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。本实验室已成功地使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将破伤风类毒素添加到合成糖肽缀合物疫苗（α-（Man）3-Fba-TT）中诱导了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。引人注目的是，三种肽模拟表位能够在小鼠中诱导稳健的抗体应答和抗体介导的保护。本研究的总体目标是设计一种新的模拟表位-肽-TT疫苗，可用于人类使用，并进一步测试疫苗在一种新的小鼠模型中的效力，该小鼠模型通过具有C.白色念珠菌。在目的1中，我们将通过用新鉴定的肽-模拟表位取代聚糖部分来修饰糖肽缀合物α-（Man）3-Fba，然后将测试新的模拟表位-Fba缀合物疫苗在小鼠中的保护效力。目的2，将小鼠改造成具有持久的胃肠道定殖与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. My 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. Strikingly, three of the peptide mimotopes were able to induce robust antibody responses and antibody-mediated protection in mice. The overall goal of this research is to design a new mimotope-peptide-TT vaccine feasible for human use, and further test the vaccine efficacy 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-mimotopes, and then the new mimotope-Fba conjugate vaccines will be tested for protective efficacy in mice. 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.