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

 描述(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的住院患者中仍然是第三种最常见的血液感染。我们的疾病管理战略是预防，而不是通过免疫或注射预先形成的抗体进行治疗。我的实验室已经成功地使用了针对白色念珠菌细胞表面表位的新型全合成多肽和糖肽疫苗来对抗小鼠的播散性念珠菌病。强有力的证据表明，针对多肽FBA(来源于白色念珠菌细胞表面蛋白果糖二磷酸缩醛酶)和白色念珠菌细胞表面β-1，2-甘露三糖的抗体有助于保护。因此，这种糖肽疫苗[ç-(Man)3-FBA]能够提供双重免疫识别，以帮助确保对白色念珠菌的保护性免疫。我们还证明，在合成的糖肽结合疫苗(？)-(Man)3-FBA-TT中加入破伤风类毒素可诱导抗体依赖的保护性免疫，而不需要佐剂，这是人类使用疫苗的一大进步。最近，我们已经确定了一组新的多肽模拟表位，它在结构上模拟保护性表位？(Man)3，作为替代糖肽疫苗的部分糖蛋白的替代免疫原。引人注目的是，其中三个多肽模拟表位能够在小鼠中诱导强大的抗体反应和抗体介导性保护。这项研究的总体目标是设计一种新的可供人类使用的模拟表位-多肽-TT疫苗，并在一种新的小鼠模型上进一步测试疫苗的有效性，该模型通过白念珠菌长期在胃肠道定植来模拟人类。在目标1中，我们将用新发现的多肽-模拟表位取代糖肽的部分来修饰糖肽结合物-(Man)3-FBA，然后测试新的模拟表位-FBA结合疫苗对小鼠的保护效果。目的2，用白色念珠菌对小鼠进行改造，使其在胃肠道长期定植，并在更接近人类的宿主条件下测试疫苗的效力。

 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.