Development of a Pre-Exposure Vaccine for Population-Level ProtectionAgainst Staphylococcus aureus Infection

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PROJECT SUMMARY Staphylococcus aureus is an aggressive antibiotic-resistant human bacterial pathogen. S. aureus is a leading cause of infectious disease morbidity, mortality, and hospital-associated infection in the U.S., and a formidable health threat worldwide. Given the rapid acquisition of drug resistance by S. aureus, universal vaccination has been a premier goal in the field to provide a durable solution to S. aureus disease. Within the past 20 years, however, multiple S. aureus vaccines have failed to demonstrate efficacy in clinical trials. These failures reflect gaps in our current understanding of the natural development of human immunity to S. aureus, and how natural immunity may be harnessed through vaccination to elicit protection against disease. This STTR proposal aims to develop an innovative S. aureus vaccine designed for pre-exposure administration, predicated on our demonstration that that exposure to S. aureus -toxin (Hla) impairs the development of antigen-specific T cell response required for protective immunity. As exposure to S. aureus occurs within the first months to year of life, vaccination programs targeting adults are ‘post-exposure’ vaccines, destined to amplify an existing, immune response shaped by the immunomodulatory action of Hla. Thus, protection against Hla will need to be established prior to S. aureus exposure. This Phase I program seeks to characterize novel Hla-targeting vaccine formulations that have been strategically designed to elicit protective immunity when administered to neonates/infants. In a series of two aims, we will first comparatively evaluate each vaccine formulation for immunogenicity in a neonatal system, defining the precise nature of the immune response generated in response to immunization utilizing a multi-faceted approach. Second, we will evaluate vaccine efficacy in protection against S. aureus disease following immunization of neonatal mice. Though a combination of in vivo studies and high- dimensionality analysis of the vaccine-elicited immune response, this STTR proposal will provide a demonstration of feasibility, immunogenicity, and protective efficacy of this vaccine approach in an in vivo model of neonatal immunization. The fully-developed vaccine will shift the clinical burden of disease within the population by neutralizing the injurious effect of Hla during infection, and simultaneously counteract the precise mechanism by which S. aureus impedes the development of T cell-mediated immunity early in life. As the current standard of clinical care is limited to antibiotic treatment of existing S. aureus infection, successful implementation of a pre-exposure vaccine would elicit a foundational shift in the field toward infection prevention. The current studies will be essential for the identification of a single lead vaccine formulation to advance in pre- clinical development to a Phase II study in which vaccine production, safety/toxicity, and efficacy in a distinct animal model system can be assessed. This Phase I STTR program will thus propel a novel S. aureus vaccine toward commercial development.