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。我们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。我们还证明了在合成的糖肽结合物中添加破伤风类毒素 疫苗-(Man)3-FBA-TT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。本研究的总体目标是设计和测试一种新的基于模拟表位-多肽的、可供人类使用的双表位疫苗。此外，我们将在一种新的小鼠模型中测试糖肽结合疫苗以及新的基于模拟表位的多肽疫苗(S)的有效性，该模型通过白念珠菌长期在胃肠道定植来接近模拟人类。在目标1中，我们将用新发现的多肽模拟表位取代糖链部分来修饰糖肽偶联物？(Man)3-FBA。在目标2中，将对小鼠进行改造，使其在胃肠道长期定居白色念珠菌，并将在更接近于人类的宿主条件下测试疫苗效力。

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. 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.