Multivalent Adjuvant Immunization to Prevent Hospital Acquired Infections

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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.