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： 脑膜炎球菌根据其囊膜多糖（CP）分为血清群。在报告的13个CP组中，有5（A，B，C，W135和Y）几乎引起所有脑膜炎球菌疾病。这些CP是必不可少的毒力因素，因为它们抑制了补体的保护作用，并且是保护性抗原，因为血清IgG CP CP抗体的临界水平特异性诱导了A，C，W135和Y和Opsonophopocytic thogococci的A，C，W135和Y组的补体介导的裂解。 A，C，W135和Y组有有效的基于CP的疫苗，但对于B组脑膜炎球菌或大肠杆菌K1没有有效的疫苗。与A，C，W135和Y组相比，B组脑膜炎球菌在婴儿和幼儿中引起大量的感染。 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。已经开发了由非囊泡抗原组成的实验疫苗，包括外膜蛋白，脂多糖，铁结合蛋白以及通过检查生物体DNA鉴定的其他抗原。其中许多是多态性的，异质性的，会受到抗原变异的影响，并且可能并不代表所有B组脑膜炎球菌。此外，没有任何对大肠杆菌K1有用的。 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.它在实验室小鼠和灵长类动物中的表现已得到证实。 C组脑膜炎球菌疾病似乎是由不同脑膜炎球菌血清群引起的最严重的。在公开的B组脑膜炎球菌脑膜炎患者后遗症的研究中，没有提及自身免疫性疾病，例如Guillain Barre，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，几乎每类后遗症的率相等或较低，与B组脑膜炎球菌脑膜炎相关的死亡率相等。没有流行病学或临床证据将病理与PSA抗体联系起来。 我们对脑膜炎球菌患者进行了回顾性队列研究，以检查自身免疫性的证据。整个丹麦人群构成了我们的研究队列，其中有7,467,001个患者在1977年至2004年之间患有自身免疫性疾病。在2,984年诊断出B组脑膜炎，对照人群为914例C组脑膜炎球菌脑膜炎。自身免疫性疾病发病率的比率是衡量相对风险的量度。 B组脑膜炎球菌性脑膜炎的患者与患有C组脑膜炎球菌炎的患者相比，或者与没有脑膜炎球菌脑膜炎病史的患者没有增加自身免疫性疾病的风险。还研究了这一队列，以增加对先前患有GBM疾病的女性的早产或死产的风险，以及她们的长子是否有出生缺陷的风险增加。没有发现这样的关联。 这些发现表明，GBM的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，脑膜炎球菌病后长达31年。此外，婴儿在怀孕前患有GBM的母亲出生的婴儿确实患有异常怀孕或生育儿童，出生缺陷的发生率增加。 在1阶段研究中，将从2009年初开始注入我们的PSA结合物100名健康成年人。这项研究应在2009年底之前完成。