HUMAN IMMUNE RESPONSE TO POLYSACCHARIDE-PROTEIN CONJUGATE VACCINES

与年龄相关的，T细胞非依赖性的和免疫学特性差的 多糖限制了荚膜多糖（CP）的有效性 和其他侵入性细菌的表面多糖作为疫苗， 婴儿和免疫功能低下的成年个体。 有机 将荚膜多糖和其它多糖结合到载体上的合成方案 已经设计了蛋白质以增加免疫原性并赋予 T细胞依赖性免疫特性（增强效应） 保护性抗原 根据我们和其他人的工作，一个共轭 流感嗜血杆菌B型（HiB）疫苗，已获食物及卫生局批准 和药物管理局的常规婴儿免疫沿着DTP。 抗Hib结合物和抗Hib结合物的其他组分的血清抗体 常规免疫（DTP），已经在婴儿接受者中进行了测定， 我们的疫苗在美国和瑞典。 这项技术已经 成功扩展至聚α（2->8）NeuNAc CP（B组 脑膜炎球菌、E.大肠杆菌KI，溶血性巴氏杆菌血清型A2）， 该聚合物在中性pH下与蛋白质的多点附着。 发现交叉反应的E.大肠杆菌多糖K92， 抗C群脑膜炎球菌CP抗体。 这 该技术还扩展到新型隐球菌血清群的CP A. 对共轭过程的更详细的研究揭示了更多 对于该缀合物和葡萄球菌都有效的“间隔”臂 金黄色葡萄球菌CP与重组假单胞菌胞外蛋白A结合。 的缀合物 这些疫苗显示出增加的免疫原性和T细胞依赖性， 老鼠的属性 此外，S.金黄色葡萄球菌5型多糖，结合到 该重组蛋白已成功地在1期人体中进行了评价 问题研究

The age-related, T-independent and poor immunologic properties of polysaccharides limit the effectiveness of capsular polysaccharides (CP) and other surface polysaccharides of invasive bacteria as vaccines, in infants and adult individuals with immunocompromised states. Organic synthetic schemes, that bind capsular and other polysaccharides to carrier proteins have been devised to increase the immunogenicity of and confer T-cell dependent immunologic properties (booster effect) to these protective antigens. Based upon our and others work, a conjugated Haemophilus influenzae type b (Hib) vaccine, has been licensed by the Food and Drug Administration for routine infant immunization along with DTP. Serum antibodies to Hib conjugates and to the other components of the routine immunization (DTP), have been assayed among infant recipients of our vaccine in the United States and in Sweden. This technology has been extended successfully to poly alpha(2->8) NeuNAc CPs (group B meningococcus, E. coli KI, Pasteurella haemolytica serotype A2) by multipoint attachment of this polymer to proteins at neutral pH. It was found that a cross-reactive E. coli polysaccharide, K92, elicited antibodies to this and to the related group C meningococcus CP. This technique was also extended to the CP of Cryptococcus neoformans serogroup A. More detailed studies of the conjugation procedure have revealed more effective "spacer" arms for both this conjugate and for Staphylococcus aureus CP bound to the recombinant Pseudomonas exoprotein A. Conjugates of these vaccines showed increased immunogenicity and T-cell dependent properties in mice. Further, the S. aureus type 5 polysaccharide, bound to the recombinant protein, has been successfully evaluated in phase 1 human studies.