Multivalent Adjuvant Immunization to Prevent Hospital Acquired Infections

项目摘要/摘要 美国每年发生200万例医疗保健相关感染(HAI)，导致9万名患者死亡和 成本约为500-1000亿美元(根据CPI调整为2020美元)。人类免疫缺陷是美国第六大死因， 领先于糖尿病和肾脏疾病。减少人类免疫缺陷病毒感染是美国卫生部和 人类服务1和专家呼吁采取包括接种疫苗在内的新战略来实现这一目标2 ExBaq是一家生物技术公司，由一个由科学家和商业同事组成的财团创立 多年来一直在研究抗药性医院病原体。ExBaq正在开发一种疫苗，以 预防血吸虫病由提供广谱保护的天然免疫刺激分子组成 抗跨王国HAI病原体感染(初步数据)。我们的疫苗包括： A)氢氧化铝(Al(OH)3)，它包含在FDA批准的多种疫苗中；以及 通过多种机制增强免疫力，包括诱导仓库形成，激活 NALP3炎症体，促进巨噬细胞对颗粒的摄取； B)单磷脂A(MPL)，它也包含(与Al(OH)3结合) FDA批准的疫苗，并通过TLR4连接激活NF-κB途径； C)甘露聚糖，它刺激各种先天和获得性免疫途径，在 非肠道给药时的临床试验。 在第一阶段，我们已经证实，这种三联佐剂方案具有最广泛的保护作用 病原体，提供较低的剂量(对商品成本很重要)，与包含全菌的三联疗法相比 用葡聚糖颗粒代替甘露聚糖，或使用四重疗法(初步数据)。三位一体的功效 该方案已在耐碳青霉烯类抗生素的致死性鲍曼不动杆菌和 肺炎克雷伯菌、耐甲氧西林金黄色葡萄球菌(MRSA)和播散性感染 由真菌白色念珠菌和德拉玛根霉(毛霉病)引起。鉴于对革兰氏病的疗效- 对于阳性和阴性细菌和真菌病原体，我们的三价疫苗有可能预防 HAIS由最优先、耐药的院内病原菌引起。在建立了一个 最佳铅成分在第一阶段，第二阶段的目标是建立GMP，进行临床前免疫 毒理学研究，并完成支持IND提交的关键步骤。我们的目标是： 目标1：为我们的疫苗方案建立GMP生产。 目的2：完成临床前免疫毒性研究以支持IND应用。 目标3：在资金结束时完成支持IND备案的关键步骤。

PROJECT SUMMARY/ABSTRACT Two million Healthcare Associated Infections (HAIs) occur per year in the US, killing >90,000 patients and costing ~$50-100 billion (adjusted by CPI to 2020 dollars). HAIs are the 6th leading cause of death in the US, ahead of diabetes and kidney disease. Reducing HAIs is a top priority of the US Department of Health and Human Services1 and experts have called for novel strategies including vaccination to achieve this goal.2 ExBaq is a biotechnology company founded by a consortium of scientists and business colleagues who have spent years studying antibiotic-resistant nosocomial pathogens. ExBaq is developing a vaccine to prevent HAIs comprised of innate-immune stimulatory molecules that provide broad-spectrum protection against infection caused by cross-kingdom HAI pathogens (preliminary data). Our vaccine consists of: A) Aluminum hydroxide (Al(OH)3), which is contained in multiple FDA-approved vaccines, and enhances immunity via multiple mechanisms, including induction of depot formation, activating the NALP3 inflammasome, and enhancing particulate uptake by macrophages; B) Monophosphoryl Lipid A (MPL), which is also contained (in combination with Al(OH)3) in multiple FDA-approved vaccines and activates the NF-κB pathway via TLR4 ligation; C) Mannan, which stimulates a variety of innate and adaptive immune pathways, and was safe in clinical trials when administered parenterally. During Phase I we have confirmed that this triple adjuvant regimen has the broadest protection against pathogens, affording lower doses (important for cost of goods), compared to a triple regimen containing whole glucan particles instead of mannan, or with a quadruple regimen (preliminary data). Efficacy of the triple regimen has been confirmed in lethal mouse models of carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and disseminated infection caused by the fungi Candida albicans and Rhizopus delamar (mucormycosis). Given efficacy against Gram- positive and -negative bacteria and fungal pathogens, our trivalent vaccine has potential to prevent HAIs caused by the highest priority, antibiotic-resistant nosocomial pathogens. Having established an optimal lead composition in Phase I, the goal of Phase II is to establish GMP, conduct pre-clinical immuno- toxicology studies, and to complete key steps to supporting IND submission. Our Aims are to: AIM 1: Establish GMP manufacturing for our vaccine regimen. AIM 2: To complete pre-clinical immuno-toxicity studies to support an IND application. AIM 3: Complete key steps to support IND-filing at end of funding.