Optimal adjuvant/antigen formulation toward a Staphylococcus aureus human vaccine

金黄色葡萄球菌人疫苗的最佳佐剂/抗原配方

• 批准号: 10383513
• 负责人: Dominique M. Missiakas
• 金额: $ 25.39万
• 依托单位: IMMUNARTES LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-04 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383513
• 关键词: Address; Adjuvant; Alhydrogel; Aluminum; Aluminum Hydroxide; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Response; Antibody titer measurement; Antigens; B-Lymphocytes; Bacteremia; Benchmarking; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cavia; Chicago; Clinical; Collaborations; Communicable Diseases; Cyclic GMP; Development; Disease; Enzyme-Linked Immunosorbent Assay; FDA approved; Feces; Formulation; Generations; Genus staphylococcus; Goals; HL-60 Cells; Health; Human; Immune; Immune Cell Suppression; Immune Evasion; Immune Sera; Immune response; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulin binding proteins; Immunoglobulins; Immunotherapeutic agent; In Vitro; Incidence; Individual; Interferons; Interleukin-17; Interleukin-2; Interleukin-5; Interleukins; Lead; MF59; Measures; Mediating; Membrane Proteins; Methicillin; Modeling; Monoclonal Antibodies; Mus; Nose; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Patients; Phase; Preventive vaccine; Production; Property; Proteins; Resistance; Resistance development; Sepsis; Skin; Skin Tissue; Small Business Technology Transfer Research; Sodium Chloride; Soft Tissue Infections; Splenocyte; Staphylococcal Infections; Staphylococcal Protein A; Staphylococcus aureus; Staphylococcus aureus infection; Superantigens; Surface; T cell response; Toxic effect; United States; Universities; Vaccinated; Vaccination; Vaccinee; Vaccines; adaptive immune response; base; clinical development; commercial application; cytokine; design; improved; improved outcome; interleukin-22; lymphoblast; methicillin resistant Staphylococcus aureus; monocyte; mortality; neutralizing antibody; pathogen; peripheral blood; phase 2 study; polyclonal antibody; preclinical development; preclinical study; prevent; protective efficacy; public health relevance; recurrent infection; research clinical testing; response; standard of care; therapeutic vaccine; vaccine candidate; vaccine development; vaccine formulation; vaccine response; vaccine-induced antibodies

Project Summary / abstract: Staphylococcus aureus is a commensal of the human skin and an invasive pathogen, as well as the leading cause of skin and soft tissue infections (SSTI) or sepsis in the United States. S. aureus has developed resistance against all known antibiotics. S. aureus infection is not associated with the development of immunity and, 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 that improves the outcome of standard-of-care therapies, or that reduces the incidence of recurrent infections is of high importance. The immune evasive properties of S. aureus are primarily mediated by staphylococcal protein A (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 fully detoxified fragment of SpA which when adjuvanted with aluminum hydroxide (Alum) elicits immune responses that can prevent and reduce nasopharyngeal colonization of S. aureus and invasive S. aureus diseases. Alum drives primarily TH2-effector responses and is included in many FDA approved vaccines but several studies have suggested that stimulating a broad TH1 / TH17 immune response may be required for vaccine protection against the wide range of diseases caused by S. aureus. Therefore, the goal of this phase I proposal is the development of clinical adjuvant formulations that broadly stimulate SpA-specific humoral and cellular immune responses in animals. In specific aim 1 we will establish a clinical adjuvant that stimulates effective TH1 / TH17 cellular and TH2 humoral immune responses against SpA* antigen in mice, rabbits, and guinea pigs. Specific aim 2 will characterize the quality of the humoral vaccine responses generated against adjuvanted SpA* in sera from vaccinated animals by developing assays that measure SpA-neutralizing activity and ability to promote OPK of S. aureus. These studies are critical for determining the value of SpA-specific antibody titers required 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 the lead vaccine formulation in guinea pig and rabbit models of MRSA diseases in support of clinical testing.

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