Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of many life-threatening infections such as skin and soft tissue sepsis, pneumonia, osteomyelitis and endocarditis. Due to the growing incidence of multiple drug resistance in S. aureus strains and the absence of effective new antibiotics, treatment options are becoming increasingly limited. Difficulties in developing new antimicrobials adds to the urgent need for developing a highly protective MRSA vaccine. Subunit protein- and polysaccharide-based vaccines have failed to trigger strong immune responses in clinical studies. We propose to assess a whole-cell vaccine approach which will contain multiple antigens/virulence factors to stimulate a more robust and protective immune response. We recently developed a novel method to produce gamma radiation- inactivated vaccines in the presence of a Mn antioxidant - MDP - derived from the extremely radiation-resistant bacterium Deinococcus radiodurans. Under aqueous conditions, MDP protects the surface proteins (epitopes) of cells and viruses from oxidative damage at supralethal radiation doses, yielding completely inactivated but highly immunogenic vaccine candidates. Applying this approach, we previously demonstrated that immunization with a gamma radiation-inactivated MRSA (Ir-MRSA using USA300 strain) vaccine candidate conferred protection from MRSA infection of skin wounds using a mouse model. We propose to extend these studies to evaluate the immunogenic and protective efficacy of a new Ir-MRSA vaccine candidate in a mouse model mimicking hospital-acquired (HA-MRSA) infections that are common surgical complications. To ensure a diverse expression of bacterial proteins, we propose to propagate the bacteria under different growth conditions designed to produce planktonic and biofilm forms. In addition, we will determine whether a vaccine made from HA- MRSA can stimulate cross-protection against challenge with a community-acquired (CA)-MRSA strain. Successful completion of these proposed studies and those to follow will result in a potential universal MRSA vaccine candidate suitable for human clinical trials.
Public Health Relevance Statement: Project narrative: We propose to assess the feasibility of developing a whole cell-inactivated methicillin- resistant Staphylococcus aureus (MRSA) vaccine candidate using a novel gamma- irradiation approach. We have successfully applied this approach to a community- acquired MRSA strain in a skin-infection mouse model and aim to extend this approach to hospital-acquired infections in a surgical model. The irradiation method is rapid, cost- effective and readily scalable to any infectious pathogen, bacterial or viral.
Project Terms: Acinetobacter baumannii; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antigens; antimicrobial; Antioxidants; aqueous; Bacteria; Bacterial Proteins; bacterial resistance; base; Biological Assay; Blood Circulation; Borrelia burgdorferi; cell community; Cells; Cessation of life; Clinical Research; Clinical Trials; Communities; community setting; cost; cost effective; Coupled; cytokine; Data; Deinococcus radiodurans; design; Development; Dose; Economic Burden; Endocarditis; Ensure; Epitopes; Evaluation; Exposure to; gamma irradiation; Gamma Rays; Gel; Growth; Healthcare; Healthcare Systems; Hospitals; Human; Human poliovirus; Immune response; Immunization; immunogenic; Immunoglobulin G; Implant; Inactivated Vaccines; Incidence; Infection; Infectious Skin Diseases; Intensive Care; irradiation; Life; Linezolid; Membrane Proteins; methicillin resistant Staphylococcus aureus; Methods; Microbial Biofilms; Modeling; mouse model; Multi-Drug Resistance; Mus; Nosocomial Infections; novel; Operative Surgical Procedures; Osteomyelitis; oxidation; oxidative damage; pathogen; pathogen exposure; Patients; Pneumonia; Polysaccharides; Preparation; preservation; process optimization; Prosthesis; protective efficacy; Protein Analysis; protein profiling; Protein Subunits; Proteins; Radiation Dose Unit; radioresistant; response; Sampling; Sepsis; Series; Serum; Site; Skin Tissue; Skin wound; soft tissue; Staphylococcus aureus; Staphylococcus aureus infection; Surgical complication; Surgical Models; Technology; Testing; United States; vaccine candidate; vaccine development; Vaccines; Vancomycin; Venezuelan Equine Encephalitis Virus; Viral; Viral Vaccines; Virulence Factors; Virus; Whole Cell Vaccine
