Proactive pandemic defense: leveraging trained innate immunity in the design of broad-spectrum therapeutics

The emergence of novel pathogens to which there is limited underlying immunity remains an ongoing threat to global health, as evidenced by the COVID-19 pandemic. While conventional vaccination strategies dramatically reduced global mortality and morbidity, there remained a critical delay in pandemic response during the initial outbreak prior to the design of efficacious vaccine candidates. Deficiencies in global pandemic preparedness underscore the need for accessible broad-spectrum therapeutics which can be rapidly deployed as stop-gap measures for pandemic attenuation while target vaccines are developed. Epidemiological studies illustrate that vaccines and immune stimulatory agents can markedly reduce all-cause mortality and morbidity in off-target infections - in addition to their intended pathogen - through the induction of trained innate immunity (TII), a form of innate immune memory. We can leverage TII induction to establish broad-spectrum protection through prophylactic administration of TII-inducing vaccines or therapeutics, providing immunologically naïve populations with nonspecific immunity. Utilising high-throughput screening pipelines at the Center for Microbial Chemical Biology, I will screen a library of ~1000 bioactive molecules to identify novel inducers of TII in vitro and evaluate their ability to confer nonspecific antiviral and antibacterial protection in murine models. Characterizing novel inducers of TII presents an opportunity to develop a repertoire of potential adjuvant compounds that may be incorporated in the design of broad-spectrum vaccines, standalone therapeutics, or existing vaccines. Developing universally applicable prophylactics will strengthen pandemic preparedness and foster a proactive approach when evaluating pandemic risk.