NOVEL LINEAR PEPTIDE UNIVERSALL MALARIA VACCINES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。合成肽疫苗的临床试验表明，诱导持续免疫需要生物佐剂。虽然已经使用了几种策略来优化多肽抗原的传递，但现有的数据表明，目前还没有最佳的配方。我们最近报道了一种新的系统来递送基于多肽结构的亚单位疫苗。该战略包括我们描述的疟疾通用T细胞表位的关联，并与B细胞表位一起合成。氨基和羧基末端的半胱氨酸残基被包括在线性序列中，以增加亚基的价态。我们已经用SELDI质谱学证实了这种拓扑结构有利于这种线性多肽嵌合体(LPCs)的自发聚合，并且这些多肽结构的免疫原性依赖于通用T细胞表位和同种聚合的存在。这些LPC可诱导高抗体滴度、细胞因子产生和持久的免疫反应。随着另一组LPC免疫原的设计和测试，这种抗原传递的技术方法得到了进一步的进步，它在不同品系的小鼠中引发了高亲和力抗体以及Th1和Th2免疫反应。含有多达三个表位的复杂LPCs，其中包括一个CTL-I类限制性九聚体，可诱导针对单个组分的免疫反应。CTL表位的成功传递到MHC I类隔室，为使用含有通用T细胞表位的LPCS开发针对细胞内病原体的疫苗以及诱导抗肿瘤免疫提供了可能性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Clinical trials of synthetic peptide vaccines have indicated that biological adjuvants are required to induce a sustained immunity. Although several strategies have been used to optimize the delivery of peptide antigens, the data available show that an optimal formulation is not yet available. We recently reported a novel system to deliver subunit vaccines based in peptide constructs. The strategy includes the association of malaria universal T cell epitopes described by us and synthesized in tandem with B cell epitopes. Amino and carboxyl terminal cysteine residues were included in the linear sequences to increase subunit valence. We have confirmed that this topology favors the spontaneous polymerization of such linear peptide chimeras (LPCs) using SELDI mass spectroscopy, and that the immunogenicity of the peptide constructs depend on the presence of universal T cell epitopes and homo polymerization. These LPCs induced high antibody titers, cytokine production and long-lasting immune responses. This technological approach for antigen delivery has been advanced further, with the design and testing of an additional set of LPC immunogens, which elicited high affinity antibodies as well as Th1 and Th2 immune responses in different strains of mice. Complex LPCs containing up to three epitopes, which include a CTL-class I restricted nonamer, induce immune response against individual components. The successful delivery of CTL epitopes to the MHC class I compartment opens the possibility of using LPCs containing universal T cell epitopes for developing vaccines against intracellular pathogens as well as for induction of anti-tumoral immunity.