Synthetic glycopeptide vaccines that enhance resistance to candidiasis

增强念珠菌病抵抗力的合成糖肽疫苗

• 批准号: 8571542
• 负责人: Hong Xin
• 金额: $ 8.19万
• 依托单位: CHILDREN'S HOSPITAL (NEW ORLEANS)
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8571542
• 关键词: Active Immunization; Address; Adjuvant; Affect; Aldolase C; Animals; Antibodies; Antibody-mediated protection; Antifungal Agents; Antifungal Therapy; Blood; Candida; Candida albicans; Candidiasis; Cell Surface Proteins; Cell surface; Conjugate Vaccines; Country; Development; Disease; Disease Management; Disseminated candidiasis; Drug Formulations; Epitopes; European; Event; Frequencies; Fructosediphosphate Aldolase; Glycopeptides; Goals; Hospitals; Human; Humoral Immunities; Immune; Immunity; Immunization; Immunocompromised Host; Individual; Infection; Infectious Agent; Life; Medical; Morbidity - disease rate; Mus; Mycoses; Neutropenia; Passive Immunization; Patients; Peptide Vaccines; Peptides; Polysaccharides; Population; Prevention; Research; Resistance; Risk Factors; Sepsis; Stream; Testing; Tetanus Toxoid; Therapeutic; United States; Vaccination; Vaccines; Work; combat; disorder prevention; high risk; improved; man; mortality; novel; novel vaccines; public health relevance; synthetic peptide; vaccine development; vaccine efficacy; vaccine-induced immunity

DESCRIPTION (provided by applicant): Morbidity and mortality from invasive fungal infections remain unacceptably high despite availability of new antifungal agents, underscoring the need for more effective preventative strategies. For example, hematogenously 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. Novel fully synthetic peptide and glycopeptide vaccines against Candida albicans cell surface epitopes have been successfully used to combat disseminated candidiasis in mice in our lab. 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 ¿-1, 2-mannotriose [¿-(Man)3]) contribute to the protection. Most recently, we demonstrated that addition of tetanus toxoid to the synthetic glycopeptide conjugate vaccine induced antibody-dependent protective immunity without the need for adjuvant, which are a novel observation and a major step forward in a vaccine for human use. The overall goal of this research is to preserve the duality of vaccine protection, and broaden the range of the protection against Candida species of medical significance. In Aim 1, we will investigate peptides that are universally expressed in a variety of Candida species, and test new glycopeptide vaccines for efficacy in protecting against disseminated candidiasis. In Aim 2, we will determine whether immunity established in normal mice protects the animals during a neutropenic episode. Neutropenia is one of the most common risk factor for the development of hematogenously disseminated candidiasis in humans. This study will address the fundamental question concerning vaccine induced immunity in high-risk populations.

描述（由申请人提供）：尽管有新的抗真菌药物，侵袭性真菌感染的发病率和死亡率仍然高得不可接受，这强调了需要更有效的预防策略。例如，血源性传播的念珠菌病是一种危及生命的疾病，并且在美国和许多欧洲国家的住院患者中仍然是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。针对白念珠菌细胞表面抗原表位的新型全合成肽和糖肽疫苗在本实验室已成功地用于对抗小鼠播散性念珠菌病。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<$-1，2-甘露三糖[<$-（Man）3]）起保护作用。最近，我们证明了破伤风类毒素的合成糖肽缀合物疫苗诱导抗体依赖性保护性免疫，而不需要佐剂，这是一个新的观察和人类使用的疫苗向前迈出的重要一步。本研究的总体目标是保持疫苗保护的双重性，并扩大对具有医学意义的念珠菌属的保护范围。在目标1中，我们将研究在各种念珠菌属中普遍表达的肽，并测试新的糖肽疫苗在预防播散性念珠菌病方面的功效。在目标2中，我们将确定在正常小鼠中建立的免疫力是否在贫血发作期间保护动物。中性粒细胞增多症是人类发生血源性播散性念珠菌病最常见的危险因素之一。这项研究将解决有关疫苗诱导的免疫力在高危人群中的基本问题。