The long-term goal of this project is to develop a safe, efficacious vaccine and recombinant human monoclonal antibody for bacterial nosocomial infections (NI). The current proposal is focused on the development of a vaccine and recombinant human monoclonal antibodies effective against diseases caused by Staphylococcus aureus and coagulase negative staphylococci (CoNS, mostly S. epidermidis). S. aureas and CoNS are Gram-positive opportunistic nosomial pathogens that are responsible for nearly 25% (approximately 500,000) of all NI infections and contribute to a significant portion of pathogens that are responsible for nearly 25% (approximately 500,000) of all NI infections and contribute to a significant portion of the estimated $4.5 billion annual costs associated with NI in the US. Up to 1% of all admissions in some hospitals result in S. aureus infections. The mortality rate of patients with nosocomial S. aureus of CoNS infections varies considerably with a range between 5% and 68%. The project will focus on three specific areas of research and development. First is the development of a glycoconjugate vaccine component by covalent coupling polysaccharides of staphylococci to a protein carrier. Second is the use of current genomic and proteomic technology to mine the existing S. aureus genomic database for surface exposed and secreted vaccine targets. Progress in this area will also include efforts to obtain the entire genomic sequence of clinical isolates of S. aureus and S. epidermidis. Thus is the development of recombinant human monoclonal antibodies effective against staphylococcal diseases. In addition to conventional methods of murine monoclonal antibody production, recombinant single chain phage libraries (scFv) will be screened for selective binding to staphylococcal surface antigens. Selected scFv will be subcloned for expression of recombinant human antibodies in a mammalian expression system. Th rapid and concurrent development of these three areas will provide multiple leads targeted to protect against staphylococcal infections in immunocompromised individuals, in patients undergoing elective surgery. Successful results of this first generation multi-valent vaccine will provide a platform technology for development of a second generation multi-component product to ward off diseases caused by other leading NI pathogens as C. difficile, P. aeruginosa, Enterococcus sp. and E. coli.
