Conjugate-induced Polysaccharide Antibodies

革兰氏阴性肠道病原菌的表面多糖，以被膜或脂多糖的形式存在，既是重要的毒力因子，又是保护性抗原。这些多糖通过与载体蛋白结合而增强了免疫原性。在伤寒发病率较高的越南，成人和儿童的连续临床研究表明，与重组铜绿假单胞菌外蛋白A(REPA)结合的胶囊多糖(Vi)可引起对伤寒的高应答。在第三阶段的试验中，大约12,000名2-5岁的儿童注射了结合疫苗，没有表现出明显的副作用。Vi-REPA主动监测27个月有效率为91%，被动监测28~40个月有效率为88%。甲型副伤寒沙门氏菌是东南亚第二常见的肠道热病因，在成人、青少年和2-4岁的儿童中被发现是安全的和免疫原性的。大肠杆菌O157是一种新出现的病原体，会导致幼儿溶血性尿毒症综合征。O157O特异性多糖-REPA结合物在成年志愿者中的第一阶段研究证明了其安全性和免疫原性。计划在2-5岁儿童中进行第二阶段研究。无毒志贺毒素I是从突变的E.ColiO157中提纯出来的，并将其与O-特异性多糖偶联制成双价疫苗。O157大肠杆菌的主要宿主是牛。脂多糖-蛋白结合物在小鼠和牛身上显示出免疫原性，并计划进行一项攻击性研究，以证明牛体内携带状态的清除。霍乱弧菌O1和O139是霍乱感染的主要血清型。O139衣壳多糖与内毒素O特异性多糖合成的偶联物可诱导小鼠产生杀弧菌抗体。这些结合物的临床试验正在计划中。

Surface polysaccharides of Gram-negative enteric pathogens, in the form of capsule or lipopolysaccharide, are both essential virulence factors and protective antigens. The immunogenicity of these polysaccharides were enhanced by binding to carrier proteins. Sequential clinical studies in adults and in children in Vietnam, an area with a high attack rate of typhoid, showed that the capsular polysaccharide (Vi) conjugates bound to the recombinant Pseudomonas aeruginosa exoprotein A (rEPA) elicited high responses against typhi. In a Phase III trial, About 12,000 2-5 years old children injected with the conjugate vaccine showed no significant side reaction. The efficacy of Vi-rEPA was 91% after 27 months active and 88% after 28-40 months passive surveillance. Salmonella paratyphi A, the second most common cause of enteric fever in Southeast Asia, was found to be safe and immunogenic in adults, teenagers and then 2-4 year old children. Escherichia coli O157, an emerging pathogen, causes hemolytic uremic syndrome in young children. Phase 1 study of O157 O-specific polysaccharide-rEPA conjugate demonstrated safety and immunogenicity in adult volunteers. A phase 2 study in ren 2-5 year old children is planned. Non-toxic shiga toxin I is purified from mutant E. coli O157 and will be conjugated with O-specific polysaccharide for a bivalent vaccine. The major reservoir of E.coli O157 is cattle. LPS-protein conjugate showed to be immunogenic in mouse and cattle and a challenge study is planned to demonstrate the clearance of the carriage state in cattle. Vibrio cholera O1 and O139 are the major sero types in cholera infections. Conjugates synthesized with capsular polysaccharide of O139 and O-specific polysaccharide of LPS elicited vibriocidal antibodies in mice. Clinical trials of these conjugates are planned.