Staphylococcus aureus is an aggressive antibiotic-resistant human bacterial pathogen. S. aureus is a leadingcause of infectious disease morbidity, mortality, and hospital-associated infection in the U.S., and a formidablehealth threat worldwide. Given the rapid acquisition of drug resistance by S. aureus, universal vaccination hasbeen 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 reflectgaps in our current understanding of the natural development of human immunity to S. aureus, and how naturalimmunity may be harnessed through vaccination to elicit protection against disease. This STTR proposal aimsto develop an innovative S. aureus vaccine designed for pre-exposure administration, predicated on ourdemonstration that that exposure to S. aureus ï¡-toxin (Hla) impairs the development of antigen-specific T cellresponse 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, immuneresponse shaped by the immunomodulatory action of Hla. Thus, protection against Hla will need to beestablished prior to S. aureus exposure. This Phase I program seeks to characterize novel Hla-targeting vaccineformulations that have been strategically designed to elicit protective immunity when administered toneonates/infants. In a series of two aims, we will first comparatively evaluate each vaccine formulation forimmunogenicity in a neonatal system, defining the precise nature of the immune response generated in responseto immunization utilizing a multi-faceted approach. Second, we will evaluate vaccine efficacy in protection againstS. 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 ademonstration of feasibility, immunogenicity, and protective efficacy of this vaccine approach in an in vivo modelof neonatal immunization. The fully-developed vaccine will shift the clinical burden of disease within thepopulation by neutralizing the injurious effect of Hla during infection, and simultaneously counteract the precisemechanism by which S. aureus impedes the development of T cell-mediated immunity early in life. As the currentstandard of clinical care is limited to antibiotic treatment of existing S. aureus infection, successfulimplementation 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 distinctanimal model system can be assessed. This Phase I STTR program will thus propel a novel S. aureus vaccinetoward commercial development.
Public Health Relevance Statement: PROJECT NARRATIVE
Staphylococcus aureus is a significant cause of infectious disease morbidity and mortality in both adults and
children worldwide. The successful development of a universal vaccine will afford the only long-term solution to
S. aureus disease. This STTR proposal will characterize novel vaccine formulations for use in pre-exposure
immunization of neonates as an initial step in development of a population-level vaccine product.
Project Terms: <21+ years old><0-11 years old> | | 