Multivalent Adjuvant Immunization to Prevent Hospital Acquired Infections

项目概要/摘要 在美国，每年发生200万起医疗相关感染（HAI），导致> 90，000名患者死亡， 成本约为500 - 1000亿美元（按CPI调整至2020年美元）。HAI是美国第六大死亡原因， 糖尿病和肾病的发病率。减少HAI是美国卫生部的首要任务， 人类服务1和专家呼吁采取包括疫苗接种在内的新策略来实现这一目标。 ExBaq是一家生物技术公司，由一群科学家和商业同事创立， 花了数年时间研究耐药性医院病原体。ExBaq正在开发一种疫苗， 预防由提供广谱保护的先天免疫刺激分子组成的HAI 对抗由跨王国HAI病原体引起的感染（初步数据）。我们的疫苗包括： A）氢氧化铝（Al（OH）3），其包含在多种FDA批准的疫苗中，以及 通过多种机制增强免疫力，包括诱导储库形成，激活 NALP 3炎性体，并增强巨噬细胞的颗粒摄取; B）单磷酰脂质A（MPL），其也被包含在多个（与Al（OH）3组合的）组合物中。 FDA批准的疫苗，并通过TLR 4连接激活NF-κB通路; C）甘露聚糖，它刺激各种先天性和适应性免疫途径，并且在 临床试验时，给药胃肠外。 在第一阶段，我们已经证实，这种三重辅助治疗方案具有最广泛的保护， 病原体，提供较低的剂量（重要的商品成本），相比，三重方案含有整个 葡聚糖颗粒代替甘露聚糖，或使用四重方案（初步数据）。三重功效 方案已在碳青霉烯类耐药鲍曼不动杆菌致死小鼠模型中得到证实， 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 由白色念珠菌和绿根霉引起的毛霉病。鉴于对革兰氏阴性菌的有效性- 阳性和阴性的细菌和真菌病原体，我们的三价疫苗有可能预防 HAI由最高优先级的耐药医院病原体引起。建立了一个 第一阶段是最佳的铅成分，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： 目的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申请。 目标3：完成关键步骤，以支持在资助结束时提交IND。

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.