Novel TLR-4 Agonists as Vaccine Adjuvants

Abstract/Project Summary Along with the many benefits of a global economy hides the ever-present risk for the world wide spread of infectious disease. While significant outbreaks of the flu in the recent past involving millions of individuals could be contained, the emergence and rapid spread of the SARS-CoV-2 virus revealed how vulnerable and unprepared the world population was to combat a previously unknown human pathogen. To limit the loss of life and economic disruption resulting from a future global event, steps toward pandemic preparedness are needed. A major component of being prepared is having the necessary tools available to act quickly to protect human health. In the ongoing pandemic, vaccines emerged as the best way to protect healthy populations and prevent hospitalization or death among those individuals who become infected. However, vaccine availability and logistical constraints regarding their distribution has left a significant proportion of the world's population still waiting for their first dose. The ability to quickly discover and develop vaccines which can be administered on a large scale is one solution towards solving this current problem. In support of this effort, it is the goal of this Phase I project to identify TLR4 agonists with immunostimulatory activity suitable for the development of safe and effective vaccine adjuvants. To achieve this goal, we will combine our years of expertise in medicinal chemistry and vaccine research and development toward completing the following specific aims: 1) Establish efficient synthesis routes for pure tri-acylated monophosphate derivatives of sucrose; 2) Identify TLR4 agonists using cell-based assays, determine their cytokine production profiles, and compare them to the full TLR4 agonist mono-phospholipid A (MPLA); and 3) Determine the immunogenic potency and safety profiles of selected sucrose based TLR4 agonists in mice and compare them against an existing subunit protein vaccines targeting West Nile Virus. We expect the product from this research to enable the development of novel adjuvants to support the preparation of new vaccines to combat current and future disease threats.