Shigellae

志贺氏菌属

• 批准号: 8149366
• 负责人: Rachel Schneerson
• 金额: $ 63.32万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149366
• 关键词: Acetylation; Adult; Antibodies; Antigens; Binding; Blinded; Developing Countries; Dysentery; Goals; Growth; Human; Immunoglobulin G; Incidence; Infant; Infection; Institution; Length; Licensing; Lipopolysaccharides; Military Personnel; Mus; Organism; Patients; Polysaccharides; Proteins; Pseudomonas aeruginosa; Randomized; Recombinants; Recruitment Activity; Refugees; Shigella; Shigella Infections; Surface; Virulence Factors; mortality; research clinical testing; young adult

Surface polysaccharides of pathogenic bacteria, including capsular polysaccharides (CP) or the O-specific polysaccharide (OSP) of lipopolysaccharides (LPS), function both as essential virulence factors and protective antigens. Covalent binding of these saccharides to medically useful proteins to form conjugates increases their immunogenicity and confers upon them T cell dependence, making them suitable vaccines for infants and children. The O-SP of Shigella sonnei bound to recombinant non-toxic P. aeruginosa exoprotein A (rEPA) had an efficacy of over 70 percent in young adults exposed to 6 to 14 percent attack rates. This conjugate and that of S. flexneri 2a bound to the succinylated exoprotein A (rEPA-succ) were safe and induced IgG antibodies to the homologous LPS in 1- to 4-year-olds. A randomized, blinded, Phase 3 study of the conjugates in 1- to 4-year-olds, with each conjugate serving as a control for the other, showed the vaccines to be safe. Immunogenicity and efficacy of the S. sonnei conjugate were age-related with no efficacy in 1- to 2-year-olds but with about 70 percent in 3- to 4-year-olds. As before, fold increases in antibody levels were similar to those for adults, but the actual achieved levels were lower. There were too few cases of S. flexneri 2a infection for statistical analysis. Protection from non-vaccine types of S. flexneri, in S. flexneri 2a conjugate recipients, was noticed. These types included type 6, the most common S. flexneri isolate during the study. The overall efficacy of S. flexneri 2a vaccine against all S. flexneri non-type 2a was 44.9%, and against type 6 alone was 51.7%; both these values were not statistically significant. More immunogenic vaccine candidates were prepared using the model of synthetic S. dysenteriae type 1 saccharides-protein conjugates. Low molecular mass O-SP-core (O-SPC) fragments containing an average of 3-4 repeat units (RU) of S. sonnei LPS were isolated and bound to carrier proteins. Levels of IgG anti-S. sonnei LPS induced by these conjugates in young outbred mice were significantly higher than those induced by the full-length O-SP conjugates. A clinical lot of this vaccine candidate was prepared. The applicability of this approach to S. flexneri types 2a and 6 and S. dysenteriae type 1 is being investigated. The structures of the O-SPC isolated from these bacteria, containing core plus 1-4 O-SP repeat units (RU), were analyzed by NMR and mass spectroscopy. The first RU attached to the core of S.flexneri 2a and 6 LPSs were different from the following RUs in their O-acetylation and/or glucosylation. Conjugates of core plus more than 1 RU were needed to induce LPS antibodies in mice. These antibody levels were comparable to those induced by the full length O-SP conjugates. In S. dysenteriae type 1, the first RU was identical to the following RUs, with the exception that the GlcNAc was bound to the core in the beta-configuration, while in all other RUs it was in the alpha-configuration. In spite of this difference, conjugates of S. dysenteriae type 1 core with 1, 2 or 3 RUs induced LPS antibodies in mice with levels similar to those induced by the synthetic S. dysenteriae type 1 saccharide conjugates and statistically higher than those of the full size O-SP conjugates. O-SPC conjugates are easy to prepare, characterize, and standardize, and their clinical evaluation is planned.

病原菌的表面多糖，包括荚膜多糖 (CP) 或脂多糖 (LPS) 的 O 特异性多糖 (OSP)，既充当必需毒力因子又充当保护性抗原。这些糖与医学上有用的蛋白质共价结合形成缀合物，增加了它们的免疫原性并赋予它们 T 细胞依赖性，使它们成为适合婴儿和儿童的疫苗。宋内志贺氏菌的 O-SP 与重组无毒铜绿假单胞菌外蛋白 A (rEPA) 结合，对遭受 6% 至 14% 攻击率的年轻人有超过 70% 的功效。这种结合物以及与琥珀酰化外蛋白 A (rEPA-succ) 结合的弗氏链球菌 2a 结合物是安全的，可在 1 至 4 岁儿童中诱导针对同源 LPS 的 IgG 抗体。对 1 至 4 岁儿童进行的一项随机、盲法第 3 期研究表明，疫苗是安全的，每种结合物作为另一种结合物的对照。 S. sonnei 结合物的免疫原性和功效与年龄相关，对 1 至 2 岁儿童无效，但对 3 至 4 岁儿童有效，约为 70%。与之前一样，抗体水平的倍数增加与成人相似，但实际达到的水平较低。福氏链球菌2a感染病例太少，无法进行统计分析。注意到福氏链球菌 2a 结合受体对非疫苗类型福氏链球菌的保护作用。这些类型包括 6 型，这是研究期间最常见的福氏链霉菌分离株。福氏沙门氏菌2a疫苗对所有非2a型福氏沙门氏菌的总体功效为44.9%，对单独6型的福氏沙门氏菌的总体功效为51.7%；这两个值均不具有统计显着性。 使用合成的痢疾杆菌 1 型糖-蛋白缀合物模型制备了更具免疫原性的候选疫苗。分离出平均含有 3-4 个 S. sonnei LPS 重复单位 (RU) 的低分子量 O-SP-核心 (O-SPC) 片段，并将其与载体蛋白结合。 IgG 抗 S 水平。这些缀合物在年轻远交小鼠中诱导的 sonnei LPS 显着高于全长 O-SP 缀合物诱导的水平。制备了该候选疫苗的临床批次。 正在研究该方法对福氏沙门氏菌 2a 型和 6 型以及痢疾沙门氏菌 1 型的适用性。从这些细菌中分离出的 O-SPC 的结构包含核心和 1-4 个 O-SP 重复单元 (RU)，通过 NMR 和质谱分析。连接到 S.flexneri 2a 和 6 LPS 核心的第一个 RU 在 O-乙酰化和/或葡萄糖基化方面与后续 RU 不同。需要核心加上超过 1 个 RU 的缀合物才能在小鼠中诱导 LPS 抗体。这些抗体水平与全长 O-SP 缀合物诱导的抗体水平相当。在 1 型痢疾沙门氏菌中，第一个 RU 与后续 RU 相同，不同之处在于 GlcNAc 以 β 构型结合到核心，而在所有其他 RU 中，它以 α 构型结合。尽管存在这种差异，1型痢疾杆菌核心与1、2或3个RU的缀合物在小鼠中诱导LPS抗体，其水平与合成的1型痢疾杆菌糖缀合物诱导的水平相似，并且统计上高于全尺寸O-SP缀合物的水平。 O-SPC 缀合物易于制备、表征和标准化，并且已计划进行临床评估。