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: 8351225
• 负责人: Rachel Schneerson
• 金额: $ 7万
• 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/8351225
• 关键词: Adult; Affect; Age; Antibiotic Therapy; Antibodies; Antigenic Variation; Antigens; Autoimmune Diseases; Autoimmunity; Binding; Child; Clinical; Cohort Studies; Complement; Congenital Abnormality; Conjugate Vaccines; Cytolysis; DNA; Development; Diagnosis; Disease; Disease Outbreaks; Epidemic; Epidemiology; Escherichia coli; Exhibits; Fetal Development; Fetus; Goals; 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; Morbidity - disease rate; Multiple Sclerosis; Neisseria meningitidis; Neonatal; Organism; Outcome; Pathology; Patients; Performance; Polysaccharides; Polysialic Acid; Population; Population Control; Primates; Publishing; Recording of previous events; Relative Risks; Reporting; Risk; Salmonella typhi; Serum; Severities; Sialic Acids; Structure; Supportive care; Surface; Syndrome; Systemic infection; Tissues; Vaccines; Virulence Factors; Woman; base; fetal; in vivo; kidney infection; killings; mortality; offspring; pathogen; stillbirth; vaccine development

Vaccine development against GBM meningitis is complicated by the pathogens capsular polysaccharide (PSA), an alpha 2-8-linked polysialic acid that is identical to the surface saccharide of the E. coli K1 capsular polysaccharide as well as to host structures, especially during fetal development. Despite effective antibiotic and supportive therapy, the mortality and morbidity of systemic infections, especially meningitis caused by GBM and Escherichia coli K1, remain unacceptably high. GBM continues to cause epidemics and outbreaks throughout the world, and E. coli K1 is a major cause of neonatal meningitis and kidney infections. With the goal of eventually providing a vaccine against these organisms, we examined evidence or the lack thereof for an association between PSA antibodies and autoimmune disease or effects on fetuses. Meningococci are classified into serogroups according to their CPs. Of the 13 reported CP groups, 5 (A, B, C, W135, and Y) cause almost all meningococcal disease. As essential virulence factors, the five group CPs inhibit the protective actions of complement; in addition, they function as protective antigens as evidenced by the fact that a critical level of serum IgG CP antibodies specifically induces both complement-mediated lysis of groups A, C, W135, and Y and opsonophagocytic killing of group GBM. Effective CP-based vaccines exist for groups A, C, W135, and Y, but none for GBM or E. coli K1. GBM causes more infections in infants and young children than do groups A, C, W135, or Y. Although PSA antibodies bind to many fetal and adult tissues in vitro, there is no evidence for in vivo binding or associated pathology. Efforts have been directed towards developing vaccines using non-capsular antigens, including outer membrane proteins, lipopolysaccharides, iron-binding proteins, and other antigens identified by examining the organisms DNA. Many of these antigens are polymorphic, heterogeneous, and subject to antigenic variation and may not be representative of all GBM. Furthermore, none will be useful against E. coli K1. Based on the performance of the Haemophilus influenzae type b, Salmonella typhi (Vi), pneumococcal, and group C meningococcal (GCM) conjugate vaccines, we developed a PSA conjugate that induced protective levels of serum IgG antiPSA. It is simple to produce and easy to standardize and should be close to 100 percent effective at all ages. Its performance in laboratory mice and primates has been confirmed. Few studies have compared severity of infection and outcome among meningococcal serogroups, and published studies of sequelae of meningococcal meningitis do not mention autoimmune diseases, such as Guillain-Barr syndrome, multiple sclerosis, etc. In the absence of 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. GBM meningitis was diagnosed in 2,984 individuals, and the control population was 914 patients with GCM meningitis. Ratios of incidence rates of autoimmune diseases provided a measure of relative risk. Patients with GBM meningitis, either in comparison with people with group C meningococcal meningitis or those with no history of meningococcal meningitis, exhibited no increased risk of autoimmune diseases. We also studied this cohort for possible increased risk of preterm or stillbirth to women with previous GBM disease and whether their first-born children were at increased risk for birth defects. We found no such associations. Our findings suggest that systemic infection with GBM is not associated with autoimmune diseases or with immunoreactive diseases that may affect the health of offspring for up to 31 years after meningococcal disease.

针对GBM脑膜炎的疫苗开发因病原体荚膜多糖（PSA）而复杂化，PSA是一种α 2-8连接的聚唾液酸，与E. coli K1荚膜多糖以及宿主结构，特别是在胎儿发育期间。尽管有有效的抗生素和支持性治疗，但全身感染，特别是由GBM和大肠杆菌K1引起的脑膜炎的死亡率和发病率仍然高得令人无法接受。GBM继续在世界范围内引起流行和爆发，E.大肠杆菌K1是新生儿脑膜炎和肾脏感染的主要原因。为了最终提供针对这些生物体的疫苗，我们检查了PSA抗体与自身免疫性疾病或对胎儿影响之间相关性的证据或缺乏证据。 脑膜炎球菌根据其CP分为血清组。在13个已报道的CP群中，5个（A、B、C、W135和Y）引起几乎所有的脑膜炎球菌病。作为重要的毒力因子，五组CP抑制补体的保护作用;此外，它们还具有保护性抗原的作用，临界水平的血清IgG CP抗体特异性诱导A、C、W135和Y组的补体介导的溶解以及GBM组的调理吞噬细胞杀伤。有效的基于CP的疫苗存在于A、C、W135和Y群，但没有用于GBM或E群。coli K1. GBM在婴儿和幼儿中引起的感染多于A、C、W135或Y组。 尽管PSA抗体在体外与许多胎儿和成人组织结合，但没有体内结合或相关病理学的证据。已经致力于开发使用非荚膜抗原的疫苗，所述非荚膜抗原包括外膜蛋白、脂多糖、铁结合蛋白和通过检查生物体DNA鉴定的其它抗原。这些抗原中的许多是多态的、异质的，并且受到抗原变异的影响，并且可能不代表所有GBM。此外，没有一个对E有用。coli K1.基于B型流感嗜血杆菌、伤寒沙门氏菌（Vi）、肺炎球菌和C群脑膜炎球菌（GCM）结合疫苗的性能，我们开发了一种PSA结合物，可诱导保护性血清IgG抗PSA水平。它生产简单，易于标准化，在所有年龄段都应该接近100%有效。它在实验室小鼠和灵长类动物中的表现已经得到证实。 很少有研究比较脑膜炎球菌血清群之间的感染和结果的严重程度，和脑膜炎球菌性脑膜炎后遗症的发表的研究没有提到自身免疫性疾病，如格林-巴利综合征，多发性硬化症等，在缺乏流行病学或临床证据，病理与PSA抗体，我们进行了一项回顾性队列研究脑膜炎球菌患者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，在1977年至2004年期间随访了7，467，001例自身免疫性疾病。在2，984例患者中诊断出GBM脑膜炎，对照人群为914例GCM脑膜炎患者。自身免疫性疾病的发病率比率提供了相对风险的量度。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，GBM脑膜炎患者未表现出自身免疫性疾病的风险增加。我们还研究了这一队列中有GBM病史的妇女早产或死产的风险可能增加，以及他们的第一个孩子是否有出生缺陷的风险增加。我们没有发现这样的联系。我们的研究结果表明，全身感染GBM与自身免疫性疾病或免疫反应性疾病无关，这些疾病可能会影响脑膜炎球菌病后长达31年的后代健康。