Vaccine Strategies for Candidal Infections

描述(申请人提供)：念珠菌是一种真菌，是美国和世界各地住院患者感染的最常见原因之一。假丝酵母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成本就超过每年至少10亿美元。即使接受治疗，40%-50%的念珠菌血液感染患者也会死于感染。此外，假丝酵母菌对抗真菌治疗的抗药性正在上升。出于这些原因，预防危及生命的念珠菌感染的疫苗特别有吸引力。这种疫苗可能对大量人群有用，包括几乎所有接受胸部或腹部手术的患者，重症监护病房的新生儿，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，可以让念珠菌附着在人类细胞上。编码这种蛋白质的基因被称为ALS1，它是至少编码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。重组Als1p(rAls1p-N)主动免疫可显著保护小鼠免受快速致死血流和深部器官念珠菌的感染。最近，我们纯化了一种相关蛋白rAls3p-N，它也是由ALS基因家族的一个成员编码的。我们发现rAls3p-N比rAls1p-N产生更广泛的免疫反应，这增加了rAls3p-N作为疫苗可能比rAls1p-N更有效的可能性。我们建议通过在小鼠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，为未来的人类临床研究做准备。我们将比较rAls1p-N与rAls3p-N与rAls1p-N+rAls3p-N与单独佐剂在我们的小鼠血流感染、口腔鹅口疮或阴道酵母菌感染模型中的疗效。尽管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，rAls1p-N疫苗在小鼠模型中对金黄色葡萄球菌具有交叉保护作用。因此，我们还将比较疫苗免疫原在我们的金黄色葡萄球菌血流感染小鼠模型中的疗效。最后，在其他系统中，激活一种名为TLR5的宿主免疫受体已被证明可以增强疫苗的效力。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TLR5的特殊蛋白混合来创造新的组合蛋白。一旦我们优化了我们的免疫原，我们打算在这个项目的未来阶段为人体试验准备疫苗产品。由于可持续生命支持的现代治疗进展，接受各种医疗程序或患有各种医疗条件的患者已面临由真菌假丝酵母菌引起的危及生命的感染的风险。这些程序和条件包括：在重症监护病房接受治疗，在大静脉内留有塑料导管，接受胸部或腹部手术，受到创伤(包括家庭创伤，如机动车事故和军事创伤)的受害者，大面积烧伤，早产儿，以及癌症和接受化疗。考虑到这些情况是多么普遍，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，并在美国和其他取得高效医学进步的国家大幅降低住院成本。

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.