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 pathogens resistance to opsonophagocytic killing (OPK) and the suppression of the hosts 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
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.
Project Terms: Abscess ; Anaphylaxis ; Anaphylactic Reaction ; Anaphylactic Shock ; Animals ; Antibiotics ; Antibiotic Agents ; Antibiotic Drugs ; Miscellaneous Antibiotic ; Antibodies ; B-Lymphocytes ; B blood cells ; B cell ; B cells ; B-Cells ; B-cell ; Bacteremia ; bacteraemia ; Bacteria ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood Circulation ; Bloodstream ; Circulation ; Cell Degranulation ; Cells ; Cell Body ; Chicago ; Communities ; Disease ; Disorder ; Endotoxins ; Escherichia coli ; E coli ; E. coli ; Exhibits ; Future ; Goals ; Cyclic GMP ; Guanosine Cyclic Monophosphate ; cGMP ; Health ; Histamine Release ; Histamine Liberation ; Hospitalization ; Hospital Admission ; Hospitals ; Community Hospitals ; Human ; Modern Man ; Immunoglobulin G ; 7S Gamma Globulin ; IgG ; Immunoglobulin M ; 19S Gamma Globulin ; IgM ; Immunity ; Natural Immunity ; Innate Immunity ; Native Immunity ; Non-Specific Immunity ; Nonspecific Immunity ; Immunization ; Immunologic Sensitization ; Immunologic Stimulation ; Immunological Sensitization ; Immunological Stimulation ; Immunostimulation ; Immunoblotting ; Immunoglobulin Idiotypes ; Idiotype ; Immunoglobulins ; Immune Globulins ; Immunotherapy ; Immune mediated therapy ; Immunologically Directed Therapy ; immune therapeutic approach ; immune therapeutic interventions ; immune therapeutic regimens ; immune therapeutic strategy ; immune therapy ; immune-based therapies ; immune-based treatments ; immuno therapy ; Infection ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; mast cell ; Marrow Mast Cell ; Tissue Basophils ; mastocyte ; Membrane Proteins ; Membrane Protein Gene ; Membrane-Associated Proteins ; Surface Proteins ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Structure of mucous membrane of nose ; Nasal Mucosa ; Outpatients ; Out-patients ; Paste substance ; Pastes ; Patients ; Production ; Proteins ; Public Health ; B-Cell Antigen Receptor ; B cell receptor ; Recurrence ; Recurrent ; Research ; Risk ; Risk Factors ; Safety ; Sales ; Staphylococcal Infections ; Staphylococcus infection ; Staphylococcal Protein A ; HMG-I ; HMGA1a ; HMGI ; S aureus protein A ; S. aureus protein A ; Staph Protein A ; Staph. Protein A ; Staphylococcus aureus Protein A ; Genus staphylococcus ; Staphylococcus ; Staphylococcus aureus ; S aureus ; S. aureus ; Staph aureus ; Surgical Wound Infection ; surgical site infection ; Testing ; Time ; United States ; United States Food and Drug Administration ; Food and Drug Administration ; USFDA ; Universities ; Vaccines ; Work ; Generations ; Catheters ; Antibiotic Resistance ; Resistance to antibiotics ; Resistant to antibiotics ; antibiotic drug resistance ; antibiotic resistant ; Cavia ; Guinea Pigs ; Guinea Pigs Mammals ; Mediating ; Soft Tissue Infections ; crosslink ; cross-link ; improved ; Surface ; Clinical ; Residual state ; Residual ; Phase ; Variant ; Variation ; Biological ; Nosocomial Infections ; Hospital Infections ; Hospital acquired infection ; institutional infection ; Superantigens ; Lesion ; soft tissue ; Childhood ; pediatric ; Individual ; treatment vaccines ; vaccine for the treatment ; vaccine for treatment ; therapeutic vaccine ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Antibiotic Treatment ; bacterial disease treatment ; bacterial infectious disease treatment ; Antibiotic Therapy ; programs ; Immunes ; Immune ; neutralizing antibody ; skeletal ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; Visit ; Receptor Protein ; receptor ; develop a vaccine ; development of a vaccine ; vaccine formulation ; vaccine development ; Disease Outcome ; cutaneous tissue ; Skin Tissue ; Devices ; Property ; response ; Fc domain ; immune drugs ; immune-based therapeutics ; immunologic preparation ; immunologic therapeutics ; immunotherapeutics ; immunotherapy agent ; Immunotherapeutic agent ; cell bank ; Molecular Interaction ; Binding ; MRSA ; Methicillin Resistant S Aureus ; Methicillin Resistant S. Aureus ; methicillin-resistant S. aureus ; methicillin resistant Staphylococcus aureus ; preventing ; prevent ; Cellular Secretion ; Cell secretion ; Address ; Preventive ; Detection ; Small Business Technology Transfer Research ; STTR ; Vaccinated ; Vaccine Design ; Molecular ; Process ; Development ; developmental ; safety study ; cost ; virtual ; design ; designing ; vaccine-induced immunity ; vaccine-induced protection ; Sepsis ; blood infection ; bloodstream infection ; clinical efficacy ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Outcome ; pathogen ; Population ; Prevalence ; Resistance ; resistant ; Antibody-mediated protection ; Ab-mediated immunity ; Ab-mediated protection ; Antibody immunity ; Antibody protection ; antibody-mediated immunity ; clinically significant ; clinical significance ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; commercial application ; public health relevance ; preclinical efficacy ; pre-clinical efficacy ; preclinical safety ; pre-clinical safety ; vaccine candidate ; safety testing ; efficacy testing ; ventilator-associated pneumonia ; ventilator-acquired pneumonia ; improved outcome ; Preventive vaccine ; Preventative vaccine ; Prophylactic vaccine ; adaptive immune response ; preclinical development ; pre-clinical development ; Immune Evasion ; Lung infections ; pulmonary infections ; Staphylococcus aureus infection ; S. aureus infection ; Staph aureus infection ; infected with S. aureus ; infected with Staph aureus ; infected with Staphylococcus aureus ; recurrent infection ; infection recurrence ;
