SBIR-STTR Award

Staphylococcus aureus is a commensal of the human skin and an invasive pathogen, as well as the leadingcause of skin and soft tissue infections (SSTI) or sepsis in the United States. S. aureus has developedresistance against all known antibiotics. S. aureus infection is not associated with the development of immunityand, even with surgical and antibiotic therapy, recurrent infections occur in up to 30% of patients. Therefore,the development of a vaccine or immune therapeutic that prevents S. aureus SSTI, bacteremia, sepsis, or thatimproves the outcome of standard-of-care therapies, or that reduces the incidence of recurrent infections is ofhigh importance. The immune evasive properties of S. aureus are primarily mediated by staphylococcal proteinA (SpA), a surface protein that binds immunoglobulin (Ig) thereby preventing opsonophagocytic killing (OPK)by immune cells and suppression of host adaptive immune responses. Our lead vaccine is SpA*, a fullydetoxified fragment of SpA which when adjuvanted with aluminum hydroxide (Alum) elicits immune responsesthat can prevent and reduce nasopharyngeal colonization of S. aureus and invasive S. aureus diseases. Alumdrives primarily TH2-effector responses and is included in many FDA approved vaccines but several studieshave suggested that stimulating a broad TH1 / TH17 immune response may be required for vaccine protectionagainst the wide range of diseases caused by S. aureus. Therefore, the goal of this phase I proposal is thedevelopment of clinical adjuvant formulations that broadly stimulate SpA-specific humoral and cellular immuneresponses in animals. In specific aim 1 we will establish a clinical adjuvant that stimulates effective TH1 / TH17cellular and TH2 humoral immune responses against SpA* antigen in mice, rabbits, and guinea pigs. Specificaim 2 will characterize the quality of the humoral vaccine responses generated against adjuvanted SpA* insera from vaccinated animals by developing assays that measure SpA-neutralizing activity and ability topromote OPK of S. aureus. These studies are critical for determining the value of SpA-specific antibody titersrequired in vaccinated subjects to promote OPK of S. aureus and neutralization of SpA's Ig-binding activity.Phase II studies will be designed to cGMP manufacture the vaccine and demonstrate protective efficacy of thelead vaccine formulation in guinea pig and rabbit models of MRSA diseases in support of clinical testing.

Public Health Relevance Statement:
MRSA, antibiotic-resistant S. aureus, is the most frequent cause of infectious disease mortality in the United States, however a licensed vaccine that can prevent staphylococcal diseases or improve their outcome is not available. The development of vaccines or immune therapeutics against S. aureus addresses an urgent health need and would represent a breakthrough advance in infectious disease therapy.

Project Terms:
Aluminum ; Al element ; Aluminum Hydroxide ; Hydrated Alumina ; Animals ; Antibiotics ; Antibiotic Agents ; Antibiotic Drugs ; Miscellaneous Antibiotic ; Antibodies ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Antigens ; immunogen ; B-Lymphocytes ; B blood cells ; B cell ; B cells ; B-Cells ; B-cell ; Bacteremia ; bacteraemia ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Chicago ; Communicable Diseases ; Infectious Disease Pathway ; Infectious Diseases ; Infectious Disorder ; Disease ; Disorder ; Enzyme-Linked Immunosorbent Assay ; ELISA ; Feces ; stool ; Goals ; Cyclic GMP ; Guanosine Cyclic Monophosphate ; cGMP ; Health ; Human ; Modern Man ; IgA ; Immunoglobulin A ; 7S Gamma Globulin ; IgG ; Immunoglobulin G ; 19S Gamma Globulin ; IgM ; Immunoglobulin M ; Antisera ; immune serum ; Immune Sera ; Immunity ; Immunologic Sensitization ; Immunologic Stimulation ; Immunological Sensitization ; Immunological Stimulation ; Immunostimulation ; Immunization ; Immune Globulins ; Immunoglobulins ; In Vitro ; Incidence ; IFN ; Interferons ; Co-Stimulator ; Costimulator ; Epidermal Thymocyte Activating Factor ; IL-2 ; IL2 Protein ; Interleukin 2 ; Interleukin 2 Precursor ; Interleukin II ; Interleukine 2 ; Interleukine 2 Precursor ; Interleukine II ; Lymphocyte Mitogenic Factor ; Mitogenic Factor ; T cell growth factor ; T-Cell Growth Factor ; T-Cell Stimulating Factor ; Thymocyte Stimulating Factor ; Interleukin-2 ; B Cell Differentiation Factor I ; B cell growth factor 2 ; B-Cell Growth Factor-II ; BCGF-II ; BCGF2 ; Eo-CSF ; Eosinophil Differentiation Factor ; IL-5 ; IgA enhancing factor ; Interleukin 5 Precursor ; T cell replacing factor ; T-Cell Replacing Factor ; Interleukin-5 ; Interleukins ; Pb element ; heavy metal Pb ; heavy metal lead ; Lead ; Membrane Protein Gene ; Membrane-Associated Proteins ; Surface Proteins ; Membrane Proteins ; 2,6 dimethoxyphenylpenicillin ; Dimethoxyphenyl Penicillin ; Methicillin ; Blood monocyte ; Marrow monocyte ; monocyte ; mortality ; Mice ; Mice Mammals ; Murine ; Mus ; Nasal ; Nasal Passages Nose ; Respiratory System, Nose, Nasal Passages ; Nose ; Patients ; Production ; Proteins ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Oryctolagus cuniculus ; salt ; Sodium Chloride ; Staphylococcus infection ; Staphylococcal Infections ; HMG-I ; HMGA1a ; HMGI ; S aureus protein A ; S. aureus protein A ; Staph Protein A ; Staph. Protein A ; Staphylococcus aureus Protein A ; Staphylococcal Protein A ; Staphylococcus ; Genus staphylococcus ; S aureus ; S. aureus ; Staph aureus ; Staphylococcus aureus ; CD4 Cells ; CD4 T cells ; CD4 helper T cell ; CD4 lymphocyte ; CD4+ T-Lymphocyte ; CD4-Positive Lymphocytes ; T4 Cells ; T4 Lymphocytes ; CD4 Positive T Lymphocytes ; United States ; Universities ; Vaccination ; Vaccines ; cytokine ; Generations ; Measures ; Resistance to antibiotics ; Resistant to antibiotics ; antibiotic drug resistance ; antibiotic resistant ; Antibiotic Resistance ; Guinea Pigs ; Guinea Pigs Mammals ; Cavia ; Mediating ; Soft Tissue Infections ; base ; improved ; Surface ; Clinical ; Phase ; Superantigens ; lymphoblast ; peripheral blood ; Individual ; Collaborations ; HL60 Cells ; HL-60 Cells ; MF59 ; treatment vaccines ; vaccine for the treatment ; vaccine for treatment ; therapeutic vaccine ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; polyclonal antibody ; Antibiotic Treatment ; bacterial disease treatment ; bacterial infectious disease treatment ; Antibiotic Therapy ; CTLA-8 ; CTLA8 ; Cytotoxic T-Lymphocyte-Associated Antigen 8 ; Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 ; IL-17 ; IL-17A ; IL17 Protein ; IL17A ; Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) ; Interleukin 17 Precursor ; Interleukin-17 ; Immunes ; Immune ; antibody titering ; Antibody titer measurement ; neutralizing antibody ; Best Practice Analysis ; Benchmarking ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; develop a vaccine ; development of a vaccine ; vaccine formulation ; vaccine development ; Toxicities ; Toxic effect ; cutaneous tissue ; Skin Tissue ; Alhydrogel ; Modeling ; Property ; response ; immune drugs ; immune-based therapeutics ; immunologic preparation ; immunologic therapeutics ; immunotherapeutics ; immunotherapy agent ; Immunotherapeutic agent ; IL-22 ; interleukin-22 ; Skin ; Molecular Interaction ; Binding ; MRSA ; Methicillin Resistant S Aureus ; Methicillin Resistant S. Aureus ; methicillin-resistant S. aureus ; methicillin resistant Staphylococcus aureus ; preventing ; prevent ; Immunoglobulin Binding Factor ; Immunoglobulin binding proteins ; Address ; Immune Cell Suppression ; Clinical Evaluation ; Clinical Testing ; clinical test ; research clinical testing ; STTR ; Small Business Technology Transfer Research ; Splenocyte ; Vaccinated ; Adjuvant ; developmental ; Development ; pre-clinical study ; preclinical study ; design ; designing ; Sepsis ; blood infection ; bloodstream infection ; Outcome ; Resistance development ; Resistant development ; developing resistance ; pathogen ; Resistance ; resistant ; commercial application ; public health relevance ; FDA approved ; standard of care ; vaccine candidate ; protective efficacy ; phase 2 study ; phase II study ; T cell response ; vaccine response ; Antibody Response ; Formulation ; improved outcome ; Preventive vaccine ; Preventative vaccine ; Prophylactic vaccine ; adaptive immune response ; clinical development ; preclinical development ; pre-clinical development ; Immune Evasion ; 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 ; vaccine-induced antibodies ; vaccine antibodies ; vaccine induced antibodies ;