Multivalent Adjuvant Immunization to Prevent Hospital Acquired Infections

多价佐剂免疫预防医院获得性感染

• 批准号: 10378255
• 负责人: BRAD J SPELLBERG
• 金额: $ 99.51万
• 依托单位: EXBAQ LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378255
• 关键词: Acinetobacter baumannii; Adjuvant; Aluminum Hydroxide; Antibiotic Resistance; Antimicrobial Resistance; Bacteria; Biological Assay; Biotechnology; Businesses; Candida albicans; Cause of Death; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Protocols; Clinical Trials; Contracts; Dangerousness; Data; Diabetes Mellitus; Dose; FDA approved; Funding; Future; Glucans; Goals; Health; Hospitals; Human; Immune; Immunity; Immunization; Immunotoxicology; In Vitro; Infection; Infection prevention; Inflammasome; Innate Immune System; Kidney Diseases; Klebsiella pneumoniae; Lead; Ligation; Lipid A; Mannans; Mucormycosis; Mus; Nosocomial Infections; Particulate; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II/III Trial; Phylogenetic Analysis; Protocols documentation; Regimen; Rhizopus; Rivers; Scientist; Small Business Technology Transfer Research; Source; Sterility; TLR4 gene; Toxicology; United States Dept. of Health and Human Services; Vaccination; Vaccine Clinical Trial; Vaccines; Vendor; base; carbapenem resistance; clinical toxicology; cost; experience; fungus; healthcare-associated infections; immunotoxicity; macrophage; meetings; member; methicillin resistant Staphylococcus aureus; mouse model; new technology; novel strategies; novel vaccines; particle; pathogen; pathogenic bacteria; pathogenic fungus; phase I trial; pre-clinical; prevent; programs; scale up; uptake; vaccine development; vaccine strategy

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.

项目摘要/摘要 美国每年发生200万次医疗保健相关感染（HAI），杀死90,000名患者， 耗资约500亿美元（由CPI调整为2020美元）。海斯是美国第六个主要死因， 糖尿病和肾脏疾病的早期。减少HAI是美国卫生部的重中之重， 人类服务1和专家呼吁采用新的策略，包括实现这一目标的疫苗。2 EXBAQ是一家由科学家和商业同事联盟创立的生物技术公司 已经花费了多年的时间研究了抗抗生素的医院病原体。 EXBAQ正在开发一种疫苗 防止Hais包括先天性免疫刺激分子，这些刺激分子可提供广谱保护 针对由跨王朝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），该铝包含多种FDA批准的疫苗，并且 通过多种机制增强免疫力，包括引入仓库形成，激活 nalp3炎症体，并增强巨噬细胞的特定吸收； b）单磷酸脂质A（MPL），该脂质A（MPL）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）曼南（Mannan 肠胃外治疗时进行临床试验。 在第一阶段，我们已经确认，这种三重调整方案具有最广泛的保护 与包含整体的三重方案相比 葡聚糖颗粒而不是曼南或具有四倍方案（初步数据）。三重的功效 在抗碳青霉烯的致命小鼠模型中已证实了疗法的baumannii和 克雷伯菌肺炎，耐甲氧西林金黄色葡萄球菌（MRSA）和弥散感染 由真菌白色念珠菌和Delamar（粘膜菌病）引起的。给出效率针对革兰氏 阳性和阴性细菌和真菌病原体，我们的三价疫苗具有预防的潜力 HAI由最高优先级，抗抗生素的医院病原体引起。建立了一个 第一阶段的最佳铅组成，II期的目标是建立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： AIM 1：为我们的疫苗方案建立GMP制造。 目标2：完成临床前免疫毒性研究以支持IND应用。 目标3：完成资金结束时支持IND申请的关键步骤。