以及高度特异性的T细胞识别，增强疫苗的免疫原性和保护作用。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的疫苗；长期免疫力;更低的剂量要求（因此更安全）；而且，很可能老年人和儿童具有更强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.