Shigellae

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），既是重要的毒力因子，又是保护性抗原。这些抗体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。与重组无毒铜绿假单胞菌外蛋白A（rEPA）结合的宋内志贺菌O-SP在暴露于6%至14%发作率的年轻人中具有超过70%的疗效。这个共轭和S.与琥珀酰化外蛋白A（rEPA-succ）结合的福氏2a是安全的，并在1至4岁儿童中诱导针对同源LPS的IgG抗体。一项在1至4岁儿童中进行的随机、盲法、3期研究表明，这些疫苗是安全的，每种疫苗都作为另一种疫苗的对照。免疫原性和效力的S。Sonnei偶联物与年龄相关，在1- 2岁儿童中没有效力，但在3- 4岁儿童中约有70%效力。如前所述，抗体水平的倍数增加与成人相似，但实际达到的水平较低。S.用于统计分析的福氏2a感染。预防非疫苗类型的S。flexneri，在S.福氏2a结合物受体。这些类型包括6型，最常见的S。福氏杆菌分离株。S.福氏2a疫苗抗所有沙门氏菌。弗氏非2a型为44.9%，单独的6型为51.7%;这两个值均无统计学显著性。 利用合成的S. 1型糖-蛋白质缀合物。低分子量O-SP-核心（O-SPC）片段，平均含有3-4个S重复单元（RU）。分离Sonnei LPS并与载体蛋白结合。IgG抗S水平。这些缀合物在年轻远交系小鼠中诱导的sonnei LPS显著高于全长O-SP缀合物诱导的那些。制备了该候选疫苗的临床批次。 该方法对S.弗氏2a型和6型;正在研究1型螺旋藻。从这些细菌中分离的O-SPC的结构，含有核心加1-4个O-SP重复单元（RU），通过NMR和质谱分析。与福氏志贺菌2a和6个LPS的核心连接的第一个RU在其O-乙酰化和/或葡糖基化方面与以下罗斯不同。需要核心加上超过1 RU的缀合物来诱导小鼠中的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。In S.在拟南芥1型中，第一个RU与随后的罗斯相同，除了GlcNAc以β-构型结合到核心，而在所有其他罗斯中，其为α-构型。尽管存在这种差异，但S.具有1、2或3个罗斯的1型螺旋藻核心在小鼠中诱导LPS抗体，其水平与合成S. P. 1型糖缀合物的糖链长度在统计学上高于全尺寸O-SP缀合物。O-SPC偶联物易于制备、表征和标准化，并计划进行临床评价。

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.