Optimal adjuvant/antigen formulation toward a Staphylococcus aureus human vaccine

项目总结/摘要： 金黄色葡萄球菌是人类皮肤的寄生虫，是一种侵袭性病原体，也是主要的致病菌。 皮肤和软组织感染（SSTI）或败血症的原因。S.金黄色葡萄球菌已经发展出 对所有已知抗生素的耐药性。S.金黄色葡萄球菌感染与免疫力的发展无关 而且，即使采用外科手术和抗生素治疗，仍有高达30%的患者发生复发性感染。因此，我们认为， 预防沙门氏菌的疫苗或免疫治疗的发展。金黄色葡萄球菌SSTI，菌血症，败血症，或 改善标准治疗的结果，或降低复发性感染的发生率， 高度重要性。研究了S.金黄色葡萄球菌主要由葡萄球菌蛋白介导 A（SpA），一种结合免疫球蛋白（IG）从而阻止调理吞噬杀伤（OPK）的表面蛋白 通过免疫细胞和宿主适应性免疫反应的抑制。我们的主要疫苗是SpA*，一种完全 SpA的解毒片段，当用氢氧化铝（明矾）作为佐剂时， 能预防和减少S. aureus和侵袭性S.金黄色葡萄球菌病明矾 主要驱动TH 2效应子应答，并包含在许多FDA批准的疫苗中，但一些研究 已经表明，刺激广泛的TH 1/TH 17免疫应答可能是疫苗保护所必需的 针对由S.金黄色。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。在具体的目标1中，我们将建立一种刺激有效的TH 1/TH 17的临床佐剂， 在小鼠、兔和豚鼠中针对SpA* 抗原的细胞和TH 2体液免疫应答。具体 目的2将描述在以下条件下产生的抗佐剂SpA* 的体液疫苗应答的质量： 通过开发测定SpA中和活性和 促进S.金黄色。这些研究对于确定SpA特异性抗体滴度值至关重要 需要在接种疫苗的受试者中促进S.金黄色葡萄球菌和中和SpA的Ig结合活性。 II期研究将被设计为cGMP生产疫苗，并证明疫苗的保护效力。 在MRSA疾病豚鼠和兔模型中的主要疫苗制剂，以支持临床试验。

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.