Vaccine development for Group B Neisseria meningitidis and Escherichia coli K1

B 组脑膜炎奈瑟菌和大肠杆菌 K1 的疫苗开发

• 批准号: 7734839
• 负责人: Rachel Schneerson
• 金额: $ 6.78万
• 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/7734839
• 关键词: Adult; Affect; Age; Antibiotics; Antibodies; Antigenic Variation; Antigens; Autoimmune Diseases; Autoimmunity; Binding; Categories; Child; Clinical; Cohort Studies; Complement; Congenital Abnormality; Cytolysis; DNA; Development; Diagnosis; Disease; Disease Outbreaks; Epidemic; Escherichia coli; Haemophilus influenzae type b bacteria; Health; Immunoglobulin G; In Vitro; Incidence; Individual; Infant; Infection; Iron-Binding Proteins; Laboratory mice; Link; Lipopolysaccharides; Measures; Mediating; Membrane Proteins; Meningitis; Meningococcal meningitis; Meningococcal vaccine; Morbidity - disease rate; Mothers; Multiple Sclerosis; Neisseria meningitidis; Neonatal; Numbers; Organism; Pathology; Patients; Performance; Phase I Clinical Trials; Polysaccharides; Population; Population Control; Pregnancy; Primates; Publishing; Rate; Recording of previous events; Relative Risks; Reporting; Risk; Salmonella typhi; Serum; Sialic Acids; Structure; Supportive care; Surface; Systemic infection; Tissues; Vaccines; Virulence Factors; Woman; anti-IgG; base; child bearing; cohort; fetal; in vivo; kidney infection; killings; mortality; stillbirth; vaccine development

Summary: Meningococci are classified into serogroups according to their capsular polysaccharides (CP). Of the 13 reported CP groups, 5 (A, B, C, W135, and Y) cause almost all meningococcal disease. These CPs are essential virulence factors because they inhibit the protective actions of complement and are protective antigens because a critical level of serum IgG CP antibodies specifically induces complement mediated lysis of groups A, C, W135, and Y and opsonophagocytic killing of group B meningococci. There are effective CP-based vaccines for groups A, C, W135, and Y but not for group B meningococci or E. coli K1. Compared to groups A, C, W135, and Y, group B meningococci causes a disproportionately large number of infections in infants and young children. Although PSA antibodies bind to many fetal and adult tissues in vitro, there is no evidence for in-vivo binding or associated pathology. Experimental vaccines have been developed that are composed of non-capsular antigens including outer membrane proteins, lipopolysaccharide, iron-binding proteins, and other antigens identified by examination of the organism's DNA. Many of these are polymorphic, heterogeneous, subject to antigenic variation, and may not be representative of all group B meningococci. Further, none will be useful for E. coli K1. Based upon the performance of the Haemophilus influenzae type b, Salmonella typhi (Vi), pneumococcal and group C meningococcal (GCM) vaccines, we developed a PSA conjugate that induced protective levels of serum IgG anti PSA that is simple to produce, easy to standardize and should be close to 100% effective at all ages. Its performance in laboratory mice and primates has been confirmed. Group C meningococcal disease seems to be the most severe among those caused by different meningococcal serogroups. There is no mention of autoimmune diseases, such as Guillain Barre, multiple sclerosis, etc. in published studies of sequelae of group B meningococcal meningitis patients. Our review shows equal or lower rates in nearly every category of sequelae and of mortality associated with group B meningococcal meningitis compared to those of other meningococcal serogroups. There is no epidemiological or clinical evidence to associate pathology with PSA antibodies. We conducted a retrospective cohort study of meningococcal patients to examine evidence for autoimmunity. The entire Danish population constituted our study cohort of 7,467,001 individuals followed for autoimmune disease between 1977 and 2004. Group B meningitis was diagnosed in 2,984 and the control population was 914 patients with group C meningococcal meningitis. Ratios of incidence rates of autoimmune diseases served as a measure of relative risk. Patients with group B meningococcal meningitis, either in comparison with people who had group C meningococcal meningitis or with those that had no history of meningococcal meningitis had no increased risk of autoimmune diseases. This cohort was also studied for a possible increased risk of preterm or stillbirth to women with previous GBM disease, and whether their first-born children were at an increased risk of having birth defects. No such associations were found. These findings suggest that systemic infection with GBM is not associated with autoimmune diseases or with immunoreactive diseases that may affect offspring health, for up to 31 years after meningococcal disease. Further, infants born of mothers who had sustained GBM prior to their pregnancy did have unusual pregnancies or bear children with an increased incidence of birth defects. In a phase 1 study 100 healthy adults will be injected with our PSA conjugate starting in early 2009. This study should be completed by the end of 2009.

概括： 脑膜炎球菌根据其荚膜多糖（CP）分为血清群。在已报告的 13 个 CP 组中，5 个组（A、B、C、W135 和 Y）几乎引起所有脑膜炎球菌疾病。这些 CP 是重要的毒力因子，因为它们抑制补体的保护作用，并且是保护性抗原，因为血清 IgG CP 抗体的临界水平会特异性诱导补体介导的 A、C、W135 和 Y 群裂解以及调理吞噬性杀死 B 群脑膜炎球菌。有针对 A、C、W135 和 Y 群的有效 CP 疫苗，但不适用于 B 群脑膜炎球菌或大肠杆菌 K1。与 A、C、W135 和 Y 群相比，B 群脑膜炎球菌在婴幼儿中引起的感染数量异常多。 尽管 PSA 抗体在体外与许多胎儿和成人组织结合，但没有证据表明体内结合或相关病理学。已经开发出由非荚膜抗原组成的实验性疫苗，包括外膜蛋白、脂多糖、铁结合蛋白和通过检查生物体 DNA 鉴定的其他抗原。其中许多是多态性、异质性的，易发生抗原变异，并且可能不能代表所有 B 组脑膜炎球菌。此外，没有一个对大肠杆菌 K1 有用。基于 b 型流感嗜血杆菌、伤寒沙门氏菌 (Vi)、肺炎球菌和 C 组脑膜炎球菌 (GCM) 疫苗的性能，我们开发了一种 PSA 缀合物，可诱导血清 IgG 抗 PSA 的保护水平，且生产简单、易于标准化并且在所有年龄段都应该接近 100% 有效。其在实验室小鼠和灵长类动物中的表现已得到证实。 C 组脑膜炎球菌病似乎是由不同脑膜炎球菌血清群引起的疾病中最严重的。已发表的B群脑膜炎球菌性脑膜炎患者后遗症研究中并未提及自身免疫性疾病，如格林巴利、多发性硬化症等。我们的综述显示，与其他脑膜炎球菌血清群相比，B 组脑膜炎球菌性脑膜炎相关的几乎所有后遗症类别和死亡率均相同或更低。没有流行病学或临床证据表明病理学与 PSA 抗体相关。 我们对脑膜炎球菌患者进行了一项回顾性队列研究，以检查自身免疫的证据。整个丹麦人口构成了我们的研究队列，该队列由 1977 年至 2004 年间的 7,467,001 名自身免疫性疾病患者组成。B 组脑膜炎患者中有 2,984 人被诊断出来，对照人群是 914 名患有 C 组脑膜炎球菌性脑膜炎的患者。自身免疫性疾病的发病率比率作为相对风险的衡量标准。与 C 组脑膜炎球菌性脑膜炎患者或无脑膜炎球菌性脑膜炎病史的患者相比，B 组脑膜炎球菌性脑膜炎患者患自身免疫性疾病的风险并未增加。该队列还研究了既往患有 GBM 疾病的女性早产或死产的风险是否增加，以及她们的第一个孩子出生缺陷的风险是否增加。没有发现这样的关联。 这些发现表明，在脑膜炎球菌病发生后长达 31 年内，GBM 全身感染与自身免疫性疾病或可能影响后代健康的免疫反应性疾病无关。此外，怀孕前患有 GBM 的母亲所生的婴儿确实会出现异常怀孕或生出出生缺陷发生率增加的孩子。 在一项 1 期研究中，将从 2009 年初开始，对 100 名健康成年人注射我们的 PSA 结合物。这项研究应于 2009 年底完成。