Design of a mimotope-peptide based double epitope vaccine against candidiasis

描述（由申请人提供）：播散性念珠菌病是一种危及生命的疾病，在美国和许多欧洲国家，它仍然是住院患者中第三常见的血流感染。我们的疾病管理策略是通过免疫或预先形成的抗体进行预防，而不是治疗。本实验室已成功地利用新型全合成肽和糖肽疫苗对抗小鼠播散性白念珠菌病。强有力的证据表明，对肽Fba（来源于C. albicans细胞表面蛋白果糖二磷酸醛缩酶）和C.白念珠菌细胞表面的β-1，2-甘露三糖[β-（Man）3]）起保护作用。因此，这种糖肽疫苗[α-（Man）3-Fba]能够提供双重免疫识别，以帮助确保针对C的保护性免疫。白色念珠菌我们还证明了在合成的糖肽结合物中加入破伤风类毒素， 疫苗β-（Man）3-Fba-TT）诱导的抗体依赖性保护性免疫而不需要佐剂，这是人类使用的疫苗的主要进步。最近，我们已经确定了一组新的肽模拟表位，其在结构上模拟保护性表位α-（Man）3，作为替代免疫原，取代糖肽疫苗的聚糖部分。本研究的总体目标是设计和测试一种新的基于模拟表位-肽的双表位疫苗，该疫苗可用于人类。此外，我们将在新的小鼠模型中测试糖肽缀合物疫苗以及基于新的模拟表位-肽的疫苗的功效，该小鼠模型通过具有C.白色念珠菌目的一：用新鉴定的肽模拟表位取代糖肽偶联物α-（Man）3-Fba的聚糖部分，对糖肽偶联物α-（Man）3-Fba进行修饰。在目标2中，小鼠将被修饰为具有C.白色念珠菌，疫苗效力将在更接近模拟人类的宿主条件下进行测试。

DESCRIPTION (provided by applicant): Disseminated candidiasis is a life-threatening disease and remains the third most common bloodstream infection in hospitalized patients both in the United States and many European countries. Our strategy for disease management is prevention, rather than treatment, through immunization or administration of preformed antibodies. Our lab has successfully used novel fully synthetic peptide and glycopeptide vaccines against Candida albicans cell surface epitopes combat disseminated candidiasis in mice. Strong evidences show that antibodies specific for the peptide Fba (derived from C. albicans cell surface protein fructose bisphosphate aldolase) and C. albicans cell surface ß-1, 2-mannotriose [ß-(Man)3]) contribute to the protection. Therefore, this glycopeptide vaccine [ß-(Man)3-Fba] is able to provide dual immune recognition to help ensure protective immunity against C. albicans. We also demonstrated that addition of tetanus toxoid to the synthetic glycopeptide conjugate vaccine ß-(Man)3-Fba-TT) induced antibody-dependent protective immunity without the need for adjuvant, which are a major step forward in a vaccine for human use. Most recently, we have identified a panel of novel peptide mimotopes, which structurally mimics protective epitope ß-(Man)3, as surrogate immunogens that substitute glycan part of glycopeptide vaccine. The overall goal of this research is to design and test a new mimotope-peptide based double epitope vaccine feasible for human use. Furthermore, we will test the efficacy of glycopeptide conjugate vaccine, as well as the new mimotope-peptide based vaccine(s), in a new mouse model that closely simulates humans by having protracted GI tract colonization with C. albicans. In Aim 1, we will modify the glycopeptide conjugate ß-(Man)3-Fba by taking place of glycan part with newly identified peptide-mimotope. In Aim 2, mice will be modified to have protracted GI tract colonization with C. albicans, and vaccine efficacy will be tested under host conditions that more closely simulate those of humans.