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

基本信息

批准号：
9093696
负责人：
Hong Xin
金额：
$ 17.12万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-17 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9093696
关键词：
Address Adjuvant Affect Aldolase C Animals Antibodies Antibody Response Antibody-mediated protection 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 fungus immunogenicity immunological intervention improved man mortality mouse model neonate novel pediatric patients prophylactic protective efficacy response synthetic peptide vaccine development vaccine efficacy

项目摘要

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.

描述（由适用提供）：传播的念珠菌病是一种威胁生命的疾病，仍然是美国和许多欧洲国家住院患者中第三大常见的血液感染。我们的疾病管理策略是通过免疫抑制或给药预防而不是治疗。我的实验室成功地使用了新型的全合成肽和糖肽疫苗，以针对白色念珠菌的细胞表面表位作战小鼠的散布念珠菌。有力的证据表明，对肽FBA（源自白色念珠菌细胞表面蛋白双磷酸醛糖酶）和白色念珠菌细胞表面ß-1、2-甘露三糖[ß-（MAN）3]的抗体（源自肽C. c. c. c. c. c. bic-（man）3]）有助于保护。因此，这种糖肽疫苗[ß-（MAN）3-FBA]能够提供双重免疫认知，以帮助确保对白色念珠菌的保护性免疫学。我们还证明，在合成糖肽结合疫苗（ß-（MAN）3-FBA-TT）诱导的抗体依赖性保护的免疫组织化学无需调整的情况下，将TETANIUS毒素添加到合成糖肽偶联疫苗（ß-（MAN）3-FBA-TT）中，这是人类使用疫苗的主要步骤。最近，我们已经确定了一组新型的肽模拟物，在结构上模仿了受保护的表位表位β-（MAN）3，是替代糖肽的替代糖肽的替代性糖肽，其中三个辣椒模仿能够诱导强大的抗体反应和抗体抗体介导的抗体抗体介导的鼠标介导的保护。这项研究的总体目标是设计一种可行使用的新型模ep肽-TT疫苗，并在新的小鼠模型中进一步测试疫苗效率，该疫苗效率通过与白色念珠菌持久的胃肠道结合来密切模拟人类。在AIM 1中，我们将通过与新鉴定的新鉴定的肽模仿者进行聚糖部分来修改糖肽共轭β-（MAN）3-FBA，然后将测试新的MIMOTOPE-FBA偶联疫苗，以在小鼠中测试受保护的有效性。 AIM 2，将修改小鼠，以保护与白色念珠菌的胃肠道结构化，并将在更紧密地模拟人类的宿主条件下测试疫苗效率。