Virus-like particles (VLPs) are a flexible vaccination platform for targeting either the virus from which they were or for use in displaying practically any epitope in a multivalent format. VLPs induce strong antibody responses because the periodicity of their capsid structure presents antigenic epitopes as dense, highly repetitive arrays that robustly stimulate B lymphocytes. While VLPs have been pursued for host defense against viral infections, their use for prevention of bacterial infection has been limited. Methicillin resistant Staphylococcus aureus (MRSA) has emerged as a major public health threat and the emergence of a single clone (USA300) associated with life threatening infections in the US and at least 9 other countries has re-focused interest in vaccines to prevent this infection. Because the virulence factors most identified with invasive MRSA infection are controlled by a quorum sensing operon, agr, we propose to use VLP-based vaccination to induce neutralizing antibodies against the autoinducing peptide pheromone (AIP) that activates this global regulator of virulence. Because of its size (8 amino acids) AIP is poorly immunogenic unless complexed to a large carrier protein. Therefore, display of AIP as a dense array on a VLP represents a potential strategy for the induction of high affinity antibody for the neutralization of its biologic function. The goal of this exploratory R21 is to test the hypothesis that VLPs can be used as a vaccine platform to induce adaptive immunity targeting S. aureus virulence. To test this hypothesis, we will pursue two specific aims: 1) To determine if VLPs bearing S. aureus virulence peptides can induce protective immunity in normal and immunodeficient mice. 2) To determine if VLPs bearing S. aureus virulence peptides can induce protective immunity in colonized normal and immunodeficient mice. PUBLIC HEALTH RELEVANCE: Antibiotic resistant Staphylococcus aureus infections are emerging as a major public health threat. No vaccines are currently available to prevent these infections and the most recent vaccine clinical trials have not been successful. Because of this, there is interest in developing novel vaccination strategies to protect people most susceptible to these potentially lethal infections. We are proposing to use virus-like particles that express peptide pheromones that this bacterial pathogen uses to promote secretion of toxins and other products that cause invasive disease. This approach has not been attempted previously for S. aureus.