Project Summary / Abstract Due to advances in biomedical engineering and medicine, joint replacement has restored function and relieved pain for millions of people. However, subsequent infection of implanted joints (known as periprosthetic joint infection or PJI) is a debilitating condition that can lead to multiple surgeries, long courses of intravenous antibiotics, and/or loss of limb or even life. Staphylococcus aureus is one of the most common and virulent organisms that causes PJI. S. aureus is also associated with significant morbidity and frequent relapse following treatment. Vaccination against S. aureus is a promising strategy to prevent periprosthetic joint infection. However, traditional vaccine systems designed to prevent S. aureus infection have failed in clinical trials. The goal of this proposal is to evaluate a novel approach to immunotherapy for S. aureus PJI by engineering a biomaterials-based vaccine platform (BiVAX). BiVAX is an injectable biodegradable scaffold that elutes cytokines to recruit dendritic cells, contains adjuvant for activation, and is loaded with antigen at high concentration for uptake by recruited cells. Our group has previously demonstrated that by using bacterial lysate enriched for glycans as antigen in this biomaterials-based vaccine system, BiVAX is effective against preventing S. aureus abscesses and lethality from sepsis due to different gram-negative species in mouse models. PJI is a more challenging biofilm-associated device infection, and it is unknown if vaccination can prevent disease. In this proposal, I will evaluate the effects of infection and vaccination on the host immune response and determine the efficacy of BiVAX for preventing PJI in a well-characterized murine model of disease. I will determine murine immune responses to PJI as a function of host immunity and pathogen virulence in Aim 1 and evaluate the effect of BiVAX against PJI and compare its efficacy to traditional vaccination strategies in Aim 2. I am supported in these efforts by world experts in immunotherapy, vaccine science, and PJI including: primary mentor David Mooney (immunoengineering); co-mentor Ruanne Barnabas (vaccine science), collaborator David Scadden (stem cell biology/immunology); collaborator Jean Lee (murine S. aureus vaccination); collaborator Michael Super (immunology and glycobiology); advisor Antonia Chen (arthroplasty and human clinical trials for S. aureus vaccines); advisor Sandra Nelson (clinical periprosthetic joint infection); and advisor Hang Lee (biostatistics). The resource-rich ecosystem of Massachusetts General Hospital, Harvard University, and the Wyss Institute for Biologically Inspired Engineering have afforded me the necessary tools to conduct this multidisciplinary work at the interface of bioengineering, microbiology, and immunology. This proposal includes a robust training plan designed with my mentors to acquire additional skills in immunoengineering and vaccine science necessary for la...