Multivalent Adjuvant Immunization to Prevent Hospital Acquired Infections

项目摘要 根据CDC的数据，美国每年发生550，000例医疗相关感染（HAI）， 约1000亿美元，杀死数万名患者。减少HAI是美国DHHS的首要任务， NIH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是由科学家和商业同事创立的，他们花了数年时间研究抗生素， 耐药的医院病原体。我们做了一个惊人的观察， 激活先天免疫可提供广谱、短期保护，防止致命感染 由多种HAI病原体引起（初步数据）。我们的三重辅助治疗方案包括：1） 氢氧化铝（Al（OH）3）; 2）单磷酰脂质A（MPL）;和3）全葡聚糖颗粒（WGP）。 这种三重佐剂方案保护小鼠免受由革兰氏阳性菌引起的致死性菌血症。 病原菌，耐甲氧西林S.金黄色葡萄球菌（MRSA）和极端耐药（XDR）革兰氏阴性 病原体A.鲍曼不动杆菌。特别是WGP和MPL分别影响革兰阳性和革兰阴性 Al（OH）3是有效的，两者都需要Al（OH）3。最后，初步数据表明，多糖， 甘露聚糖，可以进一步加强保护。鉴于对革兰氏阳性菌和革兰氏阴性菌的有效性 病原体，我们的疫苗有可能预防HAI引起的最高优先级， 急性住院患者中最致命和耐药的医院病原体。的目标 这一原理验证的I期STTR是为了确定最佳的佐剂剂量和组成，以支持II期 该应用程序将使GMP生产、药物毒理学和生物标志物研究能够支持未来的IND。 目的1：确定最佳剂量的三重辅助治疗方案，以达到最大疗效， 病原体我们将确定是否可以提高疗效和持久性延长增加佐剂 在患有菌血症或肺炎的小鼠中，小鼠将用递增的佐剂剂量接种疫苗，或 安慰剂，然后在7、21和42天后IV或经肺感染（涵盖US的1、2和3 STDEV 住院时间）与高毒力临床血液和肺分离的A.鲍曼不动杆菌（HUMC 1）或a MRSA（LAC）的USA 300临床分离株。主要结局将是至濒死状态的时间（死亡不是 根据IACUC/NIH允许），肺和/或血液细菌负荷和细胞因子作为次要结局。 目的2：确定将甘露聚糖掺入四倍佐剂中是否进一步提高疗效和/或 能够降低三倍佐剂的剂量以降低商品成本。我们将决定是否在 三佐剂混合物的不同剂量提高了功效和/或能够降低有效剂量。小鼠将 通过静脉或肺部感染A. baumannii和S.金黄色。结果指标如上所述。 这些原理证明/可行性结果将为第二阶段STTR奠定基础，该阶段将侧重于GMP 和药物毒性研究，以及定义与保护相关的生物标志物，以实现IND申请。

PROJECT SUMMARY According to the CDC, 550,000 Healthcare Associated Infections (HAIs) occur per year in the US, costing ~$100 billion and killing tens of thousands of patients. Reducing HAIs is a top priority of the US DHHS and NIH and experts have called for novel strategies including vaccination to achieve this goal. ExBaq was founded by scientists and business colleagues who have spent years studying antibiotic- resistant nosocomial pathogens. We made the striking observation that an adjuvant-only approach to activate innate immunity can provide broad-spectrum, short-term protection against lethal infection caused by a variety of HAI pathogens (preliminary data). Our triple adjuvant regimen consists of: 1) Aluminum hydroxide (Al(OH)3); 2) monophosphoryl Lipid A (MPL); and 3) Whole Glucan Particles (WGP). This triple adjuvant regimen protected mice against lethal bacteremia caused by the Gram positive pathogen, methicillin-resistant S. aureus (MRSA) and the extreme drug resistant (XDR) Gram negative pathogen, A. baumannii. In particular, WGP and MPL respectively affected Gram-positive and Gram-negative efficacy, and Al(OH)3 was required for both. Finally, preliminary data suggest that the polysaccharide, mannan, could further enhance protection. Given efficacy against Gram positive and Gram negative pathogens, our adjuvant-only vaccine has the potential to prevent HAIs caused by the highest priority, most lethal and antibiotic-resistant nosocomial pathogens in acutely hospitalized patients. The goal of this proof-of-principle Phase I STTR is to define optimal adjuvant dosing and composition to support a Phase II application that will enable GMP manufacturing, pharm-tox, and biomarker studies to support a future IND. AIM 1: Identify optimal dosing of the triple adjuvant regimen for maximal efficacy against nosocomial pathogens. We will determine if efficacy can be improved and durability prolonged by increasing adjuvant doses in mice with bacteremia or pneumonia. Mice will be vaccinated with escalating adjuvant doses or placebo and then infected IV or via the lung 7, 21, and 42 days later (covering 1, 2, and 3 STDEV of US hospital lengths of stay) with a hyper-virulent clinical blood and lung isolate of A. baumannii (HUMC1) or a USA300 clinical isolate of MRSA (LAC). The primary outcome will be time to moribund condition (death is not allowed per IACUC/NIH), with lung and/or blood bacterial burden and cytokines as secondary outcomes. AIM 2: Determine if incorporating mannan into a quadruple adjuvant further improves efficacy and/or enables lower doses of triple adjuvants to lower cost-of-goods. We will determine if adding mannan at various doses to the triple-adjuvant mixture improves efficacy and/or enables lower effective dosing. Mice will be infected IV or via the lung with A. baumannii and S. aureus. Outcome measures will be as above. These proof of principle/feasibility results will lay the groundwork for a Phase II STTR, which will focus on GMP and pharm-tox studies, as well as defining biomarkers that correlate with protection to enable IND filing.