Synthetic glycopeptide vaccines that enhance resistance to candidiasis

描述（由申请人提供）：尽管有新的抗真菌药物可用，侵袭性真菌感染的发病率和死亡率仍然高得令人无法接受，强调需要更有效的预防策略。例如，血源性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，它仍然是住院患者中第三大最常见的血液感染。我们的疾病管理战略是通过免疫或预先形成的抗体进行预防，而不是治疗。在我们的实验室中，针对白色念珠菌细胞表面表位的新型全合成肽和糖肽疫苗已成功用于对抗小鼠播散性念珠菌病。强有力的证据表明，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- 1,2 -甘露糖[-(Man)3])的特异性抗体有助于保护。最近，我们证明了在合成糖肽结合疫苗中添加破伤风类毒素可诱导抗体依赖性保护性免疫，而无需佐剂，这是一种新的观察结果，也是人类使用疫苗的重要一步。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物种的保护范围。在Aim 1中，我们将研究在多种念珠菌中普遍表达的肽，并测试新的糖肽疫苗对预防播散性念珠菌病的功效。在Aim 2中，我们将确定在正常小鼠中建立的免疫是否在中性粒细胞减少发作期间保护动物。中性粒细胞减少症是人类发生血液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高危人群疫苗诱导免疫的基本问题。

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.