Knowledge-based Vaccines Built on Paradigm Changes in Antigen Presentation

描述（由申请人提供）：目前的糖缀合物疫苗是凭经验合成的，没有基于科学的抗原呈递优化。我们建议建立新一代基于知识的、靶特异性的、结构设计的、高免疫原性和保护性的疫苗，其可以以低得多的成本生产，允许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细胞应答和糖缀合物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，T细胞活化反过来又提供B细胞的帮助。作为我们研究的模型抗原，我们将使用B群链球菌糖缀合物疫苗。 我们的初步数据表明，与传统的范式相反，复杂的糖缀合物分子并不像以前认为的那样由内体隔室处理。因此，目前由疫苗制造商和设计者进行的糖缀合物疫苗的经验构建未能优化免疫原性潜力。更具体地说，目前的糖缀合物疫苗的设计没有考虑哪些表位应呈递给T细胞以获得最佳免疫应答。我们的数据表明，糖肽抗原表位的糖缀合物疫苗，而不是单独的肽表位，实际上提出的主要组织相容性复合物II类（MHCII）的抗原呈递细胞（APC）的表面上的背景下的T细胞。在拟议的研究中，我们将确定CD4 + T细胞是否可以区分糖肽肽和糖肽表位是否可以诱导IgM到IgG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，在T细胞帮助方面，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，我们将生产具有更高免疫原性的疫苗;更长的免疫力;更低的剂量要求（因此更高的安全性）;并且很可能在老年人和儿童中具有更高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.