Development of a Vaccine for Staphylococcal Infections

Project Summary / abstract: Staphylococcus aureus causes skin and soft tissue infections (SSTI) that result in 14.2 million outpatient visits per year and 850,000 hospital admissions. S. aureus infection is not associated with the development of immunity and, even with surgical and antibiotic therapy, recurrent infections occur frequently. Infections with antibiotic-resistant S. aureus strains, designated MRSA (methicillin-resistant S. aureus) are associated with poor disease outcomes and are now identified in 22% of hospital isolates. In order to address the public health crisis of MRSA, we are developing a vaccine to prevent invasive S. aureus infections. Key features of S. aureus disease are the pathogen’s resistance to opsonophagocytic killing (OPK) and the suppression of the host’s adaptive immune responses. Staphylococcal binding to immunoglobulin (Ig) is mediated by staphylococcal protein A (SpA), a surface protein that associates with the Fc-domain of IgG and the heavy chain of VH3 clan IgG and IgM. While the former activity provides protection from antibodies that induce OPK, the latter, through the crosslinking of IgM receptors, triggers proliferation and B cells and secretion of non- protective VH3 antibodies, thereby disrupting adaptive immune responses and the development of protective immunity. We have developed SpA*, a vaccine that elicits SpA-neutralizing antibodies that effectively promote OPK of the pathogen while also allowing the host to generate many different pathogen specific antibodies that together eliminate S. aureus colonization and reduce the risk of invasive disease. This phase I STTR proposal aims to establish the feasibility of generating the SpA* vaccine by establishing its preclinical safety and biological efficacy.Public Health Relevance Statement: In the United States alone, there are 3.4 million cases per year of community-acquired Staphylocococcus aureus invasive disease (skin and soft tissue infections [SSTI], skeletal, lung, and bloodstream infections) with annual costs of $10 billion. There are 460,000 cases per year of hospital-acquired S. aureus disease (surgical wound infections, ventilator associated pneumonia, bloodstream-, catheter- and device-associated infections) with annual costs of $40 billion. A licensed vaccine that can prevent staphylococcal diseases or improve their outcome is not available. Research developing immune therapeutics that prevent S. aureus disease and improve the outcome of staphylococcal disease will have fundamental impact on human health and provide exciting opportunities for commercial development.