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），既是必需的毒力因子，也是保护性抗原。这些糖与医学上有用的蛋白质共价结合形成偶联物，增加了它们的免疫原性，并赋予它们T细胞依赖性，使它们成为婴儿和儿童的合适疫苗。sonnei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，在暴露于6%至14%的发病率的年轻人中，其有效性超过70%。该偶联物与S. flexneri 2a结合琥珀酰化外蛋白A （repa -suc）的偶联物是安全的，可诱导1- 4岁儿童产生针对同源LPS的IgG抗体。在1至4岁儿童中进行的一项随机、盲法的三期研究表明，疫苗是安全的，每种结合物作为另一种结合物的对照。sonnei链球菌结合物的免疫原性和效力与年龄有关，在1- 2岁的儿童中没有效力，但在3- 4岁的儿童中约有70%的效力。和以前一样，抗体水平增加了几倍，与成人相似，但实际达到的水平要低一些。弗氏胞杆菌2a感染病例太少，无法进行统计分析。在flexneri 2a结合受体中，注意到对非疫苗类型的flexneri具有保护作用。这些类型包括6型，这是研究中最常见的flexneri菌株。弗氏沙门氏菌2a疫苗对所有非2a型弗氏沙门氏菌的总有效率为44.9%，仅对6型的总有效率为51.7%；这两个值均无统计学意义。

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.