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.

项目概要/摘要： 金黄色葡萄球菌是人类皮肤的共生菌，是一种侵入性病原体，也是主要的致病菌。 在美国，这是导致皮肤和软组织感染 (SSTI) 或败血症的原因。金黄色葡萄球菌已发育 对所有已知抗生素产生耐药性。金黄色葡萄球菌感染与免疫力的发展无关 而且，即使采用手术和抗生素治疗，仍有高达 30% 的患者出现复发性感染。所以， 开发预防金黄色葡萄球菌 SSTI、菌血症、败血症或其他疾病的疫苗或免疫疗法 改善标准护理治疗的结果，或降低复发感染的发生率 高度重要性。金黄色葡萄球菌的免疫逃避特性主要由葡萄球菌蛋白介导 A (SpA)，一种表面蛋白，可结合免疫球蛋白 (Ig)，从而防止调理吞噬杀伤 (OPK) 通过免疫细胞和抑制宿主适应性免疫反应。我们的主要疫苗是 SpA*，一种完全 SpA 的解毒片段，当辅以氢氧化铝（明矾）时会引发免疫反应 可以预防和减少金黄色葡萄球菌鼻咽定植和侵袭性金黄色葡萄球菌疾病。明矾 主要驱动 TH2 效应器反应，并包含在许多 FDA 批准的疫苗中，但有几项研究 表明疫苗保护可能需要刺激广泛的 TH1 / TH17 免疫反应 对抗由金黄色葡萄球菌引起的多种疾病。因此，第一阶段提案的目标是 开发广泛刺激 SpA 特异性体液和细胞免疫的临床佐剂制剂 动物的反应。在具体目标 1 中，我们将建立一种刺激有效 TH1/TH17 的临床佐剂 小鼠、兔子和豚鼠体内针对 SpA* 抗原的细胞和 TH2 体液免疫反应。具体的 目标 2 将表征针对佐剂 SpA* 产生的体液疫苗反应的质量 通过开发测定 SpA 中和活性和能力的测定方法，从接种疫苗的动物中提取血清 促进金黄色葡萄球菌的OPK。这些研究对于确定 SpA 特异性抗体滴度的值至关重要 接种疫苗的受试者需要促进金黄色葡萄球菌的 OPK 并中和 SpA 的 Ig 结合活性。 II 期研究将旨在生产疫苗的 cGMP 并证明疫苗的保护功效 在 MRSA 疾病的豚鼠和兔子模型中开发先导疫苗配方，以支持临床测试。