Vaccine Strategies for Candidal Infections

念珠菌感染的疫苗策略

• 批准号: 7157044
• 负责人: John E Edwards
• 金额: $ 12.88万
• 依托单位: NOVADIGM THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2007-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7157044
• 关键词: Candida; antigens; candidiasis; genes; infection; model; proteins

DESCRIPTION (provided by applicant): Candida is a fungus that is among the most common causes of infections in hospitalized patients in the United States and worldwide. Candida spp. are 1 of the most common microbes that infect the blood and urine of hospitalized patients. The cost associated with Candida blood infections alone exceeds at least $1 billion per year in the US. Even with therapy, 40-50% of patients with Candida blood infections die from the infection. Furthermore, resistance to antifungal therapies is rising among Candida organisms. For these reasons, a vaccine to prevent life threatening Candida infections is particularly attractive. Such a vaccine could potentially be useful for large populations including nearly all patients who undergo surgery to the chest or abdomen, newborns in intensive care units, and other patients with weakened immune systems, including cancer patients receiving chemotherapy. We have isolated a protein that allows Candida to adhere to human cells. The gene that encodes this protein is called ALS1, and it is a member of a family of related genes that code for at least 9 proteins, most of which are also adhesins. Active immunization with the recombinant N-terminus of Als1p (rAls1p-N) significantly protects mice from otherwise rapidly lethal bloodstream and deep organ Candida infection. More recently we have purified a related protein, rAls3p-N, that is also encoded by a member of the ALS gene family. We have discovered that rAls3p-N results in a broader immune response than rAls1p-N, raising the possibility that rAls3p-N might be more effective than rAls1p-N as a vaccine. We propose to define and optimize vaccine-mediated protection in preparation for future clinical studies in humans by identifying the optimally protective Als protein (Alsp) in murine models of infection. The efficacy of rAls1p-N vs. rAls3p-N vs. combination rAls1p-N + rAls3p-N vs. adjuvant alone will be compared in our murine models of bloodstream infection, oral thrush, or vaginal yeast infection. Although the current application is focused on the development of an anti-Candida vaccine, we have extremely novel data showing cross-protection of the rAls1p-N vaccine against S. aureus in the murine model. Therefore, we will also compare the efficacy of the vaccine immunogens in our murine model of S. aureus bloodstream infection. Finally, in other systems, activation of a host immune receptor called TLR5 has been shown to enhance the efficacy of vaccines. Therefore, to further enhance the immune response to the Alsp immunogens, we will create novel combination proteins by mixing the Alsp immunogens with special proteins that activate TLR5. Once we have optimized our immunogens, we intended to prepare the vaccine product for human trials in the future phases of this project. Due to modern therapeutic advances for sustained life support, patients undergoing a variety of medical procedures or with a variety of medical conditions have become at risk for developing life-threatening infections caused by the fungus Candida. Among these procedures and conditions are: being treated in an intensive care unit, having a plastic catheter in a large vein, undergoing surgery to the chest or abdomen, being the victim of trauma injuries (both domestic, such as motor vehicle accidents, and military), having extensive burn injuries, being a premature neonate, and having cancer and undergoing chemotherapy. Given how common these conditions are, the development of a vaccine that protects against Candida infections could save hundreds of thousands of lives as well as substantially reduce hospitalization costs in both the United States and other countries where highly effective medical advances have been made.

描述（由申请人提供）：念珠菌是一种真菌，是美国和全球住院患者感染的最常见原因之一。念珠菌是感染住院患者血液和尿液的最常见微生物之一。在美国，仅与念珠菌血液感染相关的费用每年就超过至少10亿美元。即使有治疗，40-50%的念珠菌血液感染患者死于感染。此外，念珠菌对抗真菌治疗的耐药性正在上升。由于这些原因，预防威胁生命的念珠菌感染的疫苗特别有吸引力。这种疫苗可能对大规模人群有用，包括几乎所有接受胸部或腹部手术的患者，重症监护室的新生儿，以及其他免疫系统较弱的患者，包括接受化疗的癌症患者。我们已经分离出一种蛋白质，使念珠菌粘附在人体细胞上。编码这种蛋白质的基因被称为ALS 1，它是编码至少9种蛋白质的相关基因家族的成员，其中大多数也是粘附素。用Als 1 p的重组N-末端（rAls 1 p-N）主动免疫显著保护小鼠免受否则快速致死的血流和深部器官念珠菌感染。最近，我们已经纯化了一个相关的蛋白质，rAls 3 p-N，这也是由ALS基因家族的成员编码。我们发现rAls 3 p-N比rAls 1 p-N产生更广泛的免疫应答，这提高了rAls 3 p-N作为疫苗可能比rAls 1 p-N更有效的可能性。我们建议定义和优化疫苗介导的保护，在未来的临床研究在人类中确定最佳的保护性Als蛋白（Alsp）在小鼠感染模型的准备。将在我们的血流感染、口腔鹅口疮或阴道酵母菌感染的鼠模型中比较rAls 1 p-N与rAls 3 p-N与组合rAls 1 p-N + rAls 3 p-N与单独佐剂的功效。虽然目前的应用集中在抗念珠菌疫苗的开发上，但我们有非常新的数据显示rAls 1 p-N疫苗对S.金黄色葡萄球菌在小鼠模型中。因此，我们还将比较疫苗免疫原在我们的S.金黄色葡萄球菌血流感染最后，在其他系统中，被称为TLR 5的宿主免疫受体的激活已被证明可以增强疫苗的功效。因此，为了进一步增强对Alsp免疫原的免疫应答，我们将通过将Alsp免疫原与激活TLR 5的特殊蛋白质混合来产生新的组合蛋白质。一旦我们优化了我们的免疫原，我们打算在该项目的未来阶段准备用于人体试验的疫苗产品。由于持续生命支持的现代治疗进展，经历各种医疗程序或患有各种医疗状况的患者已成为发展由真菌念珠菌引起的危及生命的感染的风险。这些程序和条件包括：在重症监护室接受治疗，在大静脉中插入塑料导管，接受胸部或腹部手术，成为创伤的受害者（家庭，如机动车事故和军事），具有广泛的烧伤，早产儿，以及患有癌症并接受化疗。鉴于这些情况是多么常见，开发一种预防念珠菌感染的疫苗可以挽救数十万人的生命，并大大降低美国和其他国家的住院费用，这些国家已经取得了高效的医学进步。