Multivalent Adjuvant Immunization to Prevent Hospital Acquired Infections

多价佐剂免疫预防医院获得性感染

基本信息

批准号：
10646147
负责人：
BRAD J SPELLBERG
金额：
$ 98.94万
依托单位：
EXBAQ LLC
依托单位国家：
美国
项目类别：
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/10646147
关键词：
Acinetobacter baumannii Adjuvant Aluminum Hydroxide Antibiotic Resistance Antimicrobial Resistance Bacteria Biological Assay Biotechnology Businesses Candida albicans Cause of Death Classification Clinical Protocols Clinical Trials Competitive Bidding Contracts Dangerousness Data Diabetes Mellitus Dose FDA approved Funding Future Glucans Goals Hospitals Human Immune Immunity Immunization Immunotoxicology In Vitro Infection Infection prevention Inflammasome Innate Immune System Kidney Diseases Klebsiella pneumoniae Lead Ligation Lipid A Macrophage Mannans Mucormycosis Mus Nosocomial Infections Particulate Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II/III Trial Phase III Clinical Trials 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 Vaccines Vendor carbapenem resistance cost experience fungus healthcare-associated infections immunotoxicity manufacture member methicillin resistant Staphylococcus aureus mouse model new technology novel strategies novel vaccines parenteral administration particle pathogen pathogenic bacteria pathogenic fungus phase I trial pre-Investigational New Drug meeting pre-clinical prevent programs scale up trial planning uptake vaccine development vaccine strategy vaccine trial

项目摘要

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.

项目概要/摘要美国每年发生 200 万例医疗保健相关感染 (HAI)，导致超过 90,000 名患者死亡，医院感染造成的损失约为 50-1000 亿美元（按 CPI 调整至 2020 年美元），是美国第六大死因。减少 HAI 是美国卫生和健康部的首要任务。人类服务部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。2 ExBaq 是一家生物技术公司，由科学家和商业同事组成的联盟创立，他们 ExBaq 花了数年时间研究耐抗生素的医院病原体，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 预防跨界 HAI 病原体引起的感染（初步数据）。 A) 氢氧化铝 (Al(OH)3)，多种 FDA 批准的疫苗中含有该成分，以及通过多种机制增强免疫力，包括诱导储库形成、激活 NALP3 炎症小体，增强巨噬细胞对颗粒的摄取； B) 单磷酰脂质 A (MPL)，它也包含在多个中（与 Al(OH)3 组合） FDA 批准的疫苗并通过 TLR4 连接激活 NF-κB 通路； C) 甘露聚糖，可刺激多种先天性和适应性免疫途径，并且在人体中是安全的肠胃外给药时的临床试验。在第一阶段，我们已经确认这种三联辅助疗法具有最广泛的保护作用与包含完整病原体的三联方案相比，提供较低剂量（对商品成本很重要）葡聚糖颗粒代替甘露聚糖，或采用四联方案（初步数据）。方案已在耐碳青霉烯鲍曼不动杆菌的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) 和播散性感染由真菌白色念珠菌和德拉马根霉（毛霉菌病）引起。阳性和阴性细菌和真菌病原体，我们的三价疫苗有潜力预防 HAI 由最重要的、具有抗生素耐药性的医院病原体引起。一期的目标是优化先导成分，二期的目标是建立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：目标 1：为我们的疫苗方案建立 GMP 生产。目标 2：完成临床前免疫毒性研究以支持 IND 申请。目标 3：完成资助结束时支持 IND 申请的关键步骤。