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

基于模拟表位肽的抗念珠菌病双表位疫苗的设计

• 批准号: 9117145
• 负责人: Hong Xin
• 金额: $ 21.95万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-17 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117145
• 关键词: Address; Adjuvant; Affect; Aldolase C; Animals; Antibodies; Antibody Response; Antifungal Agents; Antifungal Therapy; Antigens; Blood; Candida albicans; Candidiasis; Carbohydrates; Cell Surface Proteins; Cell surface; Communicable Diseases; Complex; Conjugate Vaccines; Country; Coupling; Developing Countries; Development; Disease; Disease Management; Disseminated candidiasis; Ensure; Epitopes; European; Extremely Low Birth Weight Infant; FDA approved; Frequencies; Fructosediphosphate Aldolase; Gastrointestinal tract structure; Generations; Glycopeptides; Goals; Health; Hospitals; Human; Immune; Immunity; Immunization; Incidence; Individual; Infection; Intestines; Lead; Life; Mass Vaccinations; Modeling; Morbidity - disease rate; Mus; Passive Immunization; Patients; Peptide Vaccines; Peptides; Polysaccharides; Prevention; Prevention approach; Reporting; Research; Resources; Sepsis; Serum; Stream; Testing; Tetanus Toxoid; Therapeutic antibodies; United States; Vaccination; Vaccines; Work; base; combat; design; disorder prevention; efficacy testing; fungus; immunogenicity; immunological intervention; improved; man; mortality; mouse model; neonate; novel; pediatric patients; peptide based vaccine; prophylactic; response; synthetic peptide; vaccine development; vaccine efficacy

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.

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，并且仍然是美国和许多欧洲国家住院患者中第三大常见的血流感染。我们的疾病管理策略是通过免疫接种进行预防，而不是治疗。我们的实验室已成功使用新型全合成肽和糖肽疫苗对抗白色念珠菌细胞表面表位，以对抗小鼠播散性念珠菌病。针对肽 Fba（源自白色念珠菌细胞表面蛋白果糖二磷酸醛缩酶）和白色念珠菌细胞表面 ß-1, 2-甘露三糖 [ß-(Man)3]）的特异性抗体有助于保护。疫苗 [ß-(Man)3-Fba] 能够提供双重免疫识别，以帮助确保针对白色念珠菌的保护性免疫力。我们还证明了破伤风的添加。类毒素与合成糖肽缀合物 疫苗 ß-(Man)3-Fba-TT) 抗体无需佐剂即可诱导依赖性保护性免疫，这是人类使用疫苗的重大进步。最近，我们鉴定了一组新型肽模拟表位，它在结构上模仿保护性表位 ß-(Man)3，作为替代糖肽疫苗的聚糖部分的替代免疫原。这项研究的总体目标是设计和测试一种新的基于模拟表位的双肽。此外，我们将在一个新的小鼠模型中测试糖肽结合疫苗以及新的模拟表位疫苗的功效，该模型通过长期的胃肠道定植来模拟人类。在目标 1 中，我们将通过用新鉴定的肽模拟表位替换聚糖部分来修饰糖肽缀合物 ß-(Man)3-Fba。 2、对小鼠进行改造，使白色念珠菌在胃肠道中长期定植，并在更接近人类条件的宿主条件下测试疫苗功效。