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中最常见的感染原因之一。念珠菌属。是感染住院患者血液和尿液的最常见微生物之一。在美国，与念珠菌血液感染相关的成本每年至少超过10亿美元。即使接受治疗，念珠菌血液感染患者中有40-50％因感染而死亡。此外，念珠菌生物之间对抗真菌疗法的抗性正在上升。由于这些原因，防止威胁生命的念珠菌感染的疫苗特别有吸引力。这样的疫苗可能对大量人群有用，包括几乎所有接受手术的患者，对胸部或腹部进行手术，重症监护病房中的新生儿以及其他免疫系统疲软的患者，包括接受化学疗法的癌症患者。我们分离了一种蛋白质，该蛋白质使念珠菌可以粘附在人类细胞上。编码该蛋白的基因称为ALS1，它是与至少9种蛋白质编码的相关基因家族的成员，其中大多数也是粘附素。用ALS1P（RALS1P-N）重组N端进行主动免疫可显着保护小鼠免受其他迅速致命的血液和深层器官念珠菌感染的影响。最近，我们纯化了相关的蛋白质RALS3P-N，该蛋白也由ALS基因家族的成员编码。我们已经发现，RALS3P-N比RARS1P-N产生更广泛的免疫反应，从而提高了RALS3P-N可能比RARS1P-N作为疫苗更有效的可能性。我们建议通过在鼠类感染模型中识别最佳保护性ALS蛋白（ALSP）来定义和优化疫苗介导的保护，以为人类的未来临床研究做准备。在我们的血液感染，口服鹅口疮或阴道酵母菌感染的鼠模型中，将比较RALS1P-N与RALS3P-N与RALS1P-N + RALS3P-N与佐剂组合的功效。尽管当前的应用集中在抗candida疫苗的开发上，但我们的数据非常新颖，显示了鼠模型中对金黄色葡萄球菌的RARS1P-N疫苗的交叉保护。因此，我们还将比较金黄色葡萄球菌感染的鼠模型中疫苗免疫原子的功效。最后，在其他系统中，已证明称为TLR5的宿主免疫受体的激活可以增强疫苗的功效。因此，为了进一步增强对ALSP免疫原子的免疫反应，我们将通过将ALSP免疫原混合到激活TLR5的特殊蛋白质来创建新型组合蛋白。一旦我们优化了免疫原，我们打算在该项目的未来阶段为人类试验准备疫苗产品。由于现代的持续生命支持的治疗进展，接受多种医疗程序或各种医疗状况的患者已面临着由真菌念珠菌引起的威胁生命的感染的风险。这些程序和条件包括：在重症监护室中接受治疗，在大静脉中具有塑料导管，对胸部或腹部进行手术，是创伤受伤的受害者（包括家用，例如汽车事故和军事），患有广泛的烧伤伤害，过早的neonanate，并且是癌症和癌症和癌症和化学疗法。鉴于这些条件是多么普遍，可以防止念珠菌感染的疫苗的开发可以挽救数十万生命，并在美国和其他已经取得了高度有效的医疗进展的国家中大大降低住院费用。