HUMAN IMMUNE RESPONSE TO POLYSACCHARIDE-PROTEIN CONJUGATE VACCINES

多糖蛋白结合疫苗的人体免疫反应

• 批准号: 5203357
• 负责人: R SCHNEERSON
• 金额: --
• 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/5203357
• 关键词: Pseudomonas aeruginosa; Shigella; Shigella vaccines; Staphylococcus aureus; Streptococcus agalactiae; Streptococcus pneumoniae; Streptococcus vaccine; active immunization; antibacterial antibody; bacterial antigens; bacterial capsules; bacterial polysaccharides; bacterial vaccines; bactericidal immunity; drug screening /evaluation; exotoxins; human subject; immunoconjugates; infant animal; infant human (0-1 year); laboratory mouse; lipopolysaccharides; opsonin; phagocytosis

The surface polysaccharides of bacterial pathogens, which include capsular polysaccharides and lipopolysaccharides, serve as protective antigens. The immunologic properties of these bacterial polysaccharides, namely their age-related and T-cell independent immunogenicity, limit their use as vaccines. Covalently attachment to medically-useful proteins to form conjugates, both increases their immunogenicity and confers T-cell dependent properties to these polysaccharides. The capsular polysaccharides of Streptococcus pneumococcus type 6B, Staphylococcus aureus types 5 and 8, Group B streptococcus type 3 have been bound to several proteins and evaluated clinically. S. aureus type 5-rEPA was evaluated in end stage renal disease patients; type 5 antibodies of the three major Ig classes rose significantly though to a lesser degree than in healthy volunteers, no booster response to reinjection at 6 weeks was found. These antibodies had opsonophagocytic activities. Pn6B-TT was evaluated in patients with sickle cell disease, healthy infants at 3, 4 and 6 months of age or at 7 and 9 months of age. Type specific antibodies of the three Ig classes, with booster responses, were induced. The magnitude of these responses was lesser than of Hib- TT. GBSIII-TT was evaluated in females of child bearing age. IgG antitype III rose similarly to the response to the polysaccharide alone. Technical problems with this lot were identified. All conjugates were safe, with only minor local reaction. The LPS of shigellae was detoxified, their O-specific polysaccharides bound to bacterial toxoids and their immunogennicity in mice found to be satisfactory. In Phase 1 and Phase 2 studies, these conjugates of the O-specific polysaccharides were safe and immunogenic: LPS antibody levels elicited by the investigational conjugates were similar to those in recruits convalescent from shigellosis. In preliminary studies, a S. sonnei-rEPA conjugate protected against shigellosis caused by this pathogen. A more extensive study showed protection of 75%.

细菌病原体的表面多糖，其中包括 荚膜多糖和脂多糖，起保护作用 抗原。 这些细菌多糖的免疫学特性， 即它们与年龄相关且与 T 细胞无关的免疫原性，限制 它们用作疫苗。 共价附着于医学上有用的 蛋白质形成缀合物，既增加其免疫原性， 赋予这些多糖 T 细胞依赖性特性。 这 肺炎链球菌6B型荚膜多糖， 金黄色葡萄球菌 5 型和 8 型、B 族链球菌 3 型有 已与多种蛋白质结合并进行临床评估。 金黄色葡萄球菌型 在终末期肾病患者中评估了 5-rEPA； 5型 三种主要 Ig 类别的抗体显着上升至 程度低于健康志愿者，没有增强反应 6周时发现再次注射。 这些抗体具有调理吞噬作用 活动。 Pn6B-TT 在镰状细胞病患者中进行了评估， 3、4 和 6 个月大或 7 和 9 个月大的健康婴儿。 三种 Ig 类别的类型特异性抗体，具有增强反应， 被诱导。 这些反应的幅度小于 Hib- TT。 GBSIII-TT 在育龄女性中进行评估。 免疫球蛋白G 抗原III的升高与单独多糖的反应类似。 已发现该批次存在技术问题。 所有缀合物均 安全，只有轻微的局部反应。 志贺氏菌的LPS为 解毒后，它们的 O 特异性多糖与细菌类毒素结合 其在小鼠中的免疫原性令人满意。 在第一阶段 和第 2 阶段研究，这些 O 特异性多糖的缀合物 安全且具有免疫原性：LPS 抗体水平由 研究中的结合物与新兵康复期的结合物相似 来自志贺氏菌病。 在初步研究中，S. sonnei-rEPA 缀合物 预防由这种病原体引起的志贺氏菌病。 更广泛的 研究显示保护率为 75%。